GRIM-19、STAT3及Survivin在人喉鳞状细胞癌中的表达及其临床意义
摘要
为了探讨GRIM-19、STAT3及Survivin基因在喉癌的发生、发展及转移中所起的作用,并分析此过程可能的分子机制,本研究利用免疫组织化学方法检测人喉鳞状细胞癌组织中GRIM-19、STAT3及Survivin的表达和三者之间的相关联性,结果发现：1.GRIM-19、STAT3及Survivin的阳性表达均主要位于胞浆,在喉癌组织中,GRIM-19、STAT3及Survivin的阳性表达率与在三者正常粘膜的阳性表达率的差别有显著性。2.GRIM-19、STAT3及Survivin在喉鳞状细胞癌中的表达与性别、肿瘤生长部位无关；与病理分级、有无淋巴结转移有关。3.GRIM-19与STAT3基因在喉鳞状细胞癌中的表达呈负相关,而STAT3与Survivin基因、GRIM-19与Survivin在喉鳞状细胞癌中的表达无相关联性。
因此,对GRIM-19、STAT3及Survivin的检测可能在喉癌的早期诊断及预后预测中起到一定辅助作用,也为研究喉癌的发生发展提供新的指标,并为喉癌的基因治疗提供新的理论支持。
Background:Laryngeal cancer is a common head and neck malignant tumor. laryngeal carcinoma-related factors including Smoking, alcohol consumption, air pollution, viral infection etc significantly increase with the improvement of people's living standards and change of lifestyle, this result in a clear growth trend on incidence of laryngeal cancer at the present. Surgery-based comprehensive treatment option is current mainly treatment principles of laryngeal cancer, however, there are still some patients who appear postoperative recurrence and metastasis. Therefore, the mechanism study concerning laryngeal carcinoma growth, invasion and metastasis is of significantly important.
GRIM-19, as a member of the GRIMs family, is located in 19p13.2, in this area a variety of genes have been proved to be cancer suppressor gene. As a regulator of cell death, GRIM-19 also participates in many kinds of ways-induced tumor cells apoptosis. In addition, GRIM-19 also has the negative effects on the expression its downstream gene__STAT3 (Signal transducers and activators of transcription3, STAT3),it can drop its transcriptional activation down and inhibit the cell expression and cell growth.
Signal transducer and activator transcription factor (STATS) is a series of important transcription factor involved in tyrosine phosphorylation signaling pathway coupling, which mainly participate in cytokine and growth factor mediated signal transduction. As a member of the STATS family, abnormal regulation of STATS is closely related to tumor development. Recently research officers use negative regulatory protein and RNAi to restrain STAT3 and its signal transduction pathway in order to interfere the tumor.
In addition, Inhibitor of apoptosis protein (IAP) family discovered recently is an important apoptosis inhibitor. Survivin gene, as a new member of IAP family, its expression product is a kind of cytoplasmic protein, which exists in a wide range of almost all malignant tumor organizations. Moreover, Survivin expression is cell cycle-dependent, with no expression or low expression in the G2 phase, and high expression in the G2/M phase, so Survivin proteine is closely linked with cell proliferation.
Methods:We detected STAT3, Survivin and GRIM-19 gene from 40 cases (30 cases were confirmed to laryngeal squamous cell carcinoma and 10 cases were confirmed to normal laryngeal mucosa tissues after surgery) by using of immunohistochemical methods.
Results and Conclusions:The results showed that STAT3, Survivin and GRIM-19 gene expression sites were mainly located in the cytoplasm, and low expression of GRIM-19, high expression of STAT3 and Survivin was closely related to the occurrence of laryngeal squamous cell carcinoma.
In addition, this study also showed expression of GRIM-19, STAT3 and Survivin gene in laryngeal carcinoma cells, based on their clinical parameters The results showed:(1) The expression rate of GRIM-19, STAT3 and Survivin protein in the laryngeal carcinoma. It's not related to the gender and the location of the tumor.(2) The low expression rate of GRIM-19, the high expression rate of STAT3 and Survivin protein in the laryngeal carcinoma is related to the pathological grading and the diversion of the lymphoma clericals. The grade malignancy of the laryngeal carcinoma is different so that the expression of GRIM-19STAT3 and Survivin is different. The higher the grade malignancy is, the lower the expression rate of GRIM-19 is, and the expression of STAT3 and Survivin is the opposite. The lower expression rate of GRIM-19, the higher expression rate of STAT3 and Survivin protein in the laryngeal carcinoma, is related to the grade malignancy of the laryngeal carcinoma. The expression rate of GRIM-19 in the laryngeal squamous cell carcinoma accompanied with cervical lymph node metastasis is lower than the one which is not accompanied with cervical lymph node metastasis. The expression rate of STAT3 and Survivin in the laryngeal squamous cell carcinoma accompanied with cervical lymph node metastasis is higher than the one which is not accompanied with cervical lymph node metastasis. In sum, the decreased expression of GRIM-19 and the increased expression of STAT3 and Survivin have a close relationship with the invasion of laryngeal cancer. This study also suggests, GRIM-19 and STAT3 in laryngeal squamous cell carcinoma was negatively correlated.
