肝癌诊断标志物的新进展及应用_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 代智 , 杨怡

复旦大学附属中山医院肝癌研究所（上海 200032）;

Corresponding author：

代智, Email: dai.zhi@zs-hospital.sh.cn

Keywords：

DOI：

10.7507/1007-9424.201801127

Video：

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Citation： 代智, 杨怡. 肝癌诊断标志物的新进展及应用. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(4): 391-395. doi: 10.7507/1007-9424.201801127 Copy

1.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3.	Kudo M, Izumi N, Sakamoto M, et al. Survival analysis over 28 years of 173,378 patients with hepatocellular carcinoma in Japan. Liver Cancer, 2016, 5(3): 190-197.
4.	Cha C. Surgical therapy for hepatocellular carcinoma: formulating a rational approach. J Clin Gastroenterol, 2013, 47 Suppl: S30-S36.
5.	Shang S, Plymoth A, Ge S, et al. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology, 2012, 55(2): 483-490.
6.	Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology, 2009, 137(1): 110-118.
7.	Taketa K, Sekiya C, Namiki M, et al. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology, 1990, 99(2): 508-518.
8.	Gao J, Song P. Combination of triple biomarkers AFP, AFP-L3, and PIVAKII for early detection of hepatocellular carcinoma in China: expectation. Drug Discov Ther, 2017, 11(3): 168-169.
9.	Bertino G, Ardiri AM, Calvagno GS, et al. Prognostic and diagnostic value of des-γ-carboxy prothrombin in liver cancer. Drug News Perspect, 2010, 23(8): 498-508.
10.	Carr BI, Kanke F, Wise M, et al. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci, 2007, 52(3): 776-782.
11.	Gao W, Kim H, Feng M, et al. Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. Hepatology, 2014, 60(2): 576-587.
12.	Liu H, Li P, Zhai Y, et al. Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. World J Gastroenterol, 2010, 16(35): 4410-4415.
13.	Tangkijvanich P, Chanmee T, Komtong S, et al. Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers. J Gastroenterol Hepatol, 2010, 25(1): 129-137.
14.	Li B, Liu H, Shang HW, et al. Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients. Afr Health Sci, 2013, 13(3): 703-709.
15.	Liu Y, Liu DL, Dong LL, et al. miR-612 suppresses stem cell-like property of hepatocellular carcinoma cells by modulating Sp1/Nanog signaling. Cell Death Dis, 2016, 7(9): e2377.
16.	Zhou SL, Hu ZQ, Zhou ZJ, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology, 2016, 63(5): 1560-1575.
17.	Cao MQ, You AB, Zhu XD, et al. miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol, 2018, 11(1): 12.
18.	Ma DN, Chai ZT, Zhu XD, et al. MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. J Hematol Oncol, 2016, 9: 1.
19.	Xu J, Wu C, Che X, et al. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog, 2011, 50(2): 136-142.
20.	Qu KZ, Zhang K, Li H, et al. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol, 2011, 45(4): 355-360.
21.	Li LM, Hu ZB, Zhou ZX, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res, 2010, 70(23): 9798-9807.
22.	Zhou J, Yu L, Gao X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol, 2011, 29(36): 4781-4788.
23.	Hashimoto K, Suzuki AM, Dos Santos A, et al. CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors. Genome Res, 2015, 25(12): 1812-1824.
24.	Yao J, Chen Y, Wang Y, et al. Decreased expression of a novel lncRNA CADM1-AS1 is associated with poor prognosis in patients with clear cell renal cell carcinomas. Int J Clin Exp Pathol, 2014, 7(6): 2758-2767.
25.	Wang Y, Zhang D, Wu K, et al. Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. Mol Cell Biol, 2014, 34(17): 3182-3193.
