四跨膜蛋白TM4SF4在急性肝损伤和肝癌中的表达变化和功能研究
|
摘要
四跨膜蛋白是一个特殊的细胞膜糖蛋白家族,通常由4个高度疏水的保守跨膜区段,2个较短的胞内区,以及2个差异相对较大的胞外区构成。四跨膜蛋白参与细胞生长增殖、黏附、迁移和浸润等多种功能,是一个极其重要的蛋白质家族。TM4SF4蛋白(Transmembrane 4 superfamily member 4)是一个四跨膜蛋白超家族的成员,最初是作为一个在人小肠上皮细胞和肝细胞中表达的四跨膜糖蛋白被发现的,能够调控细胞密度相关的增殖抑制。我们实验室首先克隆了大鼠中的同源基因rat TM4SF4,并发现它在2/3肝切除后的再生肝中表达升高,推测可能与肝细胞再生相关。但是该蛋白在体内的具体功能和作用机制还不清楚。
本论文的第一部分工作,我们采用四氯化碳大鼠急性肝损伤模型,研究了TM4SF4在四氯化碳急性肝损伤中作用。RT-PCR和Western blot检测表明,在四氯化碳急性肝损伤的过程中,TM4SF4的mRNA和蛋白表达都急剧升高。用尾静脉注射的方法,将正义的或反义的TM4SF4表达质粒注入大鼠体内,上调或下调肝脏内TM4SF4的表达;然后用血清ALT/AST活力、肝脏组织学损伤评定等指标来评价肝脏的损伤程度,并用荧光实时定量PCR和Western blot等方法来检测损伤相关基因表达情况的变化。结果表明,TM4SF4的过表达,会加强肝脏的损伤,并使血清ALT、AST活力的升高。而下调TM4SF4基因的表达,则会减轻肝脏的坏死程度,降低血清ALT、AST的活力。TM4SF4的表达上调,还会影响一些生长因子和受体的表达水平,如TNF-α、TNFR1和c-met等。此外,TUNEL检测表明,TM4SF4的表达上调,还能促进CCl4引起的肝细胞凋亡,并且改变一些促凋亡基因和抑凋亡基因的表达。因此,我们的实验表明大鼠TM4SF4基因在四氯化碳诱导的肝脏急性损伤中表达上升,并且在促进肝脏损伤中起重要的作用,其作用机制可能与TNF-α和HGF/c-met信号通路有关。
本论文的第二部分工作,我们对TM4SF4蛋白在肝细胞癌中的表达和功能进行了研究。对临床肝癌和癌旁样品的Western blot和免疫组化的检测表明,TM4SF4蛋白在肝细胞癌中高表达,而在相应癌旁组织中的表达明显较低或检测不到。在肝癌细胞中导入TM4SF4表达质粒,TM4SF4基因的高表达能显著促进肝癌细胞的克隆形成能力和细胞增殖速度。采用RNA干扰技术抑制肝癌细胞BEL-7404中TM4SF4基因的表达后,能明显抑制细胞的生长和侵袭能力。免疫荧光共定位实验表明,TM4SF4定位于细胞膜上,并且能在EGF的刺激作用下进入到细胞质中。同时发现抑制TM4SF4的表达,能够使EGFR通路下游JAK激酶和STAT3的磷酸化程度减弱;过表达TM4SF4能够增强STAT3-诱导的启动子的转录活力。我们的实验表明,TM4SF4基因在肝细胞癌中表达上升,TM4SF4的过表达能够促进肝癌细胞的恶性增殖,并参与EGFR/STAT3信号通路的活化。
我们的工作第一次对TM4SF4的功能进行了较深入地研究,由此发现了TM4SF4的异常高表达能促进肝脏的损伤和肝癌细胞的恶性增殖,并且第一次对TM4SF4的作用机理进行了初步的探讨,发现TM4SF4与TNF-α、HGF/c-Met和EGFR/STAT3信号通路有关。目前对于这个基因的功能和作用机制、以及表达调控等方面正在进行深入的研究。
Transmembrane 4 superfamily is a group of hydrophobic proteins with four transmembrane domains and two extracellular loops, both with conserved residues. They are expressed in a wide variety of cell types and have functional roles in processes, such as cellular adhesion, migration, proliferation and tumour invasion. TM4SF4 (transmembrane 4 superfamily member 4, also known as intestine and liver tetraspan membrane protein, il-TMP) is a distant member of the transmembrane 4 superfamily that was originally identified as a tetraspan membrane glycoprotein produced in the human intestinal eptithelium and in non-dividing hepatocytes that can mediate the cell density-associated inhibition of proliferation. Our lab firstly cloned the rat homolog of TM4SF4 gene. Rat TM4SF4 was identified as a gene up-regulated in liver regeneration and supposed to be a proliferation-associated gene. However, the in vivo functions of TM4SF4 and the possible molecular mechanism for TM4SF4 action are largely unknown.
Firstly, we investigated the in vivo function of TM4SF4 in a rat carbon tetrachloride (CCl4)-mediated liver injury model. Expression of TM4SF4 was analyzed by RT-PCR and Western blot in normal and CCl4-injured rats. Our study shows that TM4SF4 gene is overexpressed in acutely injured liver. Overexpression or reduced expression of TM4SF4 in the liver was achieved by injection of sense or antisense TM4SF4 expression plasmids. Assessment of liver injury (histology, serum ALT and AST levels), apoptosis by TUNEL assay were performed. TM4SF4 overexpression is found to be associated with more elevated ALT/AST, increased necrosis, and enhanced apoptosis. Decreased TM4SF4 gene expression showed minimal liver necrosis and depressed ALT/AST levels. Expression of injury-related genes was analyzed by quantitative real-time PCR. Increased expression of TM4SF4 affected the expression levels of growth factors and receptors, such as TNF-α, TNFR1 and c-met. Furthermore, pro-apoptotic and anti-apoptotic gene expression was altered after TM4SF4 administration. Our findings suggest that TM4SF4 plays an important role in accelerating CCl4 liver injury, which may be mediated by the TNF-αand HGF/c-met signaling pathways.
Secondly, we investigated the relation between TM4SF4 expression and hepatocellular carcinoma. Western blot and immunohistological analysis showed that the TM4SF4 expression was most abundant in HCC tissues and significantly reduced or undetected in corresponding noncancerous tissues. After introduction of the sense and antisense cDNA of TM4SF4 into HCC cell line QGY-7701 and BEL-7404, we observed that the overexpression of TM4SF4 enhanced both colony formation and cell proliferation in vitro. Using the transgenic short hairpin RNA (shRNA) to knock down the expression of TM4SF4 gene in BEL-7404 HCC cell lines resulted in the cell growth greatly inhibited. Further immunofluresence analysis explored that TM4SF4 was localized on the cellular membrane and could translocate from membrane to cytoplasma with EGFR under the induction of EGF. Moreover, reduction of the TM4SF4 gene expression could also inhibit the phosphorylation of JAK and STAT3. Overexpression of TM4SF4 gene enhances transcriptional activity of STAT3-regulated promoter, which is inhibited by an inhibitor of Janus tyrosine kinase activity. Therefore, TM4SF4 might be involved in EGFR/STAT3 signaling pathway.
In conclusion, TM4SF4 gene is up-regulated in acute liver injury and hepatocellular carcinoma. Overexpression of TM4SF4 accelerates CCl4-induced acute liver injury, which might be mediated by the TNF-αand HGF/c-met signaling pathways. In addition, overexpressing TM4SF4 could enhance cell proliferation and tumor invasion in HCC, which might be associated with EGFR/JAK/STAT3 pathway. The further functional analysis and the transcriptional regulation of this gene are being performed now.