Our study revealed the expression of GRIM-19, STAT3 and Survivin in laryngeal carcinoma and the correlation of them. The detection of the above genes may contribute to early diagnosis and prognosis of laryngeal forecast and it will play a supporting role on the diagnosis and treatment of laryngeal cancer. Our study might provide a new basis for early diagnosis and prognosis evaluation of laryngeal carcinoma, and also provides a new path for the treatment of laryngeal carcinoma.
因此,对GRIM-19、STAT3及Survivin的检测可能在喉癌的早期诊断及预后预测中起到一定辅助作用,也为研究喉癌的发生发展提供新的指标,并为喉癌的基因治疗提供新的理论支持。
Background:Laryngeal cancer is a common head and neck malignant tumor. laryngeal carcinoma-related factors including Smoking, alcohol consumption, air pollution, viral infection etc significantly increase with the improvement of people's living standards and change of lifestyle, this result in a clear growth trend on incidence of laryngeal cancer at the present. Surgery-based comprehensive treatment option is current mainly treatment principles of laryngeal cancer, however, there are still some patients who appear postoperative recurrence and metastasis. Therefore, the mechanism study concerning laryngeal carcinoma growth, invasion and metastasis is of significantly important.
GRIM-19, as a member of the GRIMs family, is located in 19p13.2, in this area a variety of genes have been proved to be cancer suppressor gene. As a regulator of cell death, GRIM-19 also participates in many kinds of ways-induced tumor cells apoptosis. In addition, GRIM-19 also has the negative effects on the expression its downstream gene__STAT3 (Signal transducers and activators of transcription3, STAT3),it can drop its transcriptional activation down and inhibit the cell expression and cell growth.
Signal transducer and activator transcription factor (STATS) is a series of important transcription factor involved in tyrosine phosphorylation signaling pathway coupling, which mainly participate in cytokine and growth factor mediated signal transduction. As a member of the STATS family, abnormal regulation of STATS is closely related to tumor development. Recently research officers use negative regulatory protein and RNAi to restrain STAT3 and its signal transduction pathway in order to interfere the tumor.
In addition, Inhibitor of apoptosis protein (IAP) family discovered recently is an important apoptosis inhibitor. Survivin gene, as a new member of IAP family, its expression product is a kind of cytoplasmic protein, which exists in a wide range of almost all malignant tumor organizations. Moreover, Survivin expression is cell cycle-dependent, with no expression or low expression in the G2 phase, and high expression in the G2/M phase, so Survivin proteine is closely linked with cell proliferation.
Methods:We detected STAT3, Survivin and GRIM-19 gene from 40 cases (30 cases were confirmed to laryngeal squamous cell carcinoma and 10 cases were confirmed to normal laryngeal mucosa tissues after surgery) by using of immunohistochemical methods.
Results and Conclusions:The results showed that STAT3, Survivin and GRIM-19 gene expression sites were mainly located in the cytoplasm, and low expression of GRIM-19, high expression of STAT3 and Survivin was closely related to the occurrence of laryngeal squamous cell carcinoma.
In addition, this study also showed expression of GRIM-19, STAT3 and Survivin gene in laryngeal carcinoma cells, based on their clinical parameters The results showed:(1) The expression rate of GRIM-19, STAT3 and Survivin protein in the laryngeal carcinoma. It's not related to the gender and the location of the tumor.(2) The low expression rate of GRIM-19, the high expression rate of STAT3 and Survivin protein in the laryngeal carcinoma is related to the pathological grading and the diversion of the lymphoma clericals. The grade malignancy of the laryngeal carcinoma is different so that the expression of GRIM-19STAT3 and Survivin is different. The higher the grade malignancy is, the lower the expression rate of GRIM-19 is, and the expression of STAT3 and Survivin is the opposite. The lower expression rate of GRIM-19, the higher expression rate of STAT3 and Survivin protein in the laryngeal carcinoma, is related to the grade malignancy of the laryngeal carcinoma. The expression rate of GRIM-19 in the laryngeal squamous cell carcinoma accompanied with cervical lymph node metastasis is lower than the one which is not accompanied with cervical lymph node metastasis. The expression rate of STAT3 and Survivin in the laryngeal squamous cell carcinoma accompanied with cervical lymph node metastasis is higher than the one which is not accompanied with cervical lymph node metastasis. In sum, the decreased expression of GRIM-19 and the increased expression of STAT3 and Survivin have a close relationship with the invasion of laryngeal cancer. This study also suggests, GRIM-19 and STAT3 in laryngeal squamous cell carcinoma was negatively correlated.
