CD44V6和VEGF-C及JNK在胃癌组织中的表达及临床意义
摘要
目的:胃癌是消化道系统最常见的肿瘤之一,发病率占消化系统恶性肿瘤的首位。其生长速度快,并具有极强的局部侵润和远处转移能力,居各类癌症死亡的首位,近年来研究发现,CD44V6和VEGF-C与多种肿瘤发生、发展及转移有关,随着对c-Jun氨基末端激酶(JNK)家族的不断认识,发现JNK在胃癌的发生、发展中发挥重要作用。通过对JNK、CD44V6和VEGF-C在胃癌组织中的表达的研究将有助于加深对胃癌发生、发展及转移机制的了解的,以及为防治和评估找到新方法。
方法:本研究采用免疫组化S-P方法检测了20例正常胃组织、40例胃癌原发灶及20例淋巴结转移灶中CD44V6、VEGF-C和JNK的表达情况,并分析比较它们的不同性别、年龄、肿瘤大小、分期、分化程度、特别是原发灶与转移灶分组中表达差异。
结果:
1.胃癌组织中CD44V6蛋白表达阳性率为62.5%,其强度由+到+++,但在正常胃组织中的无表达,二者差别极有显著的统计学意义(P<0.01)。在淋巴道转移中的阳性率为80%,其强度包括更多的+++,高于原发灶的62.5%,二者差别有统计学意义(P<0.05)。
2.胃癌组织中VEGF-C蛋白表达阳性率为50%,显著高于胃良性病变及正常胃组织中的5%其强度为+,二者差别有显著的统计学意义(P<0.01)。在淋巴道转移中的阳性率为70%,其强度包括更多+++,高于原发灶的50%,二者差别有显著的统计学意义(P<0.01)。
3.胃癌组织中JNK蛋白表达阳性率为75%,显著高于胃良性病变及正常胃组织中的57.5%,二者差别有显著的统计学意义(P<0.05)。在淋巴道转移中的阳性率为60%,低于原发灶的表达,二者差别无统计学意义(P>0.05)。
4.CD44V6及VEGF-C在胃癌原发灶及淋巴结转移灶中表达强度呈正相关关系。JNK与CD44V6在胃癌原发灶中相关性分析rs=0.335,P<0.05有统计学意义,在转移灶中相关性分析rs=0.843,P<0.01有极显著统计学意义。JNK与VEGF-C在胃癌原发灶中相关性分析rs=0.341,P<0.05有统计学意义,在转移灶中相关性分析rs=0.942,P<0.01有极显著统计学意义。CD44V6及VEGF-C在胃癌原发灶相关性分析rs=0.342,P<0.05有统计学意义,在转移灶中相关性分析rs=0.942,P<0.01有极显著统计学意义。
5.JNK在胃癌原发灶的表达率的差异在肿瘤的大小、早晚期的分组中有统计学意义,在性别、年龄分组中的无显著差异。CD44V6和VEGF-C在胃癌原发灶的表达率的差异在早晚期的分组中有统计学意义,在性别、年龄、肿瘤的大小分组中的无显著差异,CD44V6、VEGF-C和JNK在胃腺癌不同分化中的表达均无统计学意义。
结论:
1. CD44V6、VEGF-C和JNK在胃癌中表达阳性率和表达强度明显高于正常胃组织,CD44V6、VEGF-C在淋巴结转移灶中表达的阳性率和表达强度也明显高于胃癌原发灶,JNK在淋巴结转移灶及原发灶中表达的阳性率和表达强度的差异无统计学意义(P>0.05)。CD44V6、VEGF-C和JNK在胃癌原发灶与转移灶表达强度呈正相关关系。因此CD44V6、VEGF-C和JNK在肿瘤的发生、发展、转移中可能起到重要作用。
2. JNK在胃癌原发灶的表达阳性率的差异在肿瘤的大小、早晚期的分组中有统计学意义,在性别、年龄分组中的无显著差异。CD44V6和VEGF-C在胃癌原发灶的表达的差异在早晚期的分组中有统计学意义,在性别、年龄、肿瘤的大小分组中的无显著差异,CD44V6、VEGF-C和JNK在胃腺癌不同分化中的表达阳性率无显著性差异。
Purpose: Gastric cancer is the fourth most common cancer and the second leading cancer-related death world wide because of its rapid growth and strong tendency of local invasiveness and distal metastasis. Recent researches found that CD44V6 and VEGF-C may have a relationship with the oncogenesis, tumor prog- ression and metastasis of some carcinomas. Along with constant acquaintance of c-Jun and JNK family members, researches found that JNK play a important role in the oncogenesis, tumor progression of gastric cancer. Investigation on expression of JNK, CD44V6 and VEGF-C in gastric cancer may provede some clues in the oncogensis, progression and metastasis of gastric cancer and be helpful for its diagnosis﹑anti-tumor treatment and prognosis evaluation.