本论文的第一部分工作,我们采用四氯化碳大鼠急性肝损伤模型,研究了TM4SF4在四氯化碳急性肝损伤中作用。RT-PCR和Western blot检测表明,在四氯化碳急性肝损伤的过程中,TM4SF4的mRNA和蛋白表达都急剧升高。用尾静脉注射的方法,将正义的或反义的TM4SF4表达质粒注入大鼠体内,上调或下调肝脏内TM4SF4的表达;然后用血清ALT/AST活力、肝脏组织学损伤评定等指标来评价肝脏的损伤程度,并用荧光实时定量PCR和Western blot等方法来检测损伤相关基因表达情况的变化。结果表明,TM4SF4的过表达,会加强肝脏的损伤,并使血清ALT、AST活力的升高。而下调TM4SF4基因的表达,则会减轻肝脏的坏死程度,降低血清ALT、AST的活力。TM4SF4的表达上调,还会影响一些生长因子和受体的表达水平,如TNF-α、TNFR1和c-met等。此外,TUNEL检测表明,TM4SF4的表达上调,还能促进CCl4引起的肝细胞凋亡,并且改变一些促凋亡基因和抑凋亡基因的表达。因此,我们的实验表明大鼠TM4SF4基因在四氯化碳诱导的肝脏急性损伤中表达上升,并且在促进肝脏损伤中起重要的作用,其作用机制可能与TNF-α和HGF/c-met信号通路有关。
本论文的第二部分工作,我们对TM4SF4蛋白在肝细胞癌中的表达和功能进行了研究。对临床肝癌和癌旁样品的Western blot和免疫组化的检测表明,TM4SF4蛋白在肝细胞癌中高表达,而在相应癌旁组织中的表达明显较低或检测不到。在肝癌细胞中导入TM4SF4表达质粒,TM4SF4基因的高表达能显著促进肝癌细胞的克隆形成能力和细胞增殖速度。采用RNA干扰技术抑制肝癌细胞BEL-7404中TM4SF4基因的表达后,能明显抑制细胞的生长和侵袭能力。免疫荧光共定位实验表明,TM4SF4定位于细胞膜上,并且能在EGF的刺激作用下进入到细胞质中。同时发现抑制TM4SF4的表达,能够使EGFR通路下游JAK激酶和STAT3的磷酸化程度减弱;过表达TM4SF4能够增强STAT3-诱导的启动子的转录活力。我们的实验表明,TM4SF4基因在肝细胞癌中表达上升,TM4SF4的过表达能够促进肝癌细胞的恶性增殖,并参与EGFR/STAT3信号通路的活化。
我们的工作第一次对TM4SF4的功能进行了较深入地研究,由此发现了TM4SF4的异常高表达能促进肝脏的损伤和肝癌细胞的恶性增殖,并且第一次对TM4SF4的作用机理进行了初步的探讨,发现TM4SF4与TNF-α、HGF/c-Met和EGFR/STAT3信号通路有关。目前对于这个基因的功能和作用机制、以及表达调控等方面正在进行深入的研究。
Transmembrane 4 superfamily is a group of hydrophobic proteins with four transmembrane domains and two extracellular loops, both with conserved residues. They are expressed in a wide variety of cell types and have functional roles in processes, such as cellular adhesion, migration, proliferation and tumour invasion. TM4SF4 (transmembrane 4 superfamily member 4, also known as intestine and liver tetraspan membrane protein, il-TMP) is a distant member of the transmembrane 4 superfamily that was originally identified as a tetraspan membrane glycoprotein produced in the human intestinal eptithelium and in non-dividing hepatocytes that can mediate the cell density-associated inhibition of proliferation. Our lab firstly cloned the rat homolog of TM4SF4 gene. Rat TM4SF4 was identified as a gene up-regulated in liver regeneration and supposed to be a proliferation-associated gene. However, the in vivo functions of TM4SF4 and the possible molecular mechanism for TM4SF4 action are largely unknown.
Firstly, we investigated the in vivo function of TM4SF4 in a rat carbon tetrachloride (CCl4)-mediated liver injury model. Expression of TM4SF4 was analyzed by RT-PCR and Western blot in normal and CCl4-injured rats. Our study shows that TM4SF4 gene is overexpressed in acutely injured liver. Overexpression or reduced expression of TM4SF4 in the liver was achieved by injection of sense or antisense TM4SF4 expression plasmids. Assessment of liver injury (histology, serum ALT and AST levels), apoptosis by TUNEL assay were performed. TM4SF4 overexpression is found to be associated with more elevated ALT/AST, increased necrosis, and enhanced apoptosis. Decreased TM4SF4 gene expression showed minimal liver necrosis and depressed ALT/AST levels. Expression of injury-related genes was analyzed by quantitative real-time PCR. Increased expression of TM4SF4 affected the expression levels of growth factors and receptors, such as TNF-α, TNFR1 and c-met. Furthermore, pro-apoptotic and anti-apoptotic gene expression was altered after TM4SF4 administration. Our findings suggest that TM4SF4 plays an important role in accelerating CCl4 liver injury, which may be mediated by the TNF-αand HGF/c-met signaling pathways.
Secondly, we investigated the relation between TM4SF4 expression and hepatocellular carcinoma. Western blot and immunohistological analysis showed that the TM4SF4 expression was most abundant in HCC tissues and significantly reduced or undetected in corresponding noncancerous tissues. After introduction of the sense and antisense cDNA of TM4SF4 into HCC cell line QGY-7701 and BEL-7404, we observed that the overexpression of TM4SF4 enhanced both colony formation and cell proliferation in vitro. Using the transgenic short hairpin RNA (shRNA) to knock down the expression of TM4SF4 gene in BEL-7404 HCC cell lines resulted in the cell growth greatly inhibited. Further immunofluresence analysis explored that TM4SF4 was localized on the cellular membrane and could translocate from membrane to cytoplasma with EGFR under the induction of EGF. Moreover, reduction of the TM4SF4 gene expression could also inhibit the phosphorylation of JAK and STAT3. Overexpression of TM4SF4 gene enhances transcriptional activity of STAT3-regulated promoter, which is inhibited by an inhibitor of Janus tyrosine kinase activity. Therefore, TM4SF4 might be involved in EGFR/STAT3 signaling pathway.
In conclusion, TM4SF4 gene is up-regulated in acute liver injury and hepatocellular carcinoma. Overexpression of TM4SF4 accelerates CCl4-induced acute liver injury, which might be mediated by the TNF-αand HGF/c-met signaling pathways. In addition, overexpressing TM4SF4 could enhance cell proliferation and tumor invasion in HCC, which might be associated with EGFR/JAK/STAT3 pathway. The further functional analysis and the transcriptional regulation of this gene are being performed now.
引文
1. Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type ofmembrane microdomain. Annu. Rev. Cell Dev. Biol. 19, 397-422 (2003).
2. Todres E, Nardi JB & Robertson HM. The tetraspanin superfamily in insects. Insect Mol Biol. 9, 581-590 (2000).
3. Kitadokoro K. et al. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J. 20, 12-18 (2001).
4. Seigneuret M, Delaguillaumie A, Lagaudriere-Gesbert C & Conjeaud H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J Biol Chem. 276, 40055-40064 (2001).
5. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 6, 801-811 (2005).
6. Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci. 114, 4143-4151 (2001).
7. Hemler ME, Mannion BA & Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta. 1287, 67-71 (1996).
8. Hemler ME. Integrin associated proteins. Curr Opin Cell Biol. 10, 578-585 (1998).
9. Lammerding J, Kazarov AR, Huang H, Lee RT & Hemler ME. Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening. Proc Natl Acad Sci U S A. 100, 7616-7621 (2003).
10. Serru V et al. Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions. Biochem J. 340, 103-111 (1999).
11. Kazarov AR, Yang X, Stipp CS, Sehgal B & Hemler ME. An extracellular site on tetraspanin CD151 determines alpha 3 and alpha 6 integrin-dependent cellular morphology. J Cell Biol. 158, 1299-1309 (2002).
12. Zhang XA et al. Function of the tetraspanin CD151-alpha6beta1 integrin complex during cellular morphogenesis. Mol Biol Cell. 13, 1-11 (2002).
13. Lau LM et al. The tetraspanin superfamily member CD151 regulates outside-in integrin alphaIIbbeta3 signaling and platelet function. Blood. 104, 2368-2375 (2004).
14. Yanez-Mo M et al. Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol. 141, 791-804 (1998).
15. Sterk LM et al. Association of the tetraspanin CD151 with the laminin-binding integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 in cells in culture and in vivo. J Cell Sci. 115, 1161-1173 (2002).
16. Feigelson SW, Grabovsky V, Shamri R, Levy S & Alon R. The CD81 tetraspanin facilitates instantaneous leukocyte VLA-4 adhesion strengthening to vascular cell adhesion molecule 1 (VCAM-1) under shear flow. J Biol Chem. 278, 51203-51212 (2003).
17. Mannion BA, Berditchevski F, Kraeft SK, Chen LB & Hemler ME. Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). J Immunol. 157, 2039-2047 (1996).