Our study revealed the expression of GRIM-19, STAT3 and Survivin in laryngeal carcinoma and the correlation of them. The detection of the above genes may contribute to early diagnosis and prognosis of laryngeal forecast and it will play a supporting role on the diagnosis and treatment of laryngeal cancer. Our study might provide a new basis for early diagnosis and prognosis evaluation of laryngeal carcinoma, and also provides a new path for the treatment of laryngeal carcinoma.
引文
[1]KALVAKOLANU D V. The GRIMS a new interface between cell death regulation and interferon/retinoid induced growth suppression [J].Cytokine Growth Factor Rev,2004,15(2-3):169-194.
[2]CHIDAMBARAM N V, ANGELL JE, LINGW, et al. Chromosomal localization ofhumanGRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death [J].J Interferon Cytokine,2000,20(7):661-665.
[3]Huang G, Lu H, Ha A, et al.GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Mol Cell Biol. 2004;24(19):8447-56.
[4]Bromberg J F, W Resecynska M H, et al. Stat3 as an oncogene [J].Cell 1999,98(3):295-303.
[6]Bowman T, Garcia R, Turkson J, et al. STATS as an oncogenes[J]. Oncogene,2000,19(21):2474-88.
[7]Mora L B, Buettner R, Sign J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines:direct inhibition ofStat3 signaling induces apoptosis of prostate cancer cell [J]. Cancer Research,2002,62(22):6659-6
[8]Ni Z, Lou W, Leman E S, et al. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cell [J].Cancer,2000, 60(5):1225-8.
[9]Yuan ZL, Guan YJ, Chatte D, et al. Stat3's dimidiation regulated by reversible acetylating of a single lysine residue[J].Science,2005,307 (5707): 269-273.
[10]G. Ambrosini, C Adida, DC Altieri. A novel ant apoptosis gene, SURVIVIN, expressed in cancer and lymphoma. Nat Med,1997,30:917～921
[11]明学志,综述.SURVIVIN与肿瘤.国外医学肿瘤学分册,1999,26(4)：201-202
[12]C Addax, D Barresi, M Peuchmaur et al.ant apoptosis gene, SURVIVIN, and prognosis Of neuroblastoma. The Lancet,1998,351(9106): 882-883
[13]HUANG G, LUH, HAO A, et al. GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I [J].MolCellBio,12004,24(19):8447-8456.
[14]Gritsko T, Williams A, Turkson J, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells[J].Clin Cancer Res,2006,12(1):11-19.
[15]Linda B Mora, Ralf Buettmer,John Siege et al Constitutive activation of stat3 in human prostate tumors and cell lines. Cancer Research 2002 November 62(15):6659-6666.
[16]ZHANG J,KALAKONDA S, NALLAR S C, GONG P, et al. Tumor suppressive protein gene associated with retinoid-interferon-induced mortality (GRIM)-19 inhibits src-induced oncogenic transformation a multiple levels[J].Am J Patho,1 2007,171(4):1352-1368.
[17]Yang JB,Mao ZF, Cai XD. Expression and significance of STAT3 in esophageal squalors cell carcinoma. Journal of Digestive Surgery,2006,5(3):220-222.
[18]Gritsko T, Williams A, Turkson J, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells [J].Clin Cancer Res,2006,12(1):11-19.
[19]ZHANG J, YANG J, ROY S K, et al. The cell death regular to GRIM-19 is an inhibitor of signal transducer and activator of transcription 3[J]. Proc Natl Acad SCI USA,2003,100(16):9342-9347.
[20]KALAKONDA S, NALLAR S C, LINDNER D J, et al.Tumor-suppressive activity of the cell death activatorGRIM-19 on a constitutively active signal transducer and activator of transcription [J].Cancer Res,2007,67(13): 6212-6220.
[21]Aoki Y, Feldman GM, Tosato G, et al. Inhibition of STAT3 signaling induces apoptosis and decreases surviving expression in primary effusion lymphoma[J].Blood,2003,101(4):1535-1542.
[22]Kanda N, Seno H, Konda Y, et al.STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells[J].Oncogene,2004,23(28):4921-4929.
[1]KALVAKOLANU D V. The GRIMs:a new interface between cell death regulation and interferon/retinoid induced growth suppression [J].Cytokine Growth Factor Rev,2004,15(2-3):169-194.
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[2]CHIDAMBARAM N V, ANGELL JE, LINGW, et al. Chromosomal localization ofhumanGRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death [J].J Interferon Cytokine,2000,20(7):661-665.
[3]Huang G, Lu H, Ha A, et al.GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Mol Cell Biol. 2004;24(19):8447-56.
[4]Bromberg J F, W Resecynska M H, et al. Stat3 as an oncogene [J].Cell 1999,98(3):295-303.