26.	Yan X, Hu Z, Feng Y, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell, 2015, 28(4): 529-540.
27.	Zhang L, Yang F, Yuan JH, et al. Epigenetic activation of the miR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis, 2013, 34(3): 577-586.
28.	Cui M, Xiao Z, Wang Y, et al. Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer Res, 2015, 75(5): 846-857.
29.	Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 2010, 464(7291): 1071-1076.
30.	Yang Y, Chen L, Gu J, et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun, 2017, 8: 14421.
31.	Kim SU, Park JH, Kim HS, et al. Serum dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma. Yonsei Med J, 2015, 56(5): 1296-1306.
32.	Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol, 2012, 13(8): 817-826.
33.	Zhou Y, Deng X, Zang N, et al. Transcriptomic and proteomic investigation of HSP90A as a potential biomarker for HCC. Med Sci Monit, 2015, 21: 4039-4049.
34.	Wang X, Song X, Zhuo W, et al. The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy. Proc Natl Acad Sci U S A, 2009, 106(50): 21288-21293.
35.	Fu Y, Xu X, Huang D, et al. Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver cancer: an official, large-scale, and multicenter clinical trial. EBio Medicine, 2017, 24: 56-63.
36.	Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med, 2014, 6(224): 224ra24.
37.	Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med, 2014, 20(5): 548-554.
38.	Alonso S, González B, Alibés A, et al. Analysis of somatic DNA methylation alterations of genes encoding cell surface metallopeptidases in colorectal cancer. Methods Mol Biol, 2018, 1731: 271-294.
39.	Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol, 2016, 8(9): a019505.
40.	Baylin SB, Jones PA. A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer, 2011, 11(10): 726-734.
41.	Wen L, Li J, Guo H, et al. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients. Cell Res, 2015, 25(11): 1250-1264.
42.	Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater, 2017, 16(11): 1155-1161.
43.	Sun YF, Xu Y, Yang XR, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology, 2013, 57(4): 1458-1468.
44.	Sun YF, Guo W, Xu Y, et al. Circulating tumor cells from different vascular sites exhibit spatial heterogeneity in epithelial and mesenchymal composition and distinct clinical significance in hepatocellular carcinoma. Clin Cancer Res, 2018, 24(3): 547-559.
45.	Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol, 2012, 83(11): 1484-1494.
46.	Lässer C. Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. Expert Opin Biol Ther, 2012, 12 Suppl 1: S189-S197.
47.	Cheng L, Sharples RA, Scicluna BJ, et al. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles, 2014, 3: 10.
48.	Zhou YG, Mohamadi RM, Poudineh M, et al. Interrogating circulating microsomes and exosomes using metal nanoparticles. Small, 2016, 12(6): 727-732.
49.	Sohn W, Kim J, Kang SH, et al. Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma. Exp Mol Med, 2015, 47: e184.
50.	Liu WH, Yeh SH, Lu CC, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology, 2009, 136(2): 683-693.
51.	Pineau P, Volinia S, McJunkin K, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A, 2010, 107(1): 264-269.
52.	Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med, 2012, 4(3): 143-159.
53.	Reclusa P, Taverna S, Pucci M, et al. Exosomes as diagnostic and predictive biomarkers in lung cancer. J Thorac Dis, 2017, 9(Suppl 13): S1373-S1382.
54.	Cheng L, Wu S, Zhang K, et al. A comprehensive overview of exosomes in ovarian cancer: emerging biomarkers and therapeutic strategies. J Ovarian Res, 2017, 10(1): 73.