18. Tarrant JM, Robb L, van Spriel AB & Wright MD. Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol. 24, 610-617 (2003).
19. Wright MD et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol Cell Biol. 24, 5978-5988 (2004).
20. Martin F et al. Tetraspanins in viral infections: a fundamental role in viral biology? J Virol. 79, 10839-10851 (2005).
21. Levy S, Todd SC & Maecker HT. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu Rev Immunol. 16, 89-109 (1998).
22. Maecker HT. Human CD81 directly enhances Th1 and Th2 cell activation, but preferentially induces proliferation of Th2 cells upon long-term stimulation. BMC Immunol. 4, 1-14 (2003).
23. Cherukuri A et al. B cell signaling is regulated by induced palmitoylation of CD81. J Biol Chem. 279, 31973-31982 (2004).
24. Cherukuri A et al. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol. 172, 370-380 (2004).
25. Rosa D et al. Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci U S A. 102, 18544-18549 (2005).
26. Horvath G et al. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem. 273, 30537-30543 (1998).
27. Nichols TC et al. Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes. Eur J Immunol. 28, 4123-4129 (1998).
28. Yunta M et al. Transient activation of the c-Jun N-terminal kinase (JNK) activity by ligation of the tetraspan CD53 antigen in different cell types. Eur J Biochem. 269, 1012-1021 (2002).
29. Imai T, Kakizaki M, Nishimura M & Yoshie O. Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82. J Immunol. 155, 1229-1239 (1995).
30. van Spriel AB et al. A regulatory role for CD37 in T cell proliferation. J Immunol. 172, 2953-2961 (2004).
31. Shi W, Fan H, Shum L & Derynck R. The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J Cell Biol. 148, 591-602 (2000).
32. Huang CL et al. MRP-1/CD9 gene transduction downregulates Wnt signal pathways. Oncogene. 23, 7475-7483 (2004).
33. Murayama Y, Miyagawa J & Oritani K.et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci. 117, 3379-3388 (2004).
34. Ko EM et al. Monoclonal Antibody to CD9 Inhibits Platelet-induced Human Endothelial Cell Proliferation. Mol Cells. 22, 70-77 (2006).
35. Carloni V, Mazzocca A & Ravichandran KS. Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene. 23, 1566-1574 (2004).
36. Guo XZ et al. KAI1 inhibits anchorage-dependent and -independent pancreatic cancer cell growth. Oncol Rep. 14, 59-63 (2005).
37. Takaoka A et al. Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells. Jpn J Cancer Res. 89, 397-404 (1998).
38. Suzuki H, Dong JT, Gao AC, Barrett JC & Isaacs JT. Identification of the rat homologue of KAI1 and its expression in Dunning rat prostate cancers. Prostate. 37, 253-260 (1998).
39. Guo XZ et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Hepatology. 28, 1481-1488 (1998).
40. Yang JL et al. Expression of the KAI1 metastasis suppressor gene in non-metastatic versus metastatic human colorectal cancer. Anticancer Res. 22, 3337-3342 (2002).
41. Higashiyama M et al. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 83, 466-474 (1998).
42. Longo N et al. Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells. Blood. 98, 3717-3726 (2001).
43. Zheng R et al. CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice. Oncol Res. 15, 365-372 (2005).
44. Huang CI et al. Correlation of reduction in MRP-1/CD9 and KAI1/CD82 expression with recurrences in breast cancer patients. Am J Pathol. 153, 978-983 (1998).
45. Mhawech P et al. Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck. Br J Cancer. 90, 471-475 (2004).
46. Sauer G et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res. 9, 6426-6431 (2003).
47. Jang HI & Lee H. A decrease in the expression of CD63 tetraspanin protein elevates invasive potential of human melanoma cells. Exp Mol Med. 35, 317-323 (2003).
48. Berditchevski F, Tolias KF, Wong K, Carpenter CL & Hemler ME. A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. J Biol Chem. 272, 2595-2598 (1997).
49. Yauch RL & Hemler ME. Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphoinositide 4-kinase. Biochem J. 351, 629-637 (2000).
50. Zhang XA, Bontrager AL & Hemler ME. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J Biol Chem. 276, 25005-25013 (2001).
51. Kolch W et al. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature. 364, 249-252 (1993).
52. Tachibana I & Hemler ME. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol. 146, 893-904 (1999).
53. Gu J, Sumida Y, Sanzen N & Sekiguchi K. Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway. J Biol Chem. 276, 27090-27097 (2001).
54. Shigeta M et al. CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol. 163, 165-176 (2003).
55. Sawada S, Yoshimoto M, Odintsova E, Hotchin NA & Berditchevski F. The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras. J Biol Chem. 278, 26323-26326 (2003).
56. Dong JT et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 268, 884-886 (1995).
57. Gu J et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol. 146, 389-403 (1999).
58. Klemke RL et al. CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J Cell Biol. 140, 961-972 (1998).
59. Zhang XA, He B, Zhou B & Liu L. Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J Biol Chem. 278, 27319-27328 (2003).
60. Zhang XA, Lane WS, Charrin S, Rubinstein E & Liu L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 63, 2665-2674 (2003).
61. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
62. Odintsova E, Voortman J, Gilbert E & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
1. Liu ZW, Zhao MJ & Li ZP. Identification of Up-regulated Genes in Rat Regenerating Liver Tissue by Suppression Subtractive Hybridization. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 33, 191-197 (2001).
2. Liu ZW, Zhao MJ, Yokoyama KK & Li ZP. Molecular cloning of a cDNA for rat TM4SF4, a homolog of human il-TMP (TM4SF4), and enhanced expression of the corresponding gene in regenerating rat liver. Biochim Biophys Acta. 1518, 183-189 (2001).
3. Wice BM & Gordon JI. A tetraspan membrane glycoprotein produced in the human intestinal epithelium and liver that can regulate cell density-dependent proliferation. J Biol Chem. 270, 21907-21918 (1995).
4. Michalopoulos GK & DeFrances MC. Liver regeneration. Science. 176, 60-66 (1997).
5. Boll M, Weber LW, Becker E & Stampfl A. Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites. Z Naturforsch [C]. 56, 649-659 (2001).
6. Weber LW, Boll M & Sampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 33, 105-136 (2003).
7. Court FG, Wemyss-Holden SA, Dennison AR & Maddern GJ. The mystery of liver regeneration. Br J Surg. 89, 1089-1095 (2002).
8. Palmes D & Spiegel HU. Animal models of liver regeneration. Biomaterials. 25, 1601-1611 (2004).
9. Grasl-Kraupp B et al. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology. 21, 1465-1468 (1995).
10. Shi J, Aisaki K, Ikawa Y & Wake K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol. 153, 515-525 (1998).
11. Bansal MB et al. Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. J Hepatol. 42, 548-556 (2005).
12. Lee JI et al. Apoptosis of hepatic stellate cells in carbon tetrachloride induced acute liver injury of the rat: analysis of isolated hepatic stellate cells. J Hepatol. 39, 960-966 (2003).
13. Wu J, Danielsson A & Zern MA. Toxicity of hepatotoxins: new insights into mechanisms and therapy. Expert Opin Investig Drugs. 8, 585-607 (1999).
14. Bradham CA, Plumpe J, Manns MP, Brenner DA & Trautwein C. Mechanisms of hepatictoxicity. I. TNF-induced liver injury. Am J Physiol. 275, G387-392 (1998).
15. Ding WX & Yin XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med. 8, 445-454 (2004).
16. Malhi H, Gores GJ & Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology. 43, S31-44 (2006).
17. Schwabe RF & Brenner DA. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 290, G583-589 (2006).
18. Horn TL, O'Brien TD, Schook LB & Rutherford MS. Acute hepatotoxicant exposure induces TNFR-mediated hepatic injury and cytokine/apoptotic gene expression. Toxicol Sci. 54, 262-273 (2000).
19. Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T & Sato K. Molecular process in acute liver injury and regeneration induced by carbon tetrachloride. Life Sci. 75, 1539-1549 (2004).
20. Boros P & Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet. 345, 293-295 (1995).
21. Liu Y. Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol. 277, F624-633 (1999).
22. Huh CG et al. Anti-hepatocyte growth factor antibody inhibits hepatocyte proliferation during liver regeneration. J Pathol. 185, 298-302 (1998).