Method: S-P immunhistochemical stain was employed to detect the expression of CD44V6, VEGF-C and JNK in 20 cases of normal gastric tissue, 40 cases of gastric cancers in which 20 lymphatic metastasis. The expression of CD44V6, VEGF-C and JNK was compared amony normal gastric tissue, primary gastric cancer and the lymphatic metastatic tumor. The difference of their expression among different groups of patient’s gender, age, tumor size, stage and differentiation was also analyzed.
Result:
1. Approximately two third 62.5% of the gastric cancer cases are positive for CD44V6 Expression, with a degree of intensty from weak (+) to strong (+++) more than the positive cases in normal gastric tissue 0%, The difference between the two groups is significant (P<0.01). 80% of the lymphatic metastatic tumors are positive for CD44V6 expression, more than the positive cases in primary gastric cancer 62.5%, The difference between the two groups is highly significant (P<0.01).
2. Approximately half 50% of the gastric cancer cases are positive for VEGF-C Expression, more than the positive cases in normal gastric tissue 5% in which the intensity is all weak (+), The difference between the two groups is significant (P<0.01). 70% of the lymphatic metastatic tumors are positive for VEGF-C expression, more than the positive cases in primary gastric cancer 50% and even more cases with a strong (+++) intensity. The difference between the two groups is highly significant (P<0.01).
3. Approximately three third75% of the gastric cancer cases are positive for JNK Expression, more than the positive cases in benign pathology and normal gastric tissue 5%, The difference between the two groups is highly significant (P<0.05). 60% of the lymphatic metastatic tumors are positive for JNK expression, less than the positive cases in primary gastric cancer 75%, The difference between the two groups is insignificant (P>0.05).
4. The expression intensity of CD44V6, VEGF-C and JNK between any pairs of them in gastric cancer and metastasis of gastric cancer are positively correlated. In the case of gastric cancer, Correlation Analysis between CD44V6 with VEGF-C concluded that rs=0.342 and be significant (P<0.05) in gastric cancer. And rs=0.894 and be highly significant (P<0.01) in metastasis of gastric cancer. Correlation Analysis between CD44V6 with JNK concluded that rs=0.335 and be significant (P<0.05) in gastric cancer. And rs=0.843 and be highly significant (P<0.01) in metastasis of gastric cancer.Correlation Analysis between VEGF with JNK concluded that rs=0.341 and be significant (P<0.05) in gastric cancer. And rs=0.942 and be highly significant (P<0.01) in metastasis of gastric cancer.
5. JNK expression in primary gastric cancer between different groups of tumor size, stage differentiation are significant, but between different groups of patient’s gender, age differentiation are all not significant. CD44V6 and VEGF-C expression in primary gastric cancer between different groups of stage differentiation are significant, but between different groups of patient’s gender, age tumor sizes are all not significant. CD44V6、VEGF-C and JNK expression in gastricadenocarcinoma between different groups of differentiation are all not significant.
Conclusion:
1. The positive rates of CD44V6, VEGF-C and JNK expression in gastric cancer observed using immunohistochemical stain are higher than normal gastric cancer and expression intensity is stronger in many of the positive cases. The positive rates of CD44V6 and VEGF-C expression in lymphatic metastatic tumor are higher than the primary gastric cancer and intensity is stronger in most of the positive cases. The difference of the positive rates and the expression intensity of JNK between the lymphatic metastatic tumors with the primary gastric cancer is insignificant (P>0.05). The expression intensity of CD44V6, VEGF-C and JNK in primary gastric cancer and metastastic tumor is positively correlated. So JNK maybe play a important role in the oncogenesis, tumor progression and metastasis of gastric cancer. So we believe that JNK be concerned with tumor metastasis, but the mechanism is unknown yet.
2.JNK expression in primary gastric cancer between different groups of tumor size, stage differentiation are significant, but between different groups of patient’s gender, age differentiation are all not significant. CD44V6 and VEGF-C expression in primary gastric cancer between different groups of stage differentiation are significant, but between different groups of patient’s gender, age tumor sizes are all not significant. CD44V6、VEGF-C and JNK expression in gastricadenocarcinoma between different groups of differentiation are all not significant.
