Research of The Expression of FOXA2 and Its Relationship with Prognosis in Intrahepatic Cholangiocarcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 LIChuan , SHENJun-yi ,  WENTian-fu

Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China;

Corresponding author：

WENTian-fu, Email: aderwe@163.com

Keywords：

Forkhead box A2; Intrahepatic cholangiocarcinoma; Prognosis

DOI：

10.7507/1007-9424.20160368

Video：

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Objective To investigate the expression of forkhead box A2 (FXOA2) in intrahepatic cholangiocarcinoma (ICC), and to analyze the relationship between expression of FOXA2 and patient's prognosis after liver resection. Methods Data of 85 patients with ICC who underwent liver resection between 2009 and 2013 in our hospital were collected retrospectively. The expression of FOXA2 was examined by immunohistochemical method, and then the relationship between expression of FOXA2 and patient's prognosis/clinical characteristics was expplored. Results Among the 85 patients, low expression of FOXA2 was detected in 50 patients, whereas high expression was observed in 35 patients. More advanced tumor (Ⅲ+Ⅳ staging) was found in patients with low expression of FOXA2 than patients with high expression of FOXA2 (P < 0.050). The median follow-up time was 15-month (3-73 months). During the follow-up period, 65 patients suffered from recurrence, whereas 64 patients died. The multivariate analysis suggested that, postoperative recurrence was associated with low expression of FOXA2, evaluated preoperative CA19-9, and presence of satellite nodes (P < 0.050). Low expression of FOXA2, evaluated preoperative CA19-9, nerves invasion, and presence of satellite nodes were predictive factors for postoperative prognosis (P < 0.050). Conclusion Low expression of FOXA2 was associated with poor prognosis for patients with ICC after liver resection, and FOXA2 may be a prognostic factor for ICC.

Citation： LIChuan, SHENJun-yi, WENTian-fu. Research of The Expression of FOXA2 and Its Relationship with Prognosis in Intrahepatic Cholangiocarcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2016, 23(12): 1450-1454. doi: 10.7507/1007-9424.20160368 Copy

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2.	Cui Y, Jia J. Update on epidemiology of hepatitis B and C in China. J Gastroenterol Hepatol, 2013, 28 Suppl 1:7-10.
3.	Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55(2):74-108.
4.	Nuzzo G, Giuliante F, Ardito F, et al. Intrahepatic cholangiocarci-noma:prognostic factors after liver resection. Updates Surg, 2010, 62(1):11-19.
5.	Cho SY, Park SJ, Kim SH, et al. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol, 2010, 17(7):1823-1830.
6.	Murakami Y, Uemura K, Sudo T, et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol, 2011, 18(3):651-658.
7.	Shimada K, Sano T, Sakamoto Y, et al. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma:a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg, 2007, 31(10):2016-2022.
8.	Nakagohri T, Kinoshita T, Konishi M, et al. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg, 2008, 32(12):2675-2680.
9.	Hashimoto K, Miller CM. Liver transplantation for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci, 2015, 22(2):138-143.
10.	Maganty K, Levi D, Moon J, et al. Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma:outcome after liver transplantation. Dig Dis Sci, 2010, 55(12):3597-3601.
11.	Sapisochin G, de Lope CR, Gastaca M, et al. Intrahepatic cholangio-carcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation:a Spanish matched cohort multi-center study. Ann Surg, 2014, 259(5):944-952.
12.	Yoon YI, Hwang S, Lee YJ, et al. Postresection outcomes of combined hepatocellular carcinoma-cholangiocarcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Gastrointest Surg, 2016, 20(2):411-420.
13.	Lee CS, Friedman JR, Fulmer JT, et al. The initiation of liver development is dependent on Foxa transcription factors. Nature, 2005, 435(744):944-947.
14.	Li Z, Gadue P, Chen K, et al. Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell, 2012, 151(7):1608-1616.
15.	Pristerà A, Lin W, Kaufmann AK, et al. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice. Proc Natl Acad Sci U S A, 2015, 112(35):E4929-E4938.
16.	Wang J, Zhu CP, Hu PF, et al. FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloprotei-nase-9 inhibition. Carcinogenesis, 2014, 35(11):2576-2583.
17.	Perez-Balaguer A, Ortiz-Martínez F, García-Martínez A, et al. FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma. Breast Cancer Res Treat, 2015, 153(2):465-474.
18.	Jang SM, An JH, Kim CH, et al. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. Biochem Biophys Res Commun, 2015, 463(4):961-967.
19.	Vorvis C, Hatziapostolou M, Mahurkar-Joshi S, et al. Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol, 2016, 310(11):G1124-G1137.
20.	Tang Y, Shu G, Yuan X, et al. FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Res, 2011, 21(2):316-326.
21.	Zhang Z, Yang C, Gao W, et al. FOXA2 attenuates the epithelial to mesenchymal transition by regulating the transcription of E-cadherin and ZEB2 in human breast cancer. Cancer Lett, 2015, 361(1):240-250.
22.	Song Y, Washington MK, Crawford HC. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res, 2010, 70(5):2115-2125.
23.	张正良, 孙江利, 白郑海, 等. FOXA2在胃腺癌中的表达降低.细胞与分子免疫学杂志, 2015, 31(5):672-676.
24.	Yoo T, Park SJ, Han SS, et al. Postoperative CA19-9 change is a useful predictor of intrahepatic cholangiocarcinoma survival following liver resection. Dis Markers, 2015, 2015:298985.
25.	Sulpice L, Rayar M, Boucher E, et al. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg, 2012, 99(12):1711-1717.
26.	Kondratyeva LG, Sveshnikova AA, Grankina EV, et al. Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGF beta 1 epithelial-mesen-chymal transition. Dokl Biochem Biophys, 2016, 469(1):257-259.
27.	Smith B, Neff R, Cohn DE, et al. The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role. Gynecol Oncol, 2016, 143(2):398-405.

1. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B:special emphasis on disease progression and prognostic factors. J Hepatol, 2008, 48(2):335-352.
2. Cui Y, Jia J. Update on epidemiology of hepatitis B and C in China. J Gastroenterol Hepatol, 2013, 28 Suppl 1:7-10.
3. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55(2):74-108.
4. Nuzzo G, Giuliante F, Ardito F, et al. Intrahepatic cholangiocarci-noma:prognostic factors after liver resection. Updates Surg, 2010, 62(1):11-19.
5. Cho SY, Park SJ, Kim SH, et al. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol, 2010, 17(7):1823-1830.
6. Murakami Y, Uemura K, Sudo T, et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol, 2011, 18(3):651-658.
7. Shimada K, Sano T, Sakamoto Y, et al. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma:a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg, 2007, 31(10):2016-2022.
8. Nakagohri T, Kinoshita T, Konishi M, et al. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg, 2008, 32(12):2675-2680.
9. Hashimoto K, Miller CM. Liver transplantation for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci, 2015, 22(2):138-143.
10. Maganty K, Levi D, Moon J, et al. Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma:outcome after liver transplantation. Dig Dis Sci, 2010, 55(12):3597-3601.
11. Sapisochin G, de Lope CR, Gastaca M, et al. Intrahepatic cholangio-carcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation:a Spanish matched cohort multi-center study. Ann Surg, 2014, 259(5):944-952.
12. Yoon YI, Hwang S, Lee YJ, et al. Postresection outcomes of combined hepatocellular carcinoma-cholangiocarcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Gastrointest Surg, 2016, 20(2):411-420.
13. Lee CS, Friedman JR, Fulmer JT, et al. The initiation of liver development is dependent on Foxa transcription factors. Nature, 2005, 435(744):944-947.
14. Li Z, Gadue P, Chen K, et al. Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell, 2012, 151(7):1608-1616.
15. Pristerà A, Lin W, Kaufmann AK, et al. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice. Proc Natl Acad Sci U S A, 2015, 112(35):E4929-E4938.
16. Wang J, Zhu CP, Hu PF, et al. FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloprotei-nase-9 inhibition. Carcinogenesis, 2014, 35(11):2576-2583.
17. Perez-Balaguer A, Ortiz-Martínez F, García-Martínez A, et al. FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma. Breast Cancer Res Treat, 2015, 153(2):465-474.
18. Jang SM, An JH, Kim CH, et al. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. Biochem Biophys Res Commun, 2015, 463(4):961-967.
19. Vorvis C, Hatziapostolou M, Mahurkar-Joshi S, et al. Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol, 2016, 310(11):G1124-G1137.
20. Tang Y, Shu G, Yuan X, et al. FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Res, 2011, 21(2):316-326.
21. Zhang Z, Yang C, Gao W, et al. FOXA2 attenuates the epithelial to mesenchymal transition by regulating the transcription of E-cadherin and ZEB2 in human breast cancer. Cancer Lett, 2015, 361(1):240-250.
22. Song Y, Washington MK, Crawford HC. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res, 2010, 70(5):2115-2125.
23. 张正良, 孙江利, 白郑海, 等. FOXA2在胃腺癌中的表达降低.细胞与分子免疫学杂志, 2015, 31(5):672-676.
24. Yoo T, Park SJ, Han SS, et al. Postoperative CA19-9 change is a useful predictor of intrahepatic cholangiocarcinoma survival following liver resection. Dis Markers, 2015, 2015:298985.
25. Sulpice L, Rayar M, Boucher E, et al. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg, 2012, 99(12):1711-1717.
26. Kondratyeva LG, Sveshnikova AA, Grankina EV, et al. Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGF beta 1 epithelial-mesen-chymal transition. Dokl Biochem Biophys, 2016, 469(1):257-259.
27. Smith B, Neff R, Cohn DE, et al. The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role. Gynecol Oncol, 2016, 143(2):398-405.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research of The Expression of FOXA2 and Its Relationship with Prognosis in Intrahepatic Cholangiocarcinoma

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