23. Huh CG et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 101, 4477-4482 (2004).
24. Armbrust T, Batusic D, Xia L & Ramadori G. Early gene expression of hepatocyte growth factor in mononuclear phagocytes of rat liver after administration of carbon tetrachloride. Liver. 22, 486-494 (2002).
25. Stuart KA et al. Hepatocyte growth factor/scatter factor-induced intracellular signalling. Int J Exp Pathol. 81, 17-30 (2000).
26. Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 1, 169-178 (2000).
27. Breitkopf K, Godoy P, Ciuclan L, Singer MV & Dooley S. TGF-beta/Smad signaling in the injured liver. Z Gastroenterol. 44, 57-66 (2006).
28. Cain K & Freathy C. Liver toxicity and apoptosis: role of TGF-beta1, cytochrome c and the apoptosome. Toxicol Lett. 120, 307-315 (2001).
29. Fausto N, Laird AD & Webber EM. Liver regeneration. 2. Role of growth factors and cytokinesin hepatic regeneration. FASEB J. 9, 1527-1536 (1995).
30. Templeton NS & Lasic DD. New directions in liposome gene delivery. Mol Biotechnol. 11, 175-180 (1999).
31. Kostarelos K & Miller AD. What role can chemistry play in cationic liposome-based gene therapy research today? Adv Genet. 53, 71-118 (2005).
32. Simoes S et al. Cationic liposomes for gene delivery. Expert Opin Drug Deliv. 2, 237-254 (2005).
33. Wang D, Jing NH & Lin QS. Stearylamine liposome as a new efficient reagent for DNA transfection of eukaryotic cells. Biochem Biophys Res Commun. 226, 450-455 (1996).
34. Ishak K et al. Histological grading and staging of chronic hepatitis. J Hepatol. 22, 696-699 (1995).
35. Yamakawa Y et al. Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation. Ann Surg. 231, 387-398 (2000).
36. Suyama E, Kawasaki H & Taira K. Identification of a caspase 3-independent role of pro-apoptotic factor Bak in TNF-alpha-induced apoptosis. FEBS Lett. 528, 63-69 (2002).
37. Fox SA, Kusmiaty, Loh SS, Dharmarajan AM & Garlepp MJ. Cisplatin and TNF-alpha downregulate transcription of Bcl-XL in murine malignant mesothelioma cells. Biochem Biophys Res Commun. 337, 983-991 (2005).
38. Tanaka F, Hori N & Sato K. Identification of differentially expressed genes in rat hepatoma cell lines using subtraction and microarray. J Biochem (Tokyo). 131, 39-44 (2002).
39. Morio LA et al. Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol. 172, 44-51 (2001).
40. Ishiki Y, Ohnishi H, Muto Y, Matsumoto K & Nakamura T. Direct evidence that hepatocyte growth factor is a hepatocytotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology. 16, 1227-1235 (1992).
41. Okano J, Shiota G & awasaki H. Protective action of hepatocyte growth factor for acute liver injury caused by D-galactosamine in transgenic mice. Hepatology. 26, 1241-1249 (1997).
42. Roos F, Terrell TG, Godowski PL, Chamow SM & Schwall RH. Reduction of alpha-naphthylisothiocyanate-induced hepatotoxicity by recombinant human hepatocyte growth factor. Endocrinology. 131, 2540-2544 (1992).
43. Cramer T et al. Hepatocyte growth factor and c-Met expression in rat and human liver fibrosis. Liver Int. 24, 335-344 (2004).
1. Yunta M & Lazo PA. Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal. 15, 559-564 (2003).
2. Tarrant JM, Robb L, van Spriel AB & Wright MD. Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol. 24, 610-617 (2003).
3. Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci. 114, 4143-4151 (2001).
4. Chen Z, Mustafa T & Trojanowicz B et al. CD82, and CD63 in thyroid cancer. Int J Mol Med. 14, 517-527 (2004).
5. Funakoshi T, Tachibana I & Hoshida Y et al. Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer. Oncogene. 22, 674-687 (2003).
6. Jang HI & Lee H. A decrease in the expression of CD63 tetraspanin protein elevates invasive potential of human melanoma cells. Exp Mol Med. 35, 317-323 (2003).
7. Lee JH, Park SR & Chay KO et al. KAI1 COOH-terminal interacting tetraspanin (KITENIN), a member of the tetraspanin family, interacts with KAI1, a tumor metastasis suppressor, and enhances metastasis of cancer. Cancer Res. 64, 4235-4243 (2004).
8. Murayama Y, Miyagawa J & Oritani K et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci. 117, 3379-3388 (2004).
9. Shi W, Fan H, Shum L & Derynck R. The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J Cell Biol. 148, 591-602 (2000).
10. Ang J, Lijovic M, Ashman LK, Kan K & Frauman AG. CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator? Cancer Epidemiol Biomarkers Prev. 11, 1717-1721 (2004).
11. Ferrer M, Yunta M & Lazo PA. Pattern of expression of tetraspanin antigen genes in Burkitt lymphoma cell lines. Clin Exp Immunol. 113, 346-352 (1998).
12. Sauer G et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res. 9, 6426-6431 (2003).
13. Yatomi Y, Yoneyama A & Nakahara K. Usefulness of CD9 detection in the diagnosis of acute megakaryoblastic leukemia. Eur J Haematol. 72, 229-230 (2004).
14. Boucheix C, Duc GH, Jasmin C & Rubinstein E. Tetraspanins and malignancy. Expert Rev Mol Med. 31, 1-17 (2001).
15. Szala S et al. Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proc Natl Acad Sci U S A. 87, 6833-6837 (1990).
16. Marken JS, Schieven GL & Hellstrom I. Cloning and expression of the tumor-associated antigen L6. Proc Natl Acad Sci U S A. 89, 3503-3507 (1992).
17. Wright MD, Moseley GW & van Spriel AB. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antigens. 64, 533-542 (2004).
18. Hotta H. et al. Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res. 48, 2955-2962 (1988).
19. Radford KJ, Thorner RF & Hersey P. Regulation of tumor cell motility and migration by CD63 in a human melanoma cell line. J Immunol. 158, 3353-3358 (1997).
20. Dong JT. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 268, 884-886 (1995).
21. Guo XZ et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Hepatology. 28, 1481-1488 (1998).
22. Adachi M et al. Correlation of KAI1/CD82 gene expression with good prognosis in patients with non-small cell lung cancer. Cancer Res. 56, 1751-1755 (1996).
23. Hemler ME, Mannion BA & Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta. 1287, 67-71 (1996).
24. Kawashima M, Doh-ura K, Mekada E, Fukui M & Iwaki T. CD9 expression in solid non-neuroepithelial tumors and infiltrative astrocytic tumors. J Histochem Cytochem. 50, 1195-1203 (2002).
25. Wollscheid V et al. Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas. Int J Cancer. 99, 771-775 (2002).
26. Tokuhara T et al. Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin Cancer Res. 7, 4109-4114 (2001).
27. Hashida H et al. Clinical significance of transmembrane 4 superfamily in colon cancer. Br J Cancer. 89, 158-167 (2003).
28. Adachi M et al. Novel staging protocol for non-small-cell lung cancers according to MRP-1/CD9 and KAI1/CD82 gene expression. J Clin Oncol. 16, 1397-1406 (1998).
29. Wright MD & Tomlinson MG. The ins and outs of the transmembrane 4 superfamily. Immunol. Today 15, 588-594 (1994).
30. Wright MD, Ni J & Rudy GB. The L6 membrane proteins--a new four-transmembrane superfamily. Protein Sci. 9, 1594-1600 (2000).
31. Kaji K & Kudo A. The mechanism of sperm-oocyte fusion in mammals. Reproduction. 127, 423-429 (2004).
32. van Spriel AB et al. A regulatory role for CD37 in T cell proliferation. J Immunol. 172, 2953-2961 (2004).
33. Yunta M & Lazo PA. Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal. 15, 559-564 (2003).
34. Mantegazza AR et al. CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells. Blood. 104, 1183-1190 (2004).
35. Sridhar SC & Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 25, 2367-2378 (2006).
36. Levy S & Shoham T. The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol. 5, 136-48 (2005).
37. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 6, 801-811 (2005).
38. Jackson P, Marreiros A & Russell PJ. KAI1 tetraspanin and metastasis suppressor. Int J Biochem Cell Biol. 37, 530-534 (2005).
39. Wright MD, Ni J & Rudy GB. The L6 membrane proteins--a new four-transmembrane superfamily. Protein Sci. 9, 1594-1600 (2000).