方法:本研究采用免疫组化S-P方法检测了20例正常胃组织、40例胃癌原发灶及20例淋巴结转移灶中CD44V6、VEGF-C和JNK的表达情况,并分析比较它们的不同性别、年龄、肿瘤大小、分期、分化程度、特别是原发灶与转移灶分组中表达差异。
结果:
1.胃癌组织中CD44V6蛋白表达阳性率为62.5%,其强度由+到+++,但在正常胃组织中的无表达,二者差别极有显著的统计学意义(P<0.01)。在淋巴道转移中的阳性率为80%,其强度包括更多的+++,高于原发灶的62.5%,二者差别有统计学意义(P<0.05)。
2.胃癌组织中VEGF-C蛋白表达阳性率为50%,显著高于胃良性病变及正常胃组织中的5%其强度为+,二者差别有显著的统计学意义(P<0.01)。在淋巴道转移中的阳性率为70%,其强度包括更多+++,高于原发灶的50%,二者差别有显著的统计学意义(P<0.01)。
3.胃癌组织中JNK蛋白表达阳性率为75%,显著高于胃良性病变及正常胃组织中的57.5%,二者差别有显著的统计学意义(P<0.05)。在淋巴道转移中的阳性率为60%,低于原发灶的表达,二者差别无统计学意义(P>0.05)。
4.CD44V6及VEGF-C在胃癌原发灶及淋巴结转移灶中表达强度呈正相关关系。JNK与CD44V6在胃癌原发灶中相关性分析rs=0.335,P<0.05有统计学意义,在转移灶中相关性分析rs=0.843,P<0.01有极显著统计学意义。JNK与VEGF-C在胃癌原发灶中相关性分析rs=0.341,P<0.05有统计学意义,在转移灶中相关性分析rs=0.942,P<0.01有极显著统计学意义。CD44V6及VEGF-C在胃癌原发灶相关性分析rs=0.342,P<0.05有统计学意义,在转移灶中相关性分析rs=0.942,P<0.01有极显著统计学意义。
5.JNK在胃癌原发灶的表达率的差异在肿瘤的大小、早晚期的分组中有统计学意义,在性别、年龄分组中的无显著差异。CD44V6和VEGF-C在胃癌原发灶的表达率的差异在早晚期的分组中有统计学意义,在性别、年龄、肿瘤的大小分组中的无显著差异,CD44V6、VEGF-C和JNK在胃腺癌不同分化中的表达均无统计学意义。
结论:
1. CD44V6、VEGF-C和JNK在胃癌中表达阳性率和表达强度明显高于正常胃组织,CD44V6、VEGF-C在淋巴结转移灶中表达的阳性率和表达强度也明显高于胃癌原发灶,JNK在淋巴结转移灶及原发灶中表达的阳性率和表达强度的差异无统计学意义(P>0.05)。CD44V6、VEGF-C和JNK在胃癌原发灶与转移灶表达强度呈正相关关系。因此CD44V6、VEGF-C和JNK在肿瘤的发生、发展、转移中可能起到重要作用。
2. JNK在胃癌原发灶的表达阳性率的差异在肿瘤的大小、早晚期的分组中有统计学意义,在性别、年龄分组中的无显著差异。CD44V6和VEGF-C在胃癌原发灶的表达的差异在早晚期的分组中有统计学意义,在性别、年龄、肿瘤的大小分组中的无显著差异,CD44V6、VEGF-C和JNK在胃腺癌不同分化中的表达阳性率无显著性差异。
Purpose: Gastric cancer is the fourth most common cancer and the second leading cancer-related death world wide because of its rapid growth and strong tendency of local invasiveness and distal metastasis. Recent researches found that CD44V6 and VEGF-C may have a relationship with the oncogenesis, tumor prog- ression and metastasis of some carcinomas. Along with constant acquaintance of c-Jun and JNK family members, researches found that JNK play a important role in the oncogenesis, tumor progression of gastric cancer. Investigation on expression of JNK, CD44V6 and VEGF-C in gastric cancer may provede some clues in the oncogensis, progression and metastasis of gastric cancer and be helpful for its diagnosis﹑anti-tumor treatment and prognosis evaluation.
Method: S-P immunhistochemical stain was employed to detect the expression of CD44V6, VEGF-C and JNK in 20 cases of normal gastric tissue, 40 cases of gastric cancers in which 20 lymphatic metastasis. The expression of CD44V6, VEGF-C and JNK was compared amony normal gastric tissue, primary gastric cancer and the lymphatic metastatic tumor. The difference of their expression among different groups of patient’s gender, age, tumor size, stage and differentiation was also analyzed.