[6]Bowman T, Garcia R, Turkson J, et al. STATS as an oncogenes[J]. Oncogene,2000,19(21):2474-88.
[7]Mora L B, Buettner R, Sign J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines:direct inhibition ofStat3 signaling induces apoptosis of prostate cancer cell [J]. Cancer Research,2002,62(22):6659-6
[8]Ni Z, Lou W, Leman E S, et al. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cell [J].Cancer,2000, 60(5):1225-8.
[9]Yuan ZL, Guan YJ, Chatte D, et al. Stat3's dimidiation regulated by reversible acetylating of a single lysine residue[J].Science,2005,307 (5707): 269-273.
[10]G. Ambrosini, C Adida, DC Altieri. A novel ant apoptosis gene, SURVIVIN, expressed in cancer and lymphoma. Nat Med,1997,30:917～921
[11]明学志,综述.SURVIVIN与肿瘤.国外医学肿瘤学分册,1999,26(4)：201-202
[12]C Addax, D Barresi, M Peuchmaur et al.ant apoptosis gene, SURVIVIN, and prognosis Of neuroblastoma. The Lancet,1998,351(9106): 882-883
[13]HUANG G, LUH, HAO A, et al. GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I [J].MolCellBio,12004,24(19):8447-8456.
[14]Gritsko T, Williams A, Turkson J, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells[J].Clin Cancer Res,2006,12(1):11-19.
[15]Linda B Mora, Ralf Buettmer,John Siege et al Constitutive activation of stat3 in human prostate tumors and cell lines. Cancer Research 2002 November 62(15):6659-6666.
[16]ZHANG J,KALAKONDA S, NALLAR S C, GONG P, et al. Tumor suppressive protein gene associated with retinoid-interferon-induced mortality (GRIM)-19 inhibits src-induced oncogenic transformation a multiple levels[J].Am J Patho,1 2007,171(4):1352-1368.
[17]Yang JB,Mao ZF, Cai XD. Expression and significance of STAT3 in esophageal squalors cell carcinoma. Journal of Digestive Surgery,2006,5(3):220-222.
[18]Gritsko T, Williams A, Turkson J, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells [J].Clin Cancer Res,2006,12(1):11-19.
[19]ZHANG J, YANG J, ROY S K, et al. The cell death regular to GRIM-19 is an inhibitor of signal transducer and activator of transcription 3[J]. Proc Natl Acad SCI USA,2003,100(16):9342-9347.
[20]KALAKONDA S, NALLAR S C, LINDNER D J, et al.Tumor-suppressive activity of the cell death activatorGRIM-19 on a constitutively active signal transducer and activator of transcription [J].Cancer Res,2007,67(13): 6212-6220.
[21]Aoki Y, Feldman GM, Tosato G, et al. Inhibition of STAT3 signaling induces apoptosis and decreases surviving expression in primary effusion lymphoma[J].Blood,2003,101(4):1535-1542.
[22]Kanda N, Seno H, Konda Y, et al.STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells[J].Oncogene,2004,23(28):4921-4929.
[1]KALVAKOLANU D V. The GRIMs:a new interface between cell death regulation and interferon/retinoid induced growth suppression [J].Cytokine Growth Factor Rev,2004,15(2-3):169-194.
[2]Gali-Muhtasib H, Bakkar N. Modulating cell cycle:current applications and prospects for future drug development [J]. Cure Cancer Drug Targets,2002, 2(4):309-36.
[3]Angel J E, Lindner D J, Shapiro P S, et al. Identification of GRIM-19, a novel cell death regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach [J]. J Brioche,2000,275 (43):33416-26.
[4]HUANG G, LUH, HAO A, et al.GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I[J]-MolCellBio, 12004,24(19):8447-8456.
[5]Ma X, Kalakonda S, Srinivasula SM, et al. GRIM-19 associates with the serine rot ease HtrA2 for emoting cell death. Oncogene.2007; 26(33):4842-9.
[6]CAO R, TSUKADAY, ZHANG Y Role of Bmi21 and Ringl A in H2A ubiquitylation and Hox gene silencing[J].Mol Cell 2005,20:845-854
[7]SHIX, HONG T, WALTER K L, et al.ING2 PHD domain links histoneH3 lysine 4 methylation to active gene repression [J].Nature,2006,442:96-99
[8]BRINKMAN A B, ROELOFSEN T, PENNINGSW S, et al. His tone modification patterns associated with the human X chromosome [J].EMBO Rep, 7:628-634.
[9]Zhang W, Hung Q, Yang Z et al. GW112, a novel antirational rote in that remotes tumor growth. Cancer Res.2004; 64:2474
[10]Bromberg JFS, Wrzeszczyns MHI, Devgan G, et al. Stat3 as an oncogene. Cell 1999; 98:295-303
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