40. Kaneko R et al. Amount of expression of the tumor-associated antigen L6 gene and transmembrane 4 superfamily member 5 gene in gastric cancers and gastric mucosa. Am J Gastroenterol 96, 3457-3458 (2001).
41. Schiedeck TH, Wellm C, Roblick UJ, Broll R & Bruch HP. Diagnosis and monitoring of colorectal cancer by L6 blood serum polymerase chain reaction is superior to carcinoembryonic antigen-enzyme-linked immunosorbent assay. Dis Colon Rectum. 46, 818-825 (2003).
42. Muller-Pillasch F et al. Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer. Gene. 208, 25-30 (1998).
43. Wice BM & Gordon JI. A tetraspan membrane glycoprotein produced in the human intestinal epithelium and liver that can regulate cell density-dependent proliferation. J Biol Chem. 270, 21907-21918 (1995).
44. Liu Z, Zhao M, Yokoyama KK & Li T. Molecular cloning of a cDNA for rat TM4SF4, a homolog of human il-TMP (TM4SF4), andenhanced expression of the corresponding gene in regenerating rat liver. Biochim. Biophys. Acta. 1518, 183-189 (2001).
45. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 35, S72-78 (2002).
46. Breuhahn K, Longerich T & Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 25, 3787-3800 (2006).
47. Mendelsohn J & Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 33, 369-385 (2006).
48. Chuang LY et al. Epidermal growth factor-related transforming growth factors in the urine of patients with hepatocellular carcinoma. Hepatology. 13, 1112-1116 (1991).
49. Hirano T, Ishihara K & Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 19, 2548-56 (2000).
50. Imada K & Leonard WJ. The JAK-STAT pathway. Mol Immunol. 37, 1-11 (2000).
51. Mui AL. The role of STATs in proliferation, differentiation, and apoptosis. Cell Mol Life Sci. 55, 1547-58 (1999).
52. Yu H & Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 4, 97-105 (2004).
53. Turkson J & Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 19, 6613-26 (2000).
54. Turkson J. STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets. 8, 409-422 (2004).
55. Boucheix C, Duc GH, Jasmin C & Rubinstein E. Tetraspanins and malignancy. Expert Rev Mol Med. 31, 1-17 (2001).
56. Hemler ME. Specific tetraspanin functions. J. Cell Biol, 155, 1103-1107 (2001).
57. Maecker HT, Todd SC & Levy S. The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428-442 (1997).
58. Castanotto D, Li H & Rossi JJ. Functional siRNA expression from transfected PCR products. RNA. 8, 1454-1460 (2002).
59. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther. [Epub ahead of print], (2004).
60. Black D, Lyman S, Heider TR & Behrns KE. Molecular and cellular features of hepatic regeneration. J Surg Res. 117, 306-315 (2004).
61. Lowes KN, Croager EJ, Olynyk JK, Abraham LJ & Yeoh GC. Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol. 18, 4-12 (2003).
62. Malik R, Selden C & Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol. 13, 425-431 (2002).
63. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 5, 836-847 (2004).
64. Zimmermann A. Regulation of liver regeneration. Nephrol Dial Transplant. 19, 6-10 (2004).
65. Guo XZ et al. KAI1 inhibits anchorage-dependent and -independent pancreatic cancer cell growth. Oncol Rep. 14, 59-63 (2005).
66. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
67. Odintsova E, Voortman J, Gilbert E & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
68. Jin C, Ding P, Wang Y & Ma D. Regulation of EGF receptor signaling by the MARVEL domain-containing protein CKLFSF8. FEBS Lett. 579, 6375-6382 (2005).
69. Battle TE. & Frank DA. The role of STATs in apoptosis. Curr Mol Med. 2, 381-392 (2002).
70. Benekli M. et al. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood. 99, 252-257 (2002).
71. Bowman T, Garcia R, Turkson J. & Jove R. STATs in oncogenesis. Oncogene 19, 2474-2488 (2000).
72. Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 109, 1139-1142 (2002).
73. Calo V et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. 197, 157-168 (2003).
74. Dhir R. et al. STAT3 activation in prostatic carcinomas. Prostate. 51, 241-246 (2002).
75. Garcia R. et al. Constitutive activation of STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 20, 2499-2513 (2001).
76. Leaman DW et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol. 16, 369-375 (1996).
77. Turkson J et al. STAT3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Biol Cell. 18, 2545-2552 (1998).
78. Bowman T, Garcia R, Turkson J & Jove RH. STATs in oncogenesis. Oncogene 19, 2474-2488 (2000).
79. Zhang Y et al. Activation of STAT3 in v-Src-transformed fibroblasts requires cooperation of JAK1 kinase activity. J. Biol. Chem. 275, 24935-24944 (2000).
80. Hellstrom I et al. Monoclonal mouse antibodies raised against human lung carcinoma. Cancer Res. 46, 3917-3923 (1986).
81. Kao YR et al. Tumor-associated antigen L6 and the invasion of human lung cancer cells. Clin Cancer Res. 9, 2807-2816 (2003).
82. Feng DY, Zheng H, Tan Y & Cheng RX. Effect of phosphorylation of MAPK and STAT3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol. 7, 33-36 (2001).
83. Huynh H et al. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 3, 19-40 (2003).
84. Schmidt CM, McKillop IH, Cahill PA & Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Bioch Biophy Res Comm. 236, 54-58 (1997).
85. Schmidt CM, McKillop IH, Cahill PA & Sitzmann JV. The role of cAMP-MAPK signalling in the regulation of human hepatocellular carcinoma growth in vitro. Eur J Gastroenterol Hepatol. 11, 1393-1399 (1999).
86. Nicholson RI, Gee JM & Harper ME. EGFR and cancer prognosis. Eur J Cancer. 37, S9-15 (2001).
87. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 37, S3-8 (2001).
88. DeCicco LA, Kong J & Ringer DP. Carcinogen-induced alteration in liver epidermal growth factor receptor distribution during the promotion stage of hepatocarcinogenesis in rat. Cancer Lett. 111, 149-156 (1997).
89. Hisaka T, Yano H, Haramaki M, Utsunomiya I & Kojiro M. Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol. 14, 453-460 (1999).
90. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
91. Odintsova E, Voortman J, Gilbert E. & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
92. Supino R. Methods in Molecular Biology. Humana Press Inc., Totoa, NJ (1995).
93. Buettner R, Mora LB & Jove RH. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 8, 945-954 (2002).
94. Burke WM. et al. Inhibition of constitutively active STAT3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 20, 7925-7934 (2001).
95. Catlett-Falcone R, Dalton WS & Jove R. STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. Curr Opin Oncol. 11, 490-496 (1999).
96. Frank DA. STAT signaling in cancer: insights into pathogenesis and treatment strategies. Cancer Treat Res. 115, 267-291 (2003).
97. Gamero AM, Young HA & Wiltrout RH. Inactivation of STAT3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell. 5, 111-112 (2004).
98. van Horssen R, Ten Hagen TL & Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 11, 397-408 (2006).
99. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 3, 745-756 (2003).
100. Weber LW, Boll M. & Sampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 33, 105-136 (2003).
101. Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol. 19, 397-422 (2003).
2. Todres E, Nardi JB & Robertson HM. The tetraspanin superfamily in insects. Insect Mol Biol. 9, 581-590 (2000).
3. Kitadokoro K. et al. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J. 20, 12-18 (2001).
4. Seigneuret M, Delaguillaumie A, Lagaudriere-Gesbert C & Conjeaud H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J Biol Chem. 276, 40055-40064 (2001).
5. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 6, 801-811 (2005).
6. Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci. 114, 4143-4151 (2001).
7. Hemler ME, Mannion BA & Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta. 1287, 67-71 (1996).
8. Hemler ME. Integrin associated proteins. Curr Opin Cell Biol. 10, 578-585 (1998).
9. Lammerding J, Kazarov AR, Huang H, Lee RT & Hemler ME. Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening. Proc Natl Acad Sci U S A. 100, 7616-7621 (2003).
10. Serru V et al. Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions. Biochem J. 340, 103-111 (1999).
11. Kazarov AR, Yang X, Stipp CS, Sehgal B & Hemler ME. An extracellular site on tetraspanin CD151 determines alpha 3 and alpha 6 integrin-dependent cellular morphology. J Cell Biol. 158, 1299-1309 (2002).
