Correlation of Gli1 expression with clinical characteristics and prognosis of liver cancer: a Meta-analysis_West China Medical Journal

Authors：

YANG Yashan ¹ ,  XIE Gang ² , TONG Yao ³

1. Institute of Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Department of Oncology, Sichuan Integrative Medicine Hospital, Chengdu, Sichuan 610041, P. R. China;
3. Department of Sports Medicine, Chengdu Sport Institute, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

XIE Gang, Email: xiegang0920@163.com

Keywords：

Gli1; Liver cancer; Clinical characteristics; Prognosis; Meta-analysis

DOI：

10.7507/1002-0179.201702109

Video：

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Objective To explore the correlation of Gli1 expression with clinical characteristics and prognosis of liver cancer. Methods Such Databases as PubMed, Embase, CNKI, Wanfang Database and Chinese Biomedical Literature Database were searched to collect cohort studies, which has published on the correlation between the expression of Gli1 and the clinical pathologic features of liver cancer and its prognostic value from the establishment of the databases to December 2016. Results Twelve studies with a total of 831 patients were included in this study. The high expression of Gli1 was associated with the tumor diameter >5 cm [relative risk (RR)=1.39, 95% confidence interval (CI) (1.08, 1.79)], clinical stage [RR=1.26, 95%CI (1.05, 1.51)], intrahepatic metastasis [RR=1.39, 95%CI (1.06, 1.83)] and venous invasion [RR=1.44, 95%CI (1.01, 2.04)], but the correlation of Gli1 expression was not significant with gender, histological differentiation, tumor diameter >3 cm, hepatitis B virus, cirrhosis and alpha fetoprotein. Meanwhile, the results of Meta-analysis showed that the higher Gli1 expression in liver cancer patients had a worse 3-/5-year overall survival rate and overall survival rate than those of the lower Gli1 expression group [3-year, RR=3.38, 95%CI (2.01, 5.67); 5-year, RR=1.51, 95%CI (1.19, 1.91); overall survival, RR=1.60, 95%CI (1.11, 2.30)]. And the higher Gli1 expression in liver cancer patients had a worse disease free survival rate than that in the lower Gli1 expression group [RR=1.89, 95%CI (1.35, 2.66)]. Conclusion The high expression of Gli1 is associated with poor prognostic outcome in liver cancer, and may be used as an important prognostic marker for patients with liver cancer.

Citation： YANG Yashan, XIE Gang, TONG Yao. Correlation of Gli1 expression with clinical characteristics and prognosis of liver cancer: a Meta-analysis. West China Medical Journal, 2017, 32(8): 1179-1186. doi: 10.7507/1002-0179.201702109 Copy

