原發性肝細胞癌腫瘤標志物及藥物靶點的研究進展_West China Medical Journal

Authors：

 王譽雅 ¹ ,  江舟 ²

1. ;
2. ;

Corresponding?author：

江舟, Email: jiang-yuqian@126.com

Keywords：

腫瘤標志物; 原發性肝細胞癌; 診斷; 治療; 療效; 預后

DOI：

10.7507/1002-0179.20140483

Video：

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原發性肝細胞癌（HCC）是世界上最常見的威脅人類生命的癌癥之一。但對于該疾病在不同階段的診斷、治療、預后評估仍面臨著很多難題。近年來，新的腫瘤標志物被發現，各類腫瘤標志物的聯合應用提高了HCC診斷的靈敏度和特異度。新的藥物靶點、治療方法也在進一步的驗證中，對未來提高HCC的診斷和治療提供了幫助。該文就近年來在HCC診斷和治療方面腫瘤標志物及相關藥物靶點的研究進展進行了綜述。

Citation： 王譽雅, 江舟. 原發性肝細胞癌腫瘤標志物及藥物靶點的研究進展. West China Medical Journal, 2014, 29(8): 1579-1582. doi: 10.7507/1002-0179.20140483 Copy

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2.	Liu AM, Yao TJ, Wang W, et al. Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma:a retrospective cohort study[J]. BMJ, 2012, 2(2):e000825.
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4.	Bolondi L. Screening tests for hepatocellular carcinoma[J]. Hepatology, 2003, 37(6):1493.
5.	Riener MO, Stenner F, Liewen H, et al. Alpha-fetoprotein and serum golgi phosphoprotein 2 are equally discriminative in detecting early hepatocellular carcinomas[J]. Hepatology, 2009, 50(1):326.
6.	Wu W, Yao DF, Yuan YM, et al. Combined serum hepatoma-specific alpha-fetoprotein and circulating alpha-fetoprotein-mRNA in diagnosis of hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int, 2006, 5(4):538-544.
7.	Cheng HT, Chang YH, Chen YY, et al. AFP-L3 in chronic liver diseases with persistent elevation of alpha-fetoprotein[J]. J Chin Med Assoc, 2007, 70(8):310-317.
8.	張德奎, 樊紅. 肝癌腫瘤標記物研究進展[J]. 華西醫學, 2011, 26(5):787-790.
9.	Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma[J]. World J Gastroenterol, 2006, 12(8):1175-1181.
10.	Cui R, He J, Zhang F, et al. Diagnostic value of protein induced by vitamin K absence (PIVKAⅡ) and hepatoma-specific band of serum gamma-glutamyl transferase (GGTⅡ) as hepatocellular carcinoma markers complementary to alpha-fetoprotein[J]. Br J Cancer, 2003, 88(12):1878-1882.
11.	Singhal A, Jayaraman M, Dhanasekaran DN, et al. Molecular and serum markers in hepatocellular carcinoma:predictive tools for prognosis and recurrence[J]. Crit Rev Oncol Hematol, 2012, 82(2):116-140.
12.	Wang M, Long RE, Comunale MA, et al. Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma[J]. Cancer Epidemiol Biomarkers Prev, 2009, 18(6):1914-1921.
13.	毛一雷, 楊華瑜, 徐海峰, 等. 新的肝癌血清標記物GP73在肝癌診斷中的初步研究[J]. 中華醫學雜志, 2008, 88(14):948-951.
14.	Furihata T, Sawada T, Kita J, et al. Serum alpha-fetoprotein level per tumor volume reflects prognosis in patients with hepatocellular carcinoma after curative hepatectomy[J]. Hepatogastroenterology, 2008, 55(86/87):1705-1709.
15.	Jeng KS, Sheen IS, Tsai YC. Circulating messenger RNA of alpha-fetoprotein:a possible risk factor of recurrence after resection of hepatocellular carcinoma[J]. Arch Surg, 2004, 139(10):1055-1060.
16.	Marrero JA, Su GL, Wei W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients[J]. Hepatology, 2003, 37(5):1114-1121.
17.	Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-Ⅱ in hepatitis B virus-related hepatocellular carcinoma:a prospective study[J]. J Clin Gastroenterol, 2009, 43(5):482-488.
18.	Okuda H, Nakanishi T, Takatsu K, et al. Comparison of clinicopathological features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein alone and those seropositive for des-gamma-carboxy prothrombin alone[J]. J Gastroenterol Hepatol, 2001, 16(11):1290-1296.
19.	Kobayashi M, Ikeda K, Kawamura Y, et al. High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma[J]. Cancer, 2009, 115(3):571-580.
20.	Cui J, Dong BW, Liang P, et al. Effect of c-myc, Ki-67, MMP-2 and VEGF expression on prognosis of hepatocellular carcinoma patients undergoing tumor resection[J]. World J Gastroenterol, 2004, 10(10):1533-1536.