Result:
1. Approximately two third 62.5% of the gastric cancer cases are positive for CD44V6 Expression, with a degree of intensty from weak (+) to strong (+++) more than the positive cases in normal gastric tissue 0%, The difference between the two groups is significant (P<0.01). 80% of the lymphatic metastatic tumors are positive for CD44V6 expression, more than the positive cases in primary gastric cancer 62.5%, The difference between the two groups is highly significant (P<0.01).
2. Approximately half 50% of the gastric cancer cases are positive for VEGF-C Expression, more than the positive cases in normal gastric tissue 5% in which the intensity is all weak (+), The difference between the two groups is significant (P<0.01). 70% of the lymphatic metastatic tumors are positive for VEGF-C expression, more than the positive cases in primary gastric cancer 50% and even more cases with a strong (+++) intensity. The difference between the two groups is highly significant (P<0.01).
3. Approximately three third75% of the gastric cancer cases are positive for JNK Expression, more than the positive cases in benign pathology and normal gastric tissue 5%, The difference between the two groups is highly significant (P<0.05). 60% of the lymphatic metastatic tumors are positive for JNK expression, less than the positive cases in primary gastric cancer 75%, The difference between the two groups is insignificant (P>0.05).
4. The expression intensity of CD44V6, VEGF-C and JNK between any pairs of them in gastric cancer and metastasis of gastric cancer are positively correlated. In the case of gastric cancer, Correlation Analysis between CD44V6 with VEGF-C concluded that rs=0.342 and be significant (P<0.05) in gastric cancer. And rs=0.894 and be highly significant (P<0.01) in metastasis of gastric cancer. Correlation Analysis between CD44V6 with JNK concluded that rs=0.335 and be significant (P<0.05) in gastric cancer. And rs=0.843 and be highly significant (P<0.01) in metastasis of gastric cancer.Correlation Analysis between VEGF with JNK concluded that rs=0.341 and be significant (P<0.05) in gastric cancer. And rs=0.942 and be highly significant (P<0.01) in metastasis of gastric cancer.
5. JNK expression in primary gastric cancer between different groups of tumor size, stage differentiation are significant, but between different groups of patient’s gender, age differentiation are all not significant. CD44V6 and VEGF-C expression in primary gastric cancer between different groups of stage differentiation are significant, but between different groups of patient’s gender, age tumor sizes are all not significant. CD44V6、VEGF-C and JNK expression in gastricadenocarcinoma between different groups of differentiation are all not significant.
Conclusion:
1. The positive rates of CD44V6, VEGF-C and JNK expression in gastric cancer observed using immunohistochemical stain are higher than normal gastric cancer and expression intensity is stronger in many of the positive cases. The positive rates of CD44V6 and VEGF-C expression in lymphatic metastatic tumor are higher than the primary gastric cancer and intensity is stronger in most of the positive cases. The difference of the positive rates and the expression intensity of JNK between the lymphatic metastatic tumors with the primary gastric cancer is insignificant (P>0.05). The expression intensity of CD44V6, VEGF-C and JNK in primary gastric cancer and metastastic tumor is positively correlated. So JNK maybe play a important role in the oncogenesis, tumor progression and metastasis of gastric cancer. So we believe that JNK be concerned with tumor metastasis, but the mechanism is unknown yet.
2.JNK expression in primary gastric cancer between different groups of tumor size, stage differentiation are significant, but between different groups of patient’s gender, age differentiation are all not significant. CD44V6 and VEGF-C expression in primary gastric cancer between different groups of stage differentiation are significant, but between different groups of patient’s gender, age tumor sizes are all not significant. CD44V6、VEGF-C and JNK expression in gastricadenocarcinoma between different groups of differentiation are all not significant.
引文
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42 Hibi M, Lin A, Smeal T, et al. Identification of an oncoproteinand UV-responsive protein kinase that binds and potentiates the c-Jun activation domain, Genes Dev,1993,7(11):2135-2148
43 Weston CR, Davis RJ. The JNK signal transduction pathway,Curr Opin Cell Biol, 2007,19(2): 142-149
44 Waetzig V, Herdegen T. Context-specific inhibition of JNKs:over coming the dilemma of prote cttion and damage,Trends Pharmacol Sci, 2005, 26(9): 455-461
1. Erkma G, Gerasimov G, Troshina, et al. Deregulated alternative spli-cing of CD44 mRNA transcrip ts in neop lastic and nonneop lastic le-sion of the human thyroid. Cancer Res , 1995, 55 (20) : 4594-4598.