1.	Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55(2): 74-108.
2.	Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev, 2004, 5(2): 118-125.
3.	Bosch FX, Ribes J, Díaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology, 2004, 127(5 Suppl 1): S5-S16.
4.	Zheng X, Gai XH, Han SS, et al. The human sulfatase 2 inhibitor 2, 4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer, 2013, 52(3): 225-236.
5.	Yang J, Zeng Z, Peng YY, et al. IL-7 splicing variant IL-7δ5 induces EMT and metastasis of human breast cancer cell lines MCF-7 and BT-20 through activation of PI3K/Akt pathway. Histochem Cell Biol, 2014, 142(4): 401-410.
6.	Li RH, Liu J, Wu H, et al. TIKI2 suppresses growth of osteosarcoma by targeting Wnt/beta-catenin pathway. Mol Cell Biochem, 2014, 392(1/2): 109-116.
7.	Yue D, Li H, Che JJ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res, 2014, 33: 34.
8.	Mori M, Triboulet R, Mohseni M, et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell, 2014, 156(5): 893-906.
9.	Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature, 2004, 432: 324-331.
10.	Lee SJ, Do IG, Lee J, et al. Gastric cancer (GC) patients with hedgehog pathway activation: PTCH1 and GLI2 as independent prognostic factors. Target Oncol, 2013, 8(4): 271-280.
11.	Samadani AA, Akhavan-Niaki H. Nteraction of sonic hedgehog (SHH) pathway with cancer stem cell genes in gastric cancer. Medical Oncol, 2015, 32(3): 48.
12.	Marechal R, Bachet JB, Calomme AA, et al. Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res, 2015, 21(5): 1215-1224.
13.	Khan S, Ebeling MC, Chauhan N, et al. Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res, 2015, 75(11): 2292-2304.
14.	Kim YJ, Bin Park S, Park JY, et al. The sonic hedgehog pathway as a treatment target for extrahepatic biliary tract cancer. Mol Med Rep, 2012, 5(1): 12-16.
15.	Whittaker S, Marais R, Zhu AX, et al. The role of signaling pathways in the development and treatment of human hepatocellular carcinoma. Oncogene, 2010, 29(36): 4989-5005.
16.	Barakat MT, Humke EW, Scott MP. Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer. Trends Mol Med, 2010, 16(8): 337-348.
17.	謝萍, 王茂梅, 熊小亮. 轉錄因子 GLI1 在腫瘤發生與侵襲轉移作用中的機制. 中國腫瘤臨床, 2014, 41(7): 480-483.
18.	Wells G, Shea B, O’connell D, et al. New Castle-Ottawa Quality Assessment Scale--Cohort studies. (2012-06-15)[2017-05-19]. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
19.	倪卓然, 謝坤, 趙紅川, 等. 肝細胞癌組織中 Shh、Gli1、Snail、E-cadherin 表達的臨床研究. 安徽醫科大學學報, 2016, 51(4): 536-541.
20.	Che L, Yuan YH, Jia J, et al. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin J Cancer Res, 2012, 24(4): 323-331.
21.	Chen XL, Cheng QY, She MR, et al. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch Med Res, 2010, 41(5): 315-323.
22.	Chun HW, Hong R. Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma. Oncol Lett, 2016, 12(3): 1753-1762.
23.	Eichenmüller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology, 2009, 49(2): 482-490.
24.	Huang S, He J, Zhang X, et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis, 2006, 27(7): 1334-1340.
25.	Li YC, Deng YH, Guo ZH, et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. Eur J Med Res, 2010, 15(11): 468-474.
26.	Lu JT, Zhao WD, He W, et al. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin, 2012, 33(5): 691-700.
27.	Tang L, Tan YX, Jiang BG, et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin Cancer Res, 2013, 19(8): 2014-2024.
28.	Xu QR, Liu X, Zheng X, et al. The transcriptional activity of Gli1 is negatively regulated by AMPK through Hedgehog partial agonism in hepatocellular carcinoma. Int J Mol Med, 2014, 34(3): 733-741.
29.	Zhang J, Tu K, Yang W, et al. Evaluation of jagged2 and Gli1 expression and their correlation with prognosis in human hepatocellular carcinoma. Mol Med Rep, 2014, 10(2): 749-754.
30.	Zheng X, Vittar NB, Gai XA, et al. The transcription factor GLI1 mediates TGF beta 1 driven EMT in hepatocellular carcinoma via a SNAI1-Dependent mechanism. PLoS One, 2012, 7(11): e49581.
31.	Thiery JP, Acloque H, Huang RY, et al. Epithelial-Mesenchymal transitions in development and disease. Cell, 2009, 139(5): 871-890.
32.	Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol, 2010, 21(2): 212-222.
33.	Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol, 2010, 21(Suppl 7): vii89-vii92.
34.	Zheng X, Yao Y, Xu Q, et al. Evaluation of glioma-associated oncogene 1 expression and its correlation with the expression of sonic hedgehog, E-cadherin and S100a4 in human hepatocellular carcinoma. Mol Med Rep, 2011, 3(6): 965-970.
35.	Merchan P, Bribian A, Sanchez-Camacho CA, et al. Sonic hedgehog promotes the migration and proliferation of optic nerve oligodendrocyte precursors. Mol Cell Neurosci, 2007, 36(3): 355-368.
36.	Deshpande G, Swanhart L, Chiang P, et al. Hedgehog signaling in germ cell migration. Cell, 2001, 106: 759-769.
37.	Vokes S, Yatskievych TA, Heimark RL, et al. Hedgehog signaling is essential for endothelial tube formmion during vasculogenesis. Development, 2004, 131: 4371-4380.