12. Zhang XA et al. Function of the tetraspanin CD151-alpha6beta1 integrin complex during cellular morphogenesis. Mol Biol Cell. 13, 1-11 (2002).
13. Lau LM et al. The tetraspanin superfamily member CD151 regulates outside-in integrin alphaIIbbeta3 signaling and platelet function. Blood. 104, 2368-2375 (2004).
14. Yanez-Mo M et al. Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol. 141, 791-804 (1998).
15. Sterk LM et al. Association of the tetraspanin CD151 with the laminin-binding integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 in cells in culture and in vivo. J Cell Sci. 115, 1161-1173 (2002).
16. Feigelson SW, Grabovsky V, Shamri R, Levy S & Alon R. The CD81 tetraspanin facilitates instantaneous leukocyte VLA-4 adhesion strengthening to vascular cell adhesion molecule 1 (VCAM-1) under shear flow. J Biol Chem. 278, 51203-51212 (2003).
17. Mannion BA, Berditchevski F, Kraeft SK, Chen LB & Hemler ME. Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). J Immunol. 157, 2039-2047 (1996).
18. Tarrant JM, Robb L, van Spriel AB & Wright MD. Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol. 24, 610-617 (2003).
19. Wright MD et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol Cell Biol. 24, 5978-5988 (2004).
20. Martin F et al. Tetraspanins in viral infections: a fundamental role in viral biology? J Virol. 79, 10839-10851 (2005).
21. Levy S, Todd SC & Maecker HT. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu Rev Immunol. 16, 89-109 (1998).
22. Maecker HT. Human CD81 directly enhances Th1 and Th2 cell activation, but preferentially induces proliferation of Th2 cells upon long-term stimulation. BMC Immunol. 4, 1-14 (2003).
23. Cherukuri A et al. B cell signaling is regulated by induced palmitoylation of CD81. J Biol Chem. 279, 31973-31982 (2004).
24. Cherukuri A et al. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol. 172, 370-380 (2004).
25. Rosa D et al. Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci U S A. 102, 18544-18549 (2005).
26. Horvath G et al. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem. 273, 30537-30543 (1998).
27. Nichols TC et al. Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes. Eur J Immunol. 28, 4123-4129 (1998).
28. Yunta M et al. Transient activation of the c-Jun N-terminal kinase (JNK) activity by ligation of the tetraspan CD53 antigen in different cell types. Eur J Biochem. 269, 1012-1021 (2002).
29. Imai T, Kakizaki M, Nishimura M & Yoshie O. Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82. J Immunol. 155, 1229-1239 (1995).
30. van Spriel AB et al. A regulatory role for CD37 in T cell proliferation. J Immunol. 172, 2953-2961 (2004).
31. Shi W, Fan H, Shum L & Derynck R. The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J Cell Biol. 148, 591-602 (2000).
32. Huang CL et al. MRP-1/CD9 gene transduction downregulates Wnt signal pathways. Oncogene. 23, 7475-7483 (2004).
33. Murayama Y, Miyagawa J & Oritani K.et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci. 117, 3379-3388 (2004).
34. Ko EM et al. Monoclonal Antibody to CD9 Inhibits Platelet-induced Human Endothelial Cell Proliferation. Mol Cells. 22, 70-77 (2006).
35. Carloni V, Mazzocca A & Ravichandran KS. Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene. 23, 1566-1574 (2004).
36. Guo XZ et al. KAI1 inhibits anchorage-dependent and -independent pancreatic cancer cell growth. Oncol Rep. 14, 59-63 (2005).
37. Takaoka A et al. Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells. Jpn J Cancer Res. 89, 397-404 (1998).
38. Suzuki H, Dong JT, Gao AC, Barrett JC & Isaacs JT. Identification of the rat homologue of KAI1 and its expression in Dunning rat prostate cancers. Prostate. 37, 253-260 (1998).
39. Guo XZ et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Hepatology. 28, 1481-1488 (1998).
40. Yang JL et al. Expression of the KAI1 metastasis suppressor gene in non-metastatic versus metastatic human colorectal cancer. Anticancer Res. 22, 3337-3342 (2002).
41. Higashiyama M et al. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 83, 466-474 (1998).
42. Longo N et al. Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells. Blood. 98, 3717-3726 (2001).
43. Zheng R et al. CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice. Oncol Res. 15, 365-372 (2005).
44. Huang CI et al. Correlation of reduction in MRP-1/CD9 and KAI1/CD82 expression with recurrences in breast cancer patients. Am J Pathol. 153, 978-983 (1998).
45. Mhawech P et al. Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck. Br J Cancer. 90, 471-475 (2004).
46. Sauer G et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res. 9, 6426-6431 (2003).
47. Jang HI & Lee H. A decrease in the expression of CD63 tetraspanin protein elevates invasive potential of human melanoma cells. Exp Mol Med. 35, 317-323 (2003).
48. Berditchevski F, Tolias KF, Wong K, Carpenter CL & Hemler ME. A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. J Biol Chem. 272, 2595-2598 (1997).
49. Yauch RL & Hemler ME. Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphoinositide 4-kinase. Biochem J. 351, 629-637 (2000).
50. Zhang XA, Bontrager AL & Hemler ME. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J Biol Chem. 276, 25005-25013 (2001).
51. Kolch W et al. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature. 364, 249-252 (1993).
52. Tachibana I & Hemler ME. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol. 146, 893-904 (1999).
53. Gu J, Sumida Y, Sanzen N & Sekiguchi K. Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway. J Biol Chem. 276, 27090-27097 (2001).
54. Shigeta M et al. CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol. 163, 165-176 (2003).
55. Sawada S, Yoshimoto M, Odintsova E, Hotchin NA & Berditchevski F. The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras. J Biol Chem. 278, 26323-26326 (2003).
56. Dong JT et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 268, 884-886 (1995).
57. Gu J et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol. 146, 389-403 (1999).
58. Klemke RL et al. CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J Cell Biol. 140, 961-972 (1998).
59. Zhang XA, He B, Zhou B & Liu L. Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J Biol Chem. 278, 27319-27328 (2003).
60. Zhang XA, Lane WS, Charrin S, Rubinstein E & Liu L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 63, 2665-2674 (2003).
61. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
62. Odintsova E, Voortman J, Gilbert E & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
1. Liu ZW, Zhao MJ & Li ZP. Identification of Up-regulated Genes in Rat Regenerating Liver Tissue by Suppression Subtractive Hybridization. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 33, 191-197 (2001).
2. Liu ZW, Zhao MJ, Yokoyama KK & Li ZP. Molecular cloning of a cDNA for rat TM4SF4, a homolog of human il-TMP (TM4SF4), and enhanced expression of the corresponding gene in regenerating rat liver. Biochim Biophys Acta. 1518, 183-189 (2001).
3. Wice BM & Gordon JI. A tetraspan membrane glycoprotein produced in the human intestinal epithelium and liver that can regulate cell density-dependent proliferation. J Biol Chem. 270, 21907-21918 (1995).
4. Michalopoulos GK & DeFrances MC. Liver regeneration. Science. 176, 60-66 (1997).
5. Boll M, Weber LW, Becker E & Stampfl A. Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites. Z Naturforsch [C]. 56, 649-659 (2001).
6. Weber LW, Boll M & Sampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 33, 105-136 (2003).
7. Court FG, Wemyss-Holden SA, Dennison AR & Maddern GJ. The mystery of liver regeneration. Br J Surg. 89, 1089-1095 (2002).
8. Palmes D & Spiegel HU. Animal models of liver regeneration. Biomaterials. 25, 1601-1611 (2004).
9. Grasl-Kraupp B et al. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology. 21, 1465-1468 (1995).
10. Shi J, Aisaki K, Ikawa Y & Wake K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol. 153, 515-525 (1998).
11. Bansal MB et al. Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. J Hepatol. 42, 548-556 (2005).
12. Lee JI et al. Apoptosis of hepatic stellate cells in carbon tetrachloride induced acute liver injury of the rat: analysis of isolated hepatic stellate cells. J Hepatol. 39, 960-966 (2003).
13. Wu J, Danielsson A & Zern MA. Toxicity of hepatotoxins: new insights into mechanisms and therapy. Expert Opin Investig Drugs. 8, 585-607 (1999).
14. Bradham CA, Plumpe J, Manns MP, Brenner DA & Trautwein C. Mechanisms of hepatictoxicity. I. TNF-induced liver injury. Am J Physiol. 275, G387-392 (1998).