2.辛彦,赵凤凯,张素敏,等. CD44V6基因编码蛋白表达与胃癌转移和预后的关系.世界华人消化杂志, 1999, 7 (3) : 210-214.
3. Yamaguchi A, Goi T, Seki K, et al. Clinical significance of com-bined imm unohistochem ical detection of CD44v6 and sialyl Lex ex-p ression for colorectal cancer patients undergoing curative resection. Oncol, 1998, 55 (5) : 400-403.
4. Christopher J, Amil K. CD44 isoform expression in primary and meta-static pancreatic adenocarcinoma. Cancer Res, 1995, 55 (9) : 1831-1836.
5. Matsumura Y,Tarin D. Signifieance of CD44 gene produets for eancer Diagnosis and disease evaluation. Lancet.1992,340(8827):1053-1058.
6. Kaufmann M,Heider KH,Sinn HP,et al.CD44 varia ntexon epitopes inprimary breast cancer and length of survival. Lancet.1995,345(8950):615-619.
7. WielengaVJ,HeiderKH,OfferhausGJ,et al. Expression of CD44 variant proteins in human colorectal cancer is related totumor progression.CancerRes.1993 53(20):4754-4756.
8. SaitoH,Tsujitani S,KatanoK,et al.Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric careinoma.Cancer,1998,83(6):1094-1101.
9. Lida N,Bourguign on L Y.Coexpression of CD44 varian(C10ex14)standard and isoform in breast cancer .J Cell Physiol,1997,171(2):152-160.
10. Lida N,bourguignon LY.Coexpression of CD44 varian standard and isofom in breast cancer .J Cell Physiol,1997,171(2):1152-160.
11.王玉珍,梁志清,血管内皮因子-C与恶性肿瘤的淋巴管及淋巴结转移关系研究进展[J].肿瘤防治杂志,2004,11(11):1217-1219.
12. NagamineM,OkUmuraT,TannoS,et al.PPAR-gamma ligand in duced aPoPtosis through a P532dePendent mecanism in humangastric .canercells.CancerSci,2003,94(4):338343.
13. Vidal S,Khush RS,Leulier F,et al.Mutations in the Drosophila dTAK1 gene reveal a conserved function forMAPKKKs in the control of rel/NF-kappaB-dependent innate immune respo nses.Genes Dev,2001, 15(15): 1900-1912
14. Catherine D,Carolyn W,Ann M,et al.Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor . Cellular Signalling,2002, 14(7):585-593
15. Xia Y,Karin M.The control of cell motility and epithelial morphogenesis by Jun kinases.Trends Cell Biol,2004,14:94-101
16.张文伶,金勇丰,朱成钢,等.JNK/MAPK途径调控机制研究进展.癌变·畸变·突变,2003,15(4):253-256
17. Buschmann T,Potapova O,BarShira A,et al.JunNH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.Mol.Cell.Biol,2001, 21(8): 2743-2754
18. Fuchs SY,Adler V,Buschmann T, et al.JNK targets p53 ubiquitination and degradation in non-stressed cells .Gene Dev,1998,12(17):2658-2663
19. Tournier C,Hess P,Yang DD,et al.Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway .Science,2000, 288(5467): 870-874
20. Noguchi K,Kitanaka C,Yamana H,et al.Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-termjinal kinase .J boil Chem,1999, 274(46): 32580-32587
21. Dania AV,Ze’ev R.c-Jun-NH2 Kinase(JNK) Contributes to the Regulation of c-Myc Protein Stability.J boil Chem,2004, 279(6):5008-5016
22. Cheng J,Yang J,Xia Y,et al.Synergistic interaction of MEK kinase 2,c-Jun N-terminal kinase(JNK)kinase 2,and JNK1 results in efficient and specific JNK1 activation.Mol.Cell.Biol,2000, 20(7):2334-2342
23. Garrington TP,Ishizuka T,Papst PJ,et al.MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells.EMBO J,2000, 19(20):5387-5395
24. Girardin SE,Yaniv M.A direct interaction between JNK1 and CrkII is critical for Rac 1-induced JNK activation .EMBO J 2001 20(13):3437-46.
25. Leonardi A,Ellinger-Ziegel bauer H,Frazoso G,et al. Physical and function interaction of filamin(actin-binding protein-280)and tumor necrosis factor receptor-associated factor 2.J Biol Chem,2000, 275(1)::271-278
26. Mc Donald PH,Chow CW,Miller WE,et al.Beta–arrestin:a receptor-regulated MAPK scaffold for the activation of JNK3 Science. 2000 290(5496):1574-1577.
