Molecular Biology Reports

, Volume 41, Issue 7, pp 4313–4320 | Cite as

Expression of GLP-1R protein and its clinical role in intrahepatic cholangiocarcinoma tissues

  • Ben-Dong Chen
  • Wen-Chao Zhao
  • Jian-Da Dong
  • Hui Sima


The study investigates the expression and clinical role of GLP-1R in intrahepatic cholangiocarcinoma (ICC) tissues. ICC tissue, tissue around tumour and normal liver tissue samples from 176 ICC patients were investigated for GLP-1R expression by immunohistochemistry and western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. High GLP-1R expression levels were detected in tumor tissue samples. Kaplan–Meier method was used for survival analysis of patients follow-up data. Results showed that median survival time of patients with high GLP-1R positive expression in ICC tissue were 22 months. Median survival time of patients with low GLP-1R positive expression in ICC tissue were 19.8 months. There wasn’t statistical difference (p = 0.332) between two groups. Immunohistochemistry semi-quantitative analysis showed that tissue differentiation is not prognostic risk factors. In patients with GLP-1R positive expression in ICC tissue, lymph node metastasis was important prognostic factors (p = 0.001). Although statistical analysis showed that GLP-1R can not be judged as a risk prognostic factors, GLP-1 might become a new target for therapy of ICC.