1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55(2): 74-108.
2. Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev, 2004, 5(2): 118-125.
3. Bosch FX, Ribes J, Díaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology, 2004, 127(5 Suppl 1): S5-S16.
4. Zheng X, Gai XH, Han SS, et al. The human sulfatase 2 inhibitor 2, 4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer, 2013, 52(3): 225-236.
5. Yang J, Zeng Z, Peng YY, et al. IL-7 splicing variant IL-7δ5 induces EMT and metastasis of human breast cancer cell lines MCF-7 and BT-20 through activation of PI3K/Akt pathway. Histochem Cell Biol, 2014, 142(4): 401-410.
6. Li RH, Liu J, Wu H, et al. TIKI2 suppresses growth of osteosarcoma by targeting Wnt/beta-catenin pathway. Mol Cell Biochem, 2014, 392(1/2): 109-116.
7. Yue D, Li H, Che JJ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res, 2014, 33: 34.
8. Mori M, Triboulet R, Mohseni M, et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell, 2014, 156(5): 893-906.
9. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature, 2004, 432: 324-331.
10. Lee SJ, Do IG, Lee J, et al. Gastric cancer (GC) patients with hedgehog pathway activation: PTCH1 and GLI2 as independent prognostic factors. Target Oncol, 2013, 8(4): 271-280.
11. Samadani AA, Akhavan-Niaki H. Nteraction of sonic hedgehog (SHH) pathway with cancer stem cell genes in gastric cancer. Medical Oncol, 2015, 32(3): 48.
12. Marechal R, Bachet JB, Calomme AA, et al. Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res, 2015, 21(5): 1215-1224.
13. Khan S, Ebeling MC, Chauhan N, et al. Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res, 2015, 75(11): 2292-2304.
14. Kim YJ, Bin Park S, Park JY, et al. The sonic hedgehog pathway as a treatment target for extrahepatic biliary tract cancer. Mol Med Rep, 2012, 5(1): 12-16.
15. Whittaker S, Marais R, Zhu AX, et al. The role of signaling pathways in the development and treatment of human hepatocellular carcinoma. Oncogene, 2010, 29(36): 4989-5005.
16. Barakat MT, Humke EW, Scott MP. Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer. Trends Mol Med, 2010, 16(8): 337-348.
17. 謝萍, 王茂梅, 熊小亮. 轉錄因子 GLI1 在腫瘤發生與侵襲轉移作用中的機制. 中國腫瘤臨床, 2014, 41(7): 480-483.
18. Wells G, Shea B, O’connell D, et al. New Castle-Ottawa Quality Assessment Scale--Cohort studies. (2012-06-15)[2017-05-19]. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
19. 倪卓然, 謝坤, 趙紅川, 等. 肝細胞癌組織中 Shh、Gli1、Snail、E-cadherin 表達的臨床研究. 安徽醫科大學學報, 2016, 51(4): 536-541.
20. Che L, Yuan YH, Jia J, et al. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin J Cancer Res, 2012, 24(4): 323-331.
21. Chen XL, Cheng QY, She MR, et al. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch Med Res, 2010, 41(5): 315-323.
22. Chun HW, Hong R. Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma. Oncol Lett, 2016, 12(3): 1753-1762.
23. Eichenmüller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology, 2009, 49(2): 482-490.
24. Huang S, He J, Zhang X, et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis, 2006, 27(7): 1334-1340.
25. Li YC, Deng YH, Guo ZH, et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. Eur J Med Res, 2010, 15(11): 468-474.
26. Lu JT, Zhao WD, He W, et al. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin, 2012, 33(5): 691-700.
27. Tang L, Tan YX, Jiang BG, et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin Cancer Res, 2013, 19(8): 2014-2024.
28. Xu QR, Liu X, Zheng X, et al. The transcriptional activity of Gli1 is negatively regulated by AMPK through Hedgehog partial agonism in hepatocellular carcinoma. Int J Mol Med, 2014, 34(3): 733-741.
29. Zhang J, Tu K, Yang W, et al. Evaluation of jagged2 and Gli1 expression and their correlation with prognosis in human hepatocellular carcinoma. Mol Med Rep, 2014, 10(2): 749-754.
30. Zheng X, Vittar NB, Gai XA, et al. The transcription factor GLI1 mediates TGF beta 1 driven EMT in hepatocellular carcinoma via a SNAI1-Dependent mechanism. PLoS One, 2012, 7(11): e49581.
31. Thiery JP, Acloque H, Huang RY, et al. Epithelial-Mesenchymal transitions in development and disease. Cell, 2009, 139(5): 871-890.
32. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol, 2010, 21(2): 212-222.
33. Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol, 2010, 21(Suppl 7): vii89-vii92.
34. Zheng X, Yao Y, Xu Q, et al. Evaluation of glioma-associated oncogene 1 expression and its correlation with the expression of sonic hedgehog, E-cadherin and S100a4 in human hepatocellular carcinoma. Mol Med Rep, 2011, 3(6): 965-970.
35. Merchan P, Bribian A, Sanchez-Camacho CA, et al. Sonic hedgehog promotes the migration and proliferation of optic nerve oligodendrocyte precursors. Mol Cell Neurosci, 2007, 36(3): 355-368.
36. Deshpande G, Swanhart L, Chiang P, et al. Hedgehog signaling in germ cell migration. Cell, 2001, 106: 759-769.
37. Vokes S, Yatskievych TA, Heimark RL, et al. Hedgehog signaling is essential for endothelial tube formmion during vasculogenesis. Development, 2004, 131: 4371-4380.

West China Medical Journal

Correlation of Gli1 expression with clinical characteristics and prognosis of liver cancer: a Meta-analysis

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