21.	Stroescu C, Dragnea A, Ivanov B, et al. Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma[J]. J Gastrointestin Liver Dis, 2008, 17(4):411-417.
22.	Jia JB, Zhuang PY, Sun HC, et al. Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival[J]. J Cancer Res Clin Oncol, 2009, 135(6):847-854.
23.	Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection[J]. J Cancer Res Clin Oncol, 2009, 135(10):1359-1367.
24.	Ezaki T, Ikegami T, Maeda T, et al. Prognostic value of thymidine phosphorylase activity in liver tissue adjacent to hepatocellular carcinoma[J]. Int J Clin Oncol, 2005, 10(3):171-176.
25.	Osada S, Kanematsu M, Imai H, et al. Clinical significance of serum HGF and c-Met expression in tumor tissue for evaluation of properties and treatment of hepatocellular carcinoma[J]. Hepatogastroenterology, 2008, 55(82/83):544-549.
26.	Wada H, Nagano H, Yamamoto H, et al. Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma:importance of angiopoietin-2 and hypoxia-induced factor-1 alpha[J]. Liver Int, 2006, 26(4):414-423.
27.	Morinaga S, Imada T, Shimizu A, et al. Angiogenesis in hepatocellular carcinoma as evaluated by alpha smooth muscle actin immunohistochemistry[J]. Hepatogastroenterology, 2001, 48(37):224-228.
28.	Poon RT, Ng IO, Lau C, et al. Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma:a prospective study[J]. J Clin Oncol, 2002, 20(7):1775-1785.
29.	El-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver:possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver[J]. Hepatology, 1998, 27(6):1554-1562.
30.	Nassar A, Cohen C, Siddiqui MT. Utility of glypican-3 and survivin in differentiating hepatocellular carcinoma from benign and preneoplastic hepatic lesions and metastatic carcinomas in liver fine-needle aspiration biopsies[J]. Diagn Cytopathol, 2009, 37(9):629-635.
31.	Baeuerle P A, Gires O. EpCAM (CD326) finding its role in cancer[J]. Br J Cancer, 2007, 96(3):417-423.
32.	Gires O, Klein CA, Baeuerle PA. On the abundance of EpCAM on cancer stem cells[J]. Nat Rev Cancer, 2009, 9(2):143.
33.	Benko G, Spaji? B, Kru?lin B, et al. Impact of the EpCAM expression on biochemical recurrence-free survival in clinically localized prostate cancer[J]. Urol Oncol, 2013, 31(4):468-474.
34.	Hu QY, Jiang H, Su J, et al. MicroRNAs as biomarkers for hepatocellular carcinoma:a diagnostic meta-analysis[J]. Clin Lab, 2013, 59(9/10):1113-1120.
35.	Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer[J]. Gastroenterology, 2007, 133(2):647-658.
36.	Li W, Xie L, He X, et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma[J]. Int J Cancer, 2008, 123(7):1616-1622.
37.	Fornari F, Gramantieri L, Giovannini C, et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells[J]. Cancer Res, 2009, 69(14):5761-5767.
38.	Coulouarn C, Factor VM, Andersen JB, et al. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties[J]. Oncogene, 2009, 28(40):3526-3536.
39.	Filmus J, Capurro M. Glypican-3:a marker and a therapeutic target in hepatocellular carcinoma[J]. FEBS J, 2013, 280(10):2471-2476.
40.	Maetzel D, Denzel S, Mack B, et al. Nuclear signalling by tumour-associated antigen EpCAM[J]. Nat Cell Biol, 2009, 11(2):162-171.
41.	Wang Y, Lee AT, Ma JZ, et al. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target[J]. J Biol Chem, 2008, 283(19):13205-13215.
42.	Gramantieri L, Fornari F, Ferracin M, et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality[J]. Clin Cancer Res, 2009, 15(16):5073-5081.
43.	Cui R, Wang B, Ding H, et al. Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma[J]. Chin Med J (Engl), 2002, 115(1):42-45.
44.	Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection[J]. J Cancer Res Clin Oncol, 2009, 135(10):1359-1367.