27. Yasuda J,Whitmarsh A.J,Cavanagh J,et al.The JIP group of mitogen-activated protein kinase scaffold proteins.Mol.Cell.Biol, 1999 19(10):7245-7254.
28. Tanous T,Yamamoto T,Maeda R.A Novel MAPK phosphatase MKP-7 acts prederntially on JNK/SAPK and p38 alpha and beta MAPKs J Biol Chem,2001, 276(28):26629-26639
29.张宇虹,唐建武,王绍清,等.磷酸化JNK在小鼠腹水型肝癌高、低淋巴道转移株中表达的研究,中国实验诊断学2008,11(12)1347-1349
30. Ryoko O, Junji M, Tomoki Y, et al. M-RIP, a novel target of JNK signaling and a requirement for human cancer cell invasion. Int J Mol Med,2008,22(2):199-203.
31. Ching YP, Leong VY, Lee MF, et al. P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation.Cancer Res, 2007,67(8):3601-3608.
32. Huang Z, Yan DP, Ge BX. JNK regulates cell migration through promotion of tyrosine phosphorylation of paxillin. Cell Signal,2008,20(11):2002-2012.
2. Barr RK, Bogoyevitch MA. The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). Int J Biochem Cell Biol. 2001,33(11):1047-63.
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4. Widmann C, Gibson S, Jarpe MB, et al Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999,79(1):143-180.
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7. He T, Stepulak A, Holmstr?m TH, et al .The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. J Biol Chem.2002,29;277(13): 10767-10774.
8. Xu Z, Kukekov NV, Greene LA. POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 2003 15;22(2):252-261.
9. Sung A.Lee ,MiraJung The Nucleoside Sangivamycin In duces Apoptotic cell Death in Breast Carcinoma MCF7/Adriamycin-resistant cells Via Proteinkinase C and JNK Activation .Biol Chem,2007,282(20)15271-15283.
10. BO Liu,jia-fa Wu,yan-yan.zhan.et al.egulation of the orPhan Receptor TR3 Naclear Functionsby(-)un N Tenminal Kinase phosph orylation .Endocrinoloay,2007,148(1):34-44
11. Adachi-Yamada T, O’Connor MB. Morphogenetic apoptosis:a mechanism for correcting discontinuities in morphogen gradients. Dev Biol, 2002, 251(1): 74-90.
12. Uehara T, Bennett B, Sakata ST, et al. JNK mediates hepatic ischemia reperfusion injury, J Hepatol.2005, 42(6): 850-859
13. Kaiser RA, Liang Q, Bueno O, et al. Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemiareperfusion-induced cell death in vivo, J Biol Chem,2005,280 (38): 32602-32608
14. Johnson GL, Nakamura K. The c-jun kinase/stress-activated pathway: regulation, function and role in human disease, Biochim Biophys Acta-Mol Cell Res, 2007, 1773(8): 1341-1348
15. Carboni S, Antonsson B, Gaillard P, et al. Control of death receptor and mitochon drial- dependent apoptosis by c-Jun Nterminal kinase in hippocampal CA1 neurones following global transient ischaemia, J Neurochem, 2005, 92(5):1054-1060
16. Pan J, Zhao YX, Wang ZQ, et al. Expression of FasL and its interaction with Fas are mediated by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced rat model of Parkinso- ndisease, Neurosci Lett, 2007, 428(2-3): 82-87
17. Hunot S, Vila M, Teismann P, et al. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson’s disease, Proc Natl Acad Sci USA, 2004, 101(2): 665-670
18. Manning AM, Davis RJ. Targeting JNK for therapeutic benefit:from junk to gold?, Nat Rev Drug Discov, 2003, 2(7): 554-565
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20. Morishima Y, Gotoh Y, Zieg J, et al. Beta -amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun Nterminal kinase pathway and the induction of Fas ligand, J Neurosci, 2001, 21(19): 7551-7560
21. Yao M, Nguyen TV, Pike CJ. Beta -amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w, J Neurosci, 2005, 25(5): 1149-1158
22. Resnick L, Fennell M. Targeting JNK3 for the treatment of neurodegenerative disorders, Drug Discov Today, 2004, 9(21):932-939
23. Behrens A , Jochum W, Sibilia M ,et al. Oncogenic transformation by ras and fos I mediated by c-Jun N-terminal phosphorylation.Oncogene, 2000,19(22) : 2657- 2663.