Intrahepatic cholangiocarcinoma Western blot GLP-1R Tumor 


  1. 1.
    Ahrendt SA, Nakeeb A, Pitt HA (2001) Cholangiocarcinoma. Clin Liver Dis 5:191–218CrossRefPubMedGoogle Scholar
  2. 2.
    Patel T (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Lazaridis KN, Gores GJ (2005) Cholangiocarcinoma. Gastroenterology 128:1655–1667CrossRefPubMedGoogle Scholar
  4. 4.
    Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD (2005) Cholangiocarcinoma. Lancet 366:1303–1314CrossRefPubMedGoogle Scholar
  5. 5.
    Leong TYM, Leong ASY (2005) Epidemiology and carcinogenesis of hepatocellular carcinoma. HPB 7:1–12CrossRefGoogle Scholar
  6. 6.
    Tyson GL, El-Serag HB (2011) Risk factors for cholangiocarcinoma. Hepatology 54:173–184PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Patel T (2011) Cholangiocarcinoma — controversies and challenges. Nat Rev Gastroenterol Hepatol. 8:189–200PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V, Fang YY, Wiangnon S, Sripa B, Hong ST (2010) Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci 101:579–585CrossRefPubMedGoogle Scholar
  9. 9.
    Broome U, Lofberg R, Veress B, Eriksson LS (1995) Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 22:1404–1408PubMedGoogle Scholar
  10. 10.
    Su CH, Shyr YM, Lui WY, P’Eng FK (1997) Hepatolithiasis associated with cholangiocarcinoma. Br J Surg 84:969–973CrossRefPubMedGoogle Scholar
  11. 11.
    Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, McGlynn KA (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case–control study. Clin Gastroenterol Hepatol. 5:1221–1228PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Lee TY, Lee SS, Jung SW, Jeon SH, Yun SC, Oh HC, Kwon S, Lee SK, Seo DW, Kim MH, Suh DJ (2008) Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case–control study. Am J Gastroenterol 103:1716–1720CrossRefPubMedGoogle Scholar
  13. 13.
    Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA (2005) Risk factors of intrahepatic cholangiocarcinoma in the United States: a case–control study. Gastroenterology 128:620–626CrossRefPubMedGoogle Scholar
  14. 14.
    Shaib YH, El-Serag HB, Nooka AK, Thomas M, Brown TD, Patt YZ, Hassan MM (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospitalbased case–control study. Am J Gastroenterol 102:1016–1021CrossRefPubMedGoogle Scholar
  15. 15.
    Tao LY, He XD, Qu Q, Cai L, Liu W, Zhou L, Zhang SM (2010) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a case–control study in China. Liver Int. 30:215–221CrossRefPubMedGoogle Scholar
  16. 16.
    Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA (2011) Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54:463–471PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L, Olsen JH, McGlynn KA (2007) Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case–control study. Int J Cancer 120:638–641CrossRefPubMedGoogle Scholar
  18. 18.
    Yamamoto S, Kubo S, Hai S, Uenishi T, Yamamoto T, Shuto T, Takemura S, Tanaka H, Yamazaki O, Hirohashi K, Tanaka T (2004) Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 95:592–595CrossRefPubMedGoogle Scholar
  19. 19.
    Zhou H, Wang H, Zhou D, Wang H, Wang Q, Zou S, Tu Q, Wu M, Hu H (2010) Hepatitis B virusassociated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis. Eur J Cancer 46:1056–1061CrossRefPubMedGoogle Scholar
  20. 20.
    Zhou YM, Yin ZF, Yang JM, Li B, Shao WY, Xu F, Wang YL, Li DQ (2008) Risk factors for intrahepatic cholangiocarcinoma: a case–control study in China. World J Gastroenterol: WJG. 14:632–635PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Yu TH, Yuan RH, Chen YL, Yang WC, Hsu HC, Jeng YM (2011) Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression. Mod Pathol 24:810–819CrossRefPubMedGoogle Scholar
  22. 22.
    Yin F, Chen B (1998) Detection of hepatitis C virus RNA sequences in hepatic portal cholangiocarcinoma tissue by reverse transcription polymerase chain reaction. Chinese Med J. 111:1068–1070Google Scholar
  23. 23.
    Chen MF (1999) Peripheral cholangiocarcinoma (cholangiocellularcarcinoma): clinical features, diagnosis and treatment. J Gastroenterol Hepatol 14:1144–1149CrossRefPubMedGoogle Scholar
  24. 24.
    Carriaga MT, Henson DE (1995) Liver, gallbladder, extra hepatic bile ducts, and pancreas. Cancer 75:171–190CrossRefPubMedGoogle Scholar
  25. 25.
    Chung YE, Kim MJ, Park YN, Choi JY, Pyo JY, Kim YC, Cho HJ, Kim KA, Choi SY (2009) Varying appearances of cholangiocarcinoma: radiologic–pathologic correlation. Radiographics. 29:683–700CrossRefPubMedGoogle Scholar
  26. 26.
    Poultsides GA, Zhu AX, Choti MA, Pawlik TM (2010) Intrahepatic cholangio-carcinoma. Surg Clin North Am 90:817–837CrossRefPubMedGoogle Scholar
  27. 27.
    Park J, Kim MH, Kim KP, Park do H, Moon SH, Song TJ, Eum J, Lee SS, Seo DW, Lee SK (2009) Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radio-therapy: a large-scale observational study. Gut Liver. 3:298–305PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Tan JCC, Coburn NG, Baxter NN, Kiss A, Law CHL (2008) Surgical management of intrahepatic cholangiocarcinoma—a population-based study. Ann Surg Oncol 15:600–608CrossRefPubMedGoogle Scholar
  29. 29.
    Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, Sawicki PT (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777CrossRefPubMedGoogle Scholar
  31. 31.
    Mussig K, Haring HU (2010) Insulin signal transduction in normal cells and its role in carcinogenesis. Exp Clin Endocrinol Diab. 118:356–359CrossRefGoogle Scholar
  32. 32.
    Becker S, Dossus L, Kaaks R (2009) Obesity related hyperinsulinaemia and hyperglycaemia and cancer development. Arch Physiol Biochem 115:86–96CrossRefPubMedGoogle Scholar
  33. 33.
    Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J Leukoc Biol 86:505–512CrossRefPubMedGoogle Scholar
  34. 34.
    Chakrabarty S, Kondratick L (2006) Insulin-like growth factor binding protein-2 stimulates proliferation and activates multiple cascades of the mitogen-activated protein kinase pathways in NIH-OVCAR3 human epithelial ovarian cancer cells. Cancer Biol Ther 5:189–197CrossRefPubMedGoogle Scholar
  35. 35.
    Vinikoor LC, Long MD, Keku TO, Martin CF, Galanko JA, Sandler RS (2009) The association between diabetes, insulin use, and colorectal cancer among whites and African Americans. Cancer Epidemiol Biomark Prev 18:1239–1242CrossRefGoogle Scholar
  36. 36.
    Flood A, Strayer L, Schairer C, Schatzkin A (2010) Diabetes and risk of incident colorectal cancer in a prospective cohort of women. Cancer Causes Control 21(8):1277–1284PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Rinaldi S, Rohrmann S, Jenab M, Biessy C, Sieri S, Palli D (2008) Glycosylated hemoglobin and risk of colorectal cancer in men and women, the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomark Prev 17:3108–3115CrossRefGoogle Scholar
  38. 38.
    Cust AE, Stocks T, Lukanova A, Lundin E, Hallmans G, Kaaks R, Jonsson H, Stattin P (2009) The influence of overweight and insulin resistance on breast cancer risk and tumour stage at diagnosis: a prospective study. Breast Cancer Res Treat 113:567–576CrossRefPubMedGoogle Scholar
  39. 39.
    Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, Wolff AC, Brancati FL (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Sulpice L, Rayar M, Boucher E, Pele F, Pracht M, Meunier B, Boudjema K (2013) Intrahepatic cholangiocarcinoma: impact of genetic hemochromatosis on outcome and overall survival after surgical resection. J Surg Res 180(1):56–61CrossRefPubMedGoogle Scholar
  41. 41.
    Palmer WC, Patel T (2012) Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepaticcholangiocarcinoma. J Hepatol 57(1):69–76PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439CrossRefPubMedGoogle Scholar
  43. 43.
    Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59:1030–1037PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Ben-Dong Chen
    • 1
  • Wen-Chao Zhao
    • 2
  • Jian-Da Dong
    • 3
  • Hui Sima
    • 4
  1. 1.Department of Hepatobiliary SurgeryGeneral Hospital of NingXia Medical UniversityYinchuanPeople’s Republic of China
  2. 2.Department of Hepatobiliary SurgeryNavy HospitalBeijingPeople’s Republic of China
  3. 3.Pathology Department of Basic Medical Sciences SchoolNingXia Medical UniversityYinchuanPeople’s Republic of China
  4. 4.Department of Fifth Hepatic SurgeryEastern hepatobiliary surgery hospital of Secong Militery Medical UniversityShanghaiPeople’s Republic of China

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