15. Ding WX & Yin XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med. 8, 445-454 (2004).
16. Malhi H, Gores GJ & Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology. 43, S31-44 (2006).
17. Schwabe RF & Brenner DA. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 290, G583-589 (2006).
18. Horn TL, O'Brien TD, Schook LB & Rutherford MS. Acute hepatotoxicant exposure induces TNFR-mediated hepatic injury and cytokine/apoptotic gene expression. Toxicol Sci. 54, 262-273 (2000).
19. Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T & Sato K. Molecular process in acute liver injury and regeneration induced by carbon tetrachloride. Life Sci. 75, 1539-1549 (2004).
20. Boros P & Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet. 345, 293-295 (1995).
21. Liu Y. Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol. 277, F624-633 (1999).
22. Huh CG et al. Anti-hepatocyte growth factor antibody inhibits hepatocyte proliferation during liver regeneration. J Pathol. 185, 298-302 (1998).
23. Huh CG et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 101, 4477-4482 (2004).
24. Armbrust T, Batusic D, Xia L & Ramadori G. Early gene expression of hepatocyte growth factor in mononuclear phagocytes of rat liver after administration of carbon tetrachloride. Liver. 22, 486-494 (2002).
25. Stuart KA et al. Hepatocyte growth factor/scatter factor-induced intracellular signalling. Int J Exp Pathol. 81, 17-30 (2000).
26. Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 1, 169-178 (2000).
27. Breitkopf K, Godoy P, Ciuclan L, Singer MV & Dooley S. TGF-beta/Smad signaling in the injured liver. Z Gastroenterol. 44, 57-66 (2006).
28. Cain K & Freathy C. Liver toxicity and apoptosis: role of TGF-beta1, cytochrome c and the apoptosome. Toxicol Lett. 120, 307-315 (2001).
29. Fausto N, Laird AD & Webber EM. Liver regeneration. 2. Role of growth factors and cytokinesin hepatic regeneration. FASEB J. 9, 1527-1536 (1995).
30. Templeton NS & Lasic DD. New directions in liposome gene delivery. Mol Biotechnol. 11, 175-180 (1999).
31. Kostarelos K & Miller AD. What role can chemistry play in cationic liposome-based gene therapy research today? Adv Genet. 53, 71-118 (2005).
32. Simoes S et al. Cationic liposomes for gene delivery. Expert Opin Drug Deliv. 2, 237-254 (2005).
33. Wang D, Jing NH & Lin QS. Stearylamine liposome as a new efficient reagent for DNA transfection of eukaryotic cells. Biochem Biophys Res Commun. 226, 450-455 (1996).
34. Ishak K et al. Histological grading and staging of chronic hepatitis. J Hepatol. 22, 696-699 (1995).
35. Yamakawa Y et al. Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation. Ann Surg. 231, 387-398 (2000).
36. Suyama E, Kawasaki H & Taira K. Identification of a caspase 3-independent role of pro-apoptotic factor Bak in TNF-alpha-induced apoptosis. FEBS Lett. 528, 63-69 (2002).
37. Fox SA, Kusmiaty, Loh SS, Dharmarajan AM & Garlepp MJ. Cisplatin and TNF-alpha downregulate transcription of Bcl-XL in murine malignant mesothelioma cells. Biochem Biophys Res Commun. 337, 983-991 (2005).
38. Tanaka F, Hori N & Sato K. Identification of differentially expressed genes in rat hepatoma cell lines using subtraction and microarray. J Biochem (Tokyo). 131, 39-44 (2002).
39. Morio LA et al. Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol. 172, 44-51 (2001).
40. Ishiki Y, Ohnishi H, Muto Y, Matsumoto K & Nakamura T. Direct evidence that hepatocyte growth factor is a hepatocytotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology. 16, 1227-1235 (1992).
41. Okano J, Shiota G & awasaki H. Protective action of hepatocyte growth factor for acute liver injury caused by D-galactosamine in transgenic mice. Hepatology. 26, 1241-1249 (1997).
42. Roos F, Terrell TG, Godowski PL, Chamow SM & Schwall RH. Reduction of alpha-naphthylisothiocyanate-induced hepatotoxicity by recombinant human hepatocyte growth factor. Endocrinology. 131, 2540-2544 (1992).
43. Cramer T et al. Hepatocyte growth factor and c-Met expression in rat and human liver fibrosis. Liver Int. 24, 335-344 (2004).
1. Yunta M & Lazo PA. Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal. 15, 559-564 (2003).
2. Tarrant JM, Robb L, van Spriel AB & Wright MD. Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol. 24, 610-617 (2003).
3. Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci. 114, 4143-4151 (2001).
4. Chen Z, Mustafa T & Trojanowicz B et al. CD82, and CD63 in thyroid cancer. Int J Mol Med. 14, 517-527 (2004).
5. Funakoshi T, Tachibana I & Hoshida Y et al. Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer. Oncogene. 22, 674-687 (2003).
6. Jang HI & Lee H. A decrease in the expression of CD63 tetraspanin protein elevates invasive potential of human melanoma cells. Exp Mol Med. 35, 317-323 (2003).
7. Lee JH, Park SR & Chay KO et al. KAI1 COOH-terminal interacting tetraspanin (KITENIN), a member of the tetraspanin family, interacts with KAI1, a tumor metastasis suppressor, and enhances metastasis of cancer. Cancer Res. 64, 4235-4243 (2004).
8. Murayama Y, Miyagawa J & Oritani K et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci. 117, 3379-3388 (2004).
9. Shi W, Fan H, Shum L & Derynck R. The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J Cell Biol. 148, 591-602 (2000).
10. Ang J, Lijovic M, Ashman LK, Kan K & Frauman AG. CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator? Cancer Epidemiol Biomarkers Prev. 11, 1717-1721 (2004).
11. Ferrer M, Yunta M & Lazo PA. Pattern of expression of tetraspanin antigen genes in Burkitt lymphoma cell lines. Clin Exp Immunol. 113, 346-352 (1998).
12. Sauer G et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res. 9, 6426-6431 (2003).
13. Yatomi Y, Yoneyama A & Nakahara K. Usefulness of CD9 detection in the diagnosis of acute megakaryoblastic leukemia. Eur J Haematol. 72, 229-230 (2004).
14. Boucheix C, Duc GH, Jasmin C & Rubinstein E. Tetraspanins and malignancy. Expert Rev Mol Med. 31, 1-17 (2001).
15. Szala S et al. Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proc Natl Acad Sci U S A. 87, 6833-6837 (1990).
16. Marken JS, Schieven GL & Hellstrom I. Cloning and expression of the tumor-associated antigen L6. Proc Natl Acad Sci U S A. 89, 3503-3507 (1992).
17. Wright MD, Moseley GW & van Spriel AB. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antigens. 64, 533-542 (2004).
18. Hotta H. et al. Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res. 48, 2955-2962 (1988).
19. Radford KJ, Thorner RF & Hersey P. Regulation of tumor cell motility and migration by CD63 in a human melanoma cell line. J Immunol. 158, 3353-3358 (1997).
20. Dong JT. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 268, 884-886 (1995).
21. Guo XZ et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Hepatology. 28, 1481-1488 (1998).
22. Adachi M et al. Correlation of KAI1/CD82 gene expression with good prognosis in patients with non-small cell lung cancer. Cancer Res. 56, 1751-1755 (1996).
23. Hemler ME, Mannion BA & Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta. 1287, 67-71 (1996).
24. Kawashima M, Doh-ura K, Mekada E, Fukui M & Iwaki T. CD9 expression in solid non-neuroepithelial tumors and infiltrative astrocytic tumors. J Histochem Cytochem. 50, 1195-1203 (2002).
25. Wollscheid V et al. Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas. Int J Cancer. 99, 771-775 (2002).
26. Tokuhara T et al. Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin Cancer Res. 7, 4109-4114 (2001).
27. Hashida H et al. Clinical significance of transmembrane 4 superfamily in colon cancer. Br J Cancer. 89, 158-167 (2003).
28. Adachi M et al. Novel staging protocol for non-small-cell lung cancers according to MRP-1/CD9 and KAI1/CD82 gene expression. J Clin Oncol. 16, 1397-1406 (1998).