24. She QB, Chen N, Bode AM, et al Deficiency of c-Jun-NH2-terminal kinase - 1 in mice enha- nces skin tumor developmentby 12-O- tetradecanoylphorbol-13- ace- tate CancerRes, 2002,62:1343–13481
25.郭连英.JNK/SAPK信号传导通路在榄香烯抗肝癌效应中的作用中国肿瘤生物学杂志, 2005,12(3):205-209
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29. Luedde T, Beraza N, Kotsikoris V, et al. Deletion of NEMO/IKKgamma in liver arenchy malcells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell, 2007; 11(2): 119–132.
30. Maeda S, Kamata H, Luo JL, et al. IKKbeta couples hepatocyte death to cytokine- driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell, 2005, 121(7): 977-990.
31.蒋明德.JNK信号通路在乙醛刺激的肝星状细胞凋亡中的作用第四军医大学学报,2005, 26(10):915-918.
32肖浩文.氨基末端激酶信号通路在细胞凋亡中的作用中国公共卫生.2005,01:13-171.
33 Guo L, Guo Y, Xiao S, et al. Protein kinase p-JNK is correlated with the active- tion of AP-1 and its associated Jun family proteins in hepatocellular carcinoma. Life Sci, 2005,77(15): 1869-1878.
34 Li JH, Zatloukal K, Scheuch H, et al. Proliferation of human HCC cells and chemi-cally induc- ed mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest, 2008,118(12),3943-3953.
35 Chang QS, Zhang YD, Beezhold KJ, et al. Sustained JNK1 activation is associated with alter- ed histone H3 methylations in human liver cancer. J Hepatol,2009,50(2):323-333.
36 Lee H J, Wang C J, Kuo H C, et al. Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicol Appl Ph- armacol, 2005, 203(2):124-131.
37 Suzuki T, Tsukamoto I. Manganese-induced apoptosis in hepatocytes after partial hepatictomy. Eur J Pharmaco1,2005,525(1-3):48-53.
38 Syuichi M, Keiji S, Mitsutoshi N, et al. Bcl-2 phosphorylation has pathological significance in human breast cancer.Pathobiology, 2006,73(4):205–212
39 Ryoko O, Junji M, Tomoki Y, et al. M-RIP, a novel target of JNK signaling and a requirement for human cancer cell invasion. Int J Mol Med, 2008,22(2):199-203.
40 Ching YP, Leong VY, Lee MF, et al. P21-activated protein kinase is overexpressed in hepato cellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase active tion and paxillin phosphorylation. Cancer Res, 2007,67(8):3601-3608.
41 Huang Z, Yan DP, Ge BX. JNK regulates cell migration through promotion of tyrosine phos phorylation of paxillin. Cell Signal, 2008 , 20(11):2002-2012.
42 Hibi M, Lin A, Smeal T, et al. Identification of an oncoproteinand UV-responsive protein kinase that binds and potentiates the c-Jun activation domain, Genes Dev,1993,7(11):2135-2148
43 Weston CR, Davis RJ. The JNK signal transduction pathway,Curr Opin Cell Biol, 2007,19(2): 142-149
44 Waetzig V, Herdegen T. Context-specific inhibition of JNKs:over coming the dilemma of prote cttion and damage,Trends Pharmacol Sci, 2005, 26(9): 455-461
1. Erkma G, Gerasimov G, Troshina, et al. Deregulated alternative spli-cing of CD44 mRNA transcrip ts in neop lastic and nonneop lastic le-sion of the human thyroid. Cancer Res , 1995, 55 (20) : 4594-4598.
2.辛彦,赵凤凯,张素敏,等. CD44V6基因编码蛋白表达与胃癌转移和预后的关系.世界华人消化杂志, 1999, 7 (3) : 210-214.
3. Yamaguchi A, Goi T, Seki K, et al. Clinical significance of com-bined imm unohistochem ical detection of CD44v6 and sialyl Lex ex-p ression for colorectal cancer patients undergoing curative resection. Oncol, 1998, 55 (5) : 400-403.
4. Christopher J, Amil K. CD44 isoform expression in primary and meta-static pancreatic adenocarcinoma. Cancer Res, 1995, 55 (9) : 1831-1836.
5. Matsumura Y,Tarin D. Signifieance of CD44 gene produets for eancer Diagnosis and disease evaluation. Lancet.1992,340(8827):1053-1058.
6. Kaufmann M,Heider KH,Sinn HP,et al.CD44 varia ntexon epitopes inprimary breast cancer and length of survival. Lancet.1995,345(8950):615-619.
7. WielengaVJ,HeiderKH,OfferhausGJ,et al. Expression of CD44 variant proteins in human colorectal cancer is related totumor progression.CancerRes.1993 53(20):4754-4756.