1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008[J]. Int J Cancer, 2010, 127(12):2893-2917.
2. Liu AM, Yao TJ, Wang W, et al. Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma:a retrospective cohort study[J]. BMJ, 2012, 2(2):e000825.
3. Hu Q, Huang Y, Wang Z, et al. Application of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry coupled with an artificial neural network model for the diagnosis of hepatocellular carcinoma[J]. Hepatogastroenterology, 2012, 59(118):1902-1906.
4. Bolondi L. Screening tests for hepatocellular carcinoma[J]. Hepatology, 2003, 37(6):1493.
5. Riener MO, Stenner F, Liewen H, et al. Alpha-fetoprotein and serum golgi phosphoprotein 2 are equally discriminative in detecting early hepatocellular carcinomas[J]. Hepatology, 2009, 50(1):326.
6. Wu W, Yao DF, Yuan YM, et al. Combined serum hepatoma-specific alpha-fetoprotein and circulating alpha-fetoprotein-mRNA in diagnosis of hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int, 2006, 5(4):538-544.
7. Cheng HT, Chang YH, Chen YY, et al. AFP-L3 in chronic liver diseases with persistent elevation of alpha-fetoprotein[J]. J Chin Med Assoc, 2007, 70(8):310-317.
8. 張德奎, 樊紅. 肝癌腫瘤標記物研究進展[J]. 華西醫學, 2011, 26(5):787-790.
9. Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma[J]. World J Gastroenterol, 2006, 12(8):1175-1181.
10. Cui R, He J, Zhang F, et al. Diagnostic value of protein induced by vitamin K absence (PIVKAⅡ) and hepatoma-specific band of serum gamma-glutamyl transferase (GGTⅡ) as hepatocellular carcinoma markers complementary to alpha-fetoprotein[J]. Br J Cancer, 2003, 88(12):1878-1882.
11. Singhal A, Jayaraman M, Dhanasekaran DN, et al. Molecular and serum markers in hepatocellular carcinoma:predictive tools for prognosis and recurrence[J]. Crit Rev Oncol Hematol, 2012, 82(2):116-140.
12. Wang M, Long RE, Comunale MA, et al. Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma[J]. Cancer Epidemiol Biomarkers Prev, 2009, 18(6):1914-1921.
13. 毛一雷, 楊華瑜, 徐海峰, 等. 新的肝癌血清標記物GP73在肝癌診斷中的初步研究[J]. 中華醫學雜志, 2008, 88(14):948-951.
14. Furihata T, Sawada T, Kita J, et al. Serum alpha-fetoprotein level per tumor volume reflects prognosis in patients with hepatocellular carcinoma after curative hepatectomy[J]. Hepatogastroenterology, 2008, 55(86/87):1705-1709.
15. Jeng KS, Sheen IS, Tsai YC. Circulating messenger RNA of alpha-fetoprotein:a possible risk factor of recurrence after resection of hepatocellular carcinoma[J]. Arch Surg, 2004, 139(10):1055-1060.
16. Marrero JA, Su GL, Wei W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients[J]. Hepatology, 2003, 37(5):1114-1121.
17. Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-Ⅱ in hepatitis B virus-related hepatocellular carcinoma:a prospective study[J]. J Clin Gastroenterol, 2009, 43(5):482-488.
18. Okuda H, Nakanishi T, Takatsu K, et al. Comparison of clinicopathological features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein alone and those seropositive for des-gamma-carboxy prothrombin alone[J]. J Gastroenterol Hepatol, 2001, 16(11):1290-1296.
19. Kobayashi M, Ikeda K, Kawamura Y, et al. High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma[J]. Cancer, 2009, 115(3):571-580.
20. Cui J, Dong BW, Liang P, et al. Effect of c-myc, Ki-67, MMP-2 and VEGF expression on prognosis of hepatocellular carcinoma patients undergoing tumor resection[J]. World J Gastroenterol, 2004, 10(10):1533-1536.
21. Stroescu C, Dragnea A, Ivanov B, et al. Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma[J]. J Gastrointestin Liver Dis, 2008, 17(4):411-417.
22. Jia JB, Zhuang PY, Sun HC, et al. Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival[J]. J Cancer Res Clin Oncol, 2009, 135(6):847-854.
23. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection[J]. J Cancer Res Clin Oncol, 2009, 135(10):1359-1367.
24. Ezaki T, Ikegami T, Maeda T, et al. Prognostic value of thymidine phosphorylase activity in liver tissue adjacent to hepatocellular carcinoma[J]. Int J Clin Oncol, 2005, 10(3):171-176.
25. Osada S, Kanematsu M, Imai H, et al. Clinical significance of serum HGF and c-Met expression in tumor tissue for evaluation of properties and treatment of hepatocellular carcinoma[J]. Hepatogastroenterology, 2008, 55(82/83):544-549.
26. Wada H, Nagano H, Yamamoto H, et al. Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma:importance of angiopoietin-2 and hypoxia-induced factor-1 alpha[J]. Liver Int, 2006, 26(4):414-423.
27. Morinaga S, Imada T, Shimizu A, et al. Angiogenesis in hepatocellular carcinoma as evaluated by alpha smooth muscle actin immunohistochemistry[J]. Hepatogastroenterology, 2001, 48(37):224-228.
28. Poon RT, Ng IO, Lau C, et al. Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma:a prospective study[J]. J Clin Oncol, 2002, 20(7):1775-1785.
29. El-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver:possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver[J]. Hepatology, 1998, 27(6):1554-1562.
30. Nassar A, Cohen C, Siddiqui MT. Utility of glypican-3 and survivin in differentiating hepatocellular carcinoma from benign and preneoplastic hepatic lesions and metastatic carcinomas in liver fine-needle aspiration biopsies[J]. Diagn Cytopathol, 2009, 37(9):629-635.
31. Baeuerle P A, Gires O. EpCAM (CD326) finding its role in cancer[J]. Br J Cancer, 2007, 96(3):417-423.
32. Gires O, Klein CA, Baeuerle PA. On the abundance of EpCAM on cancer stem cells[J]. Nat Rev Cancer, 2009, 9(2):143.
33. Benko G, Spaji? B, Kru?lin B, et al. Impact of the EpCAM expression on biochemical recurrence-free survival in clinically localized prostate cancer[J]. Urol Oncol, 2013, 31(4):468-474.
34. Hu QY, Jiang H, Su J, et al. MicroRNAs as biomarkers for hepatocellular carcinoma:a diagnostic meta-analysis[J]. Clin Lab, 2013, 59(9/10):1113-1120.
35. Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer[J]. Gastroenterology, 2007, 133(2):647-658.
36. Li W, Xie L, He X, et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma[J]. Int J Cancer, 2008, 123(7):1616-1622.
37. Fornari F, Gramantieri L, Giovannini C, et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells[J]. Cancer Res, 2009, 69(14):5761-5767.
38. Coulouarn C, Factor VM, Andersen JB, et al. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties[J]. Oncogene, 2009, 28(40):3526-3536.
39. Filmus J, Capurro M. Glypican-3:a marker and a therapeutic target in hepatocellular carcinoma[J]. FEBS J, 2013, 280(10):2471-2476.
40. Maetzel D, Denzel S, Mack B, et al. Nuclear signalling by tumour-associated antigen EpCAM[J]. Nat Cell Biol, 2009, 11(2):162-171.
41. Wang Y, Lee AT, Ma JZ, et al. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target[J]. J Biol Chem, 2008, 283(19):13205-13215.
42. Gramantieri L, Fornari F, Ferracin M, et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality[J]. Clin Cancer Res, 2009, 15(16):5073-5081.
43. Cui R, Wang B, Ding H, et al. Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma[J]. Chin Med J (Engl), 2002, 115(1):42-45.
44. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection[J]. J Cancer Res Clin Oncol, 2009, 135(10):1359-1367.

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West China Medical Journal

原發性肝細胞癌腫瘤標志物及藥物靶點的研究進展

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