29. Wright MD & Tomlinson MG. The ins and outs of the transmembrane 4 superfamily. Immunol. Today 15, 588-594 (1994).
30. Wright MD, Ni J & Rudy GB. The L6 membrane proteins--a new four-transmembrane superfamily. Protein Sci. 9, 1594-1600 (2000).
31. Kaji K & Kudo A. The mechanism of sperm-oocyte fusion in mammals. Reproduction. 127, 423-429 (2004).
32. van Spriel AB et al. A regulatory role for CD37 in T cell proliferation. J Immunol. 172, 2953-2961 (2004).
33. Yunta M & Lazo PA. Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal. 15, 559-564 (2003).
34. Mantegazza AR et al. CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells. Blood. 104, 1183-1190 (2004).
35. Sridhar SC & Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 25, 2367-2378 (2006).
36. Levy S & Shoham T. The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol. 5, 136-48 (2005).
37. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 6, 801-811 (2005).
38. Jackson P, Marreiros A & Russell PJ. KAI1 tetraspanin and metastasis suppressor. Int J Biochem Cell Biol. 37, 530-534 (2005).
39. Wright MD, Ni J & Rudy GB. The L6 membrane proteins--a new four-transmembrane superfamily. Protein Sci. 9, 1594-1600 (2000).
40. Kaneko R et al. Amount of expression of the tumor-associated antigen L6 gene and transmembrane 4 superfamily member 5 gene in gastric cancers and gastric mucosa. Am J Gastroenterol 96, 3457-3458 (2001).
41. Schiedeck TH, Wellm C, Roblick UJ, Broll R & Bruch HP. Diagnosis and monitoring of colorectal cancer by L6 blood serum polymerase chain reaction is superior to carcinoembryonic antigen-enzyme-linked immunosorbent assay. Dis Colon Rectum. 46, 818-825 (2003).
42. Muller-Pillasch F et al. Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer. Gene. 208, 25-30 (1998).
43. Wice BM & Gordon JI. A tetraspan membrane glycoprotein produced in the human intestinal epithelium and liver that can regulate cell density-dependent proliferation. J Biol Chem. 270, 21907-21918 (1995).
44. Liu Z, Zhao M, Yokoyama KK & Li T. Molecular cloning of a cDNA for rat TM4SF4, a homolog of human il-TMP (TM4SF4), andenhanced expression of the corresponding gene in regenerating rat liver. Biochim. Biophys. Acta. 1518, 183-189 (2001).
45. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 35, S72-78 (2002).
46. Breuhahn K, Longerich T & Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 25, 3787-3800 (2006).
47. Mendelsohn J & Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 33, 369-385 (2006).
48. Chuang LY et al. Epidermal growth factor-related transforming growth factors in the urine of patients with hepatocellular carcinoma. Hepatology. 13, 1112-1116 (1991).
49. Hirano T, Ishihara K & Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 19, 2548-56 (2000).
50. Imada K & Leonard WJ. The JAK-STAT pathway. Mol Immunol. 37, 1-11 (2000).
51. Mui AL. The role of STATs in proliferation, differentiation, and apoptosis. Cell Mol Life Sci. 55, 1547-58 (1999).
52. Yu H & Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 4, 97-105 (2004).
53. Turkson J & Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 19, 6613-26 (2000).
54. Turkson J. STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets. 8, 409-422 (2004).
55. Boucheix C, Duc GH, Jasmin C & Rubinstein E. Tetraspanins and malignancy. Expert Rev Mol Med. 31, 1-17 (2001).
56. Hemler ME. Specific tetraspanin functions. J. Cell Biol, 155, 1103-1107 (2001).
57. Maecker HT, Todd SC & Levy S. The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428-442 (1997).
58. Castanotto D, Li H & Rossi JJ. Functional siRNA expression from transfected PCR products. RNA. 8, 1454-1460 (2002).
59. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther. [Epub ahead of print], (2004).
60. Black D, Lyman S, Heider TR & Behrns KE. Molecular and cellular features of hepatic regeneration. J Surg Res. 117, 306-315 (2004).
61. Lowes KN, Croager EJ, Olynyk JK, Abraham LJ & Yeoh GC. Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol. 18, 4-12 (2003).
62. Malik R, Selden C & Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol. 13, 425-431 (2002).
63. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 5, 836-847 (2004).
64. Zimmermann A. Regulation of liver regeneration. Nephrol Dial Transplant. 19, 6-10 (2004).
65. Guo XZ et al. KAI1 inhibits anchorage-dependent and -independent pancreatic cancer cell growth. Oncol Rep. 14, 59-63 (2005).
66. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
67. Odintsova E, Voortman J, Gilbert E & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
68. Jin C, Ding P, Wang Y & Ma D. Regulation of EGF receptor signaling by the MARVEL domain-containing protein CKLFSF8. FEBS Lett. 579, 6375-6382 (2005).
69. Battle TE. & Frank DA. The role of STATs in apoptosis. Curr Mol Med. 2, 381-392 (2002).
70. Benekli M. et al. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood. 99, 252-257 (2002).
71. Bowman T, Garcia R, Turkson J. & Jove R. STATs in oncogenesis. Oncogene 19, 2474-2488 (2000).
72. Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 109, 1139-1142 (2002).
73. Calo V et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. 197, 157-168 (2003).
74. Dhir R. et al. STAT3 activation in prostatic carcinomas. Prostate. 51, 241-246 (2002).
75. Garcia R. et al. Constitutive activation of STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 20, 2499-2513 (2001).
76. Leaman DW et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol. 16, 369-375 (1996).
77. Turkson J et al. STAT3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Biol Cell. 18, 2545-2552 (1998).
78. Bowman T, Garcia R, Turkson J & Jove RH. STATs in oncogenesis. Oncogene 19, 2474-2488 (2000).
79. Zhang Y et al. Activation of STAT3 in v-Src-transformed fibroblasts requires cooperation of JAK1 kinase activity. J. Biol. Chem. 275, 24935-24944 (2000).
80. Hellstrom I et al. Monoclonal mouse antibodies raised against human lung carcinoma. Cancer Res. 46, 3917-3923 (1986).
81. Kao YR et al. Tumor-associated antigen L6 and the invasion of human lung cancer cells. Clin Cancer Res. 9, 2807-2816 (2003).
82. Feng DY, Zheng H, Tan Y & Cheng RX. Effect of phosphorylation of MAPK and STAT3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol. 7, 33-36 (2001).
83. Huynh H et al. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 3, 19-40 (2003).
84. Schmidt CM, McKillop IH, Cahill PA & Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Bioch Biophy Res Comm. 236, 54-58 (1997).
85. Schmidt CM, McKillop IH, Cahill PA & Sitzmann JV. The role of cAMP-MAPK signalling in the regulation of human hepatocellular carcinoma growth in vitro. Eur J Gastroenterol Hepatol. 11, 1393-1399 (1999).
86. Nicholson RI, Gee JM & Harper ME. EGFR and cancer prognosis. Eur J Cancer. 37, S9-15 (2001).
87. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 37, S3-8 (2001).
88. DeCicco LA, Kong J & Ringer DP. Carcinogen-induced alteration in liver epidermal growth factor receptor distribution during the promotion stage of hepatocarcinogenesis in rat. Cancer Lett. 111, 149-156 (1997).
89. Hisaka T, Yano H, Haramaki M, Utsunomiya I & Kojiro M. Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol. 14, 453-460 (1999).
90. Odintsova E, Sugiura T & Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol. 10, 1009-1012 (2000).
91. Odintsova E, Voortman J, Gilbert E. & Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 116, 4557-4566 (2003).
92. Supino R. Methods in Molecular Biology. Humana Press Inc., Totoa, NJ (1995).
93. Buettner R, Mora LB & Jove RH. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 8, 945-954 (2002).
94. Burke WM. et al. Inhibition of constitutively active STAT3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 20, 7925-7934 (2001).
95. Catlett-Falcone R, Dalton WS & Jove R. STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. Curr Opin Oncol. 11, 490-496 (1999).
96. Frank DA. STAT signaling in cancer: insights into pathogenesis and treatment strategies. Cancer Treat Res. 115, 267-291 (2003).
97. Gamero AM, Young HA & Wiltrout RH. Inactivation of STAT3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell. 5, 111-112 (2004).
98. van Horssen R, Ten Hagen TL & Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 11, 397-408 (2006).
99. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 3, 745-756 (2003).
100. Weber LW, Boll M. & Sampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 33, 105-136 (2003).
101. Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol. 19, 397-422 (2003).