8. SaitoH,Tsujitani S,KatanoK,et al.Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric careinoma.Cancer,1998,83(6):1094-1101.
9. Lida N,Bourguign on L Y.Coexpression of CD44 varian(C10ex14)standard and isoform in breast cancer .J Cell Physiol,1997,171(2):152-160.
10. Lida N,bourguignon LY.Coexpression of CD44 varian standard and isofom in breast cancer .J Cell Physiol,1997,171(2):1152-160.
11.王玉珍,梁志清,血管内皮因子-C与恶性肿瘤的淋巴管及淋巴结转移关系研究进展[J].肿瘤防治杂志,2004,11(11):1217-1219.
12. NagamineM,OkUmuraT,TannoS,et al.PPAR-gamma ligand in duced aPoPtosis through a P532dePendent mecanism in humangastric .canercells.CancerSci,2003,94(4):338343.
13. Vidal S,Khush RS,Leulier F,et al.Mutations in the Drosophila dTAK1 gene reveal a conserved function forMAPKKKs in the control of rel/NF-kappaB-dependent innate immune respo nses.Genes Dev,2001, 15(15): 1900-1912
14. Catherine D,Carolyn W,Ann M,et al.Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor . Cellular Signalling,2002, 14(7):585-593
15. Xia Y,Karin M.The control of cell motility and epithelial morphogenesis by Jun kinases.Trends Cell Biol,2004,14:94-101
16.张文伶,金勇丰,朱成钢,等.JNK/MAPK途径调控机制研究进展.癌变·畸变·突变,2003,15(4):253-256
17. Buschmann T,Potapova O,BarShira A,et al.JunNH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.Mol.Cell.Biol,2001, 21(8): 2743-2754
18. Fuchs SY,Adler V,Buschmann T, et al.JNK targets p53 ubiquitination and degradation in non-stressed cells .Gene Dev,1998,12(17):2658-2663
19. Tournier C,Hess P,Yang DD,et al.Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway .Science,2000, 288(5467): 870-874
20. Noguchi K,Kitanaka C,Yamana H,et al.Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-termjinal kinase .J boil Chem,1999, 274(46): 32580-32587
21. Dania AV,Ze’ev R.c-Jun-NH2 Kinase(JNK) Contributes to the Regulation of c-Myc Protein Stability.J boil Chem,2004, 279(6):5008-5016
22. Cheng J,Yang J,Xia Y,et al.Synergistic interaction of MEK kinase 2,c-Jun N-terminal kinase(JNK)kinase 2,and JNK1 results in efficient and specific JNK1 activation.Mol.Cell.Biol,2000, 20(7):2334-2342
23. Garrington TP,Ishizuka T,Papst PJ,et al.MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells.EMBO J,2000, 19(20):5387-5395
24. Girardin SE,Yaniv M.A direct interaction between JNK1 and CrkII is critical for Rac 1-induced JNK activation .EMBO J 2001 20(13):3437-46.
25. Leonardi A,Ellinger-Ziegel bauer H,Frazoso G,et al. Physical and function interaction of filamin(actin-binding protein-280)and tumor necrosis factor receptor-associated factor 2.J Biol Chem,2000, 275(1)::271-278
26. Mc Donald PH,Chow CW,Miller WE,et al.Beta–arrestin:a receptor-regulated MAPK scaffold for the activation of JNK3 Science. 2000 290(5496):1574-1577.
27. Yasuda J,Whitmarsh A.J,Cavanagh J,et al.The JIP group of mitogen-activated protein kinase scaffold proteins.Mol.Cell.Biol, 1999 19(10):7245-7254.
28. Tanous T,Yamamoto T,Maeda R.A Novel MAPK phosphatase MKP-7 acts prederntially on JNK/SAPK and p38 alpha and beta MAPKs J Biol Chem,2001, 276(28):26629-26639
29.张宇虹,唐建武,王绍清,等.磷酸化JNK在小鼠腹水型肝癌高、低淋巴道转移株中表达的研究,中国实验诊断学2008,11(12)1347-1349
30. Ryoko O, Junji M, Tomoki Y, et al. M-RIP, a novel target of JNK signaling and a requirement for human cancer cell invasion. Int J Mol Med,2008,22(2):199-203.
31. Ching YP, Leong VY, Lee MF, et al. P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation.Cancer Res, 2007,67(8):3601-3608.
32. Huang Z, Yan DP, Ge BX. JNK regulates cell migration through promotion of tyrosine phosphorylation of paxillin. Cell Signal,2008,20(11):2002-2012.