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3. Kudo M, Izumi N, Sakamoto M, et al. Survival analysis over 28 years of 173,378 patients with hepatocellular carcinoma in Japan. Liver Cancer, 2016, 5(3): 190-197.
4. Cha C. Surgical therapy for hepatocellular carcinoma: formulating a rational approach. J Clin Gastroenterol, 2013, 47 Suppl: S30-S36.
5. Shang S, Plymoth A, Ge S, et al. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology, 2012, 55(2): 483-490.
6. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology, 2009, 137(1): 110-118.
7. Taketa K, Sekiya C, Namiki M, et al. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology, 1990, 99(2): 508-518.
8. Gao J, Song P. Combination of triple biomarkers AFP, AFP-L3, and PIVAKII for early detection of hepatocellular carcinoma in China: expectation. Drug Discov Ther, 2017, 11(3): 168-169.
9. Bertino G, Ardiri AM, Calvagno GS, et al. Prognostic and diagnostic value of des-γ-carboxy prothrombin in liver cancer. Drug News Perspect, 2010, 23(8): 498-508.
10. Carr BI, Kanke F, Wise M, et al. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci, 2007, 52(3): 776-782.
11. Gao W, Kim H, Feng M, et al. Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. Hepatology, 2014, 60(2): 576-587.
12. Liu H, Li P, Zhai Y, et al. Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. World J Gastroenterol, 2010, 16(35): 4410-4415.
13. Tangkijvanich P, Chanmee T, Komtong S, et al. Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers. J Gastroenterol Hepatol, 2010, 25(1): 129-137.
14. Li B, Liu H, Shang HW, et al. Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients. Afr Health Sci, 2013, 13(3): 703-709.
15. Liu Y, Liu DL, Dong LL, et al. miR-612 suppresses stem cell-like property of hepatocellular carcinoma cells by modulating Sp1/Nanog signaling. Cell Death Dis, 2016, 7(9): e2377.
16. Zhou SL, Hu ZQ, Zhou ZJ, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology, 2016, 63(5): 1560-1575.
17. Cao MQ, You AB, Zhu XD, et al. miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol, 2018, 11(1): 12.
18. Ma DN, Chai ZT, Zhu XD, et al. MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. J Hematol Oncol, 2016, 9: 1.
19. Xu J, Wu C, Che X, et al. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog, 2011, 50(2): 136-142.
20. Qu KZ, Zhang K, Li H, et al. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol, 2011, 45(4): 355-360.
21. Li LM, Hu ZB, Zhou ZX, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res, 2010, 70(23): 9798-9807.
22. Zhou J, Yu L, Gao X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol, 2011, 29(36): 4781-4788.
23. Hashimoto K, Suzuki AM, Dos Santos A, et al. CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors. Genome Res, 2015, 25(12): 1812-1824.
24. Yao J, Chen Y, Wang Y, et al. Decreased expression of a novel lncRNA CADM1-AS1 is associated with poor prognosis in patients with clear cell renal cell carcinomas. Int J Clin Exp Pathol, 2014, 7(6): 2758-2767.
25. Wang Y, Zhang D, Wu K, et al. Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. Mol Cell Biol, 2014, 34(17): 3182-3193.
26. Yan X, Hu Z, Feng Y, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell, 2015, 28(4): 529-540.
27. Zhang L, Yang F, Yuan JH, et al. Epigenetic activation of the miR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis, 2013, 34(3): 577-586.
28. Cui M, Xiao Z, Wang Y, et al. Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer Res, 2015, 75(5): 846-857.
29. Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 2010, 464(7291): 1071-1076.
30. Yang Y, Chen L, Gu J, et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun, 2017, 8: 14421.
31. Kim SU, Park JH, Kim HS, et al. Serum dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma. Yonsei Med J, 2015, 56(5): 1296-1306.
32. Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol, 2012, 13(8): 817-826.
33. Zhou Y, Deng X, Zang N, et al. Transcriptomic and proteomic investigation of HSP90A as a potential biomarker for HCC. Med Sci Monit, 2015, 21: 4039-4049.
34. Wang X, Song X, Zhuo W, et al. The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy. Proc Natl Acad Sci U S A, 2009, 106(50): 21288-21293.
35. Fu Y, Xu X, Huang D, et al. Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver cancer: an official, large-scale, and multicenter clinical trial. EBio Medicine, 2017, 24: 56-63.
36. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med, 2014, 6(224): 224ra24.
37. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med, 2014, 20(5): 548-554.
38. Alonso S, González B, Alibés A, et al. Analysis of somatic DNA methylation alterations of genes encoding cell surface metallopeptidases in colorectal cancer. Methods Mol Biol, 2018, 1731: 271-294.
39. Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol, 2016, 8(9): a019505.
40. Baylin SB, Jones PA. A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer, 2011, 11(10): 726-734.
41. Wen L, Li J, Guo H, et al. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients. Cell Res, 2015, 25(11): 1250-1264.
42. Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater, 2017, 16(11): 1155-1161.
43. Sun YF, Xu Y, Yang XR, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology, 2013, 57(4): 1458-1468.
44. Sun YF, Guo W, Xu Y, et al. Circulating tumor cells from different vascular sites exhibit spatial heterogeneity in epithelial and mesenchymal composition and distinct clinical significance in hepatocellular carcinoma. Clin Cancer Res, 2018, 24(3): 547-559.
45. Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol, 2012, 83(11): 1484-1494.
46. Lässer C. Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. Expert Opin Biol Ther, 2012, 12 Suppl 1: S189-S197.
47. Cheng L, Sharples RA, Scicluna BJ, et al. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles, 2014, 3: 10.
48. Zhou YG, Mohamadi RM, Poudineh M, et al. Interrogating circulating microsomes and exosomes using metal nanoparticles. Small, 2016, 12(6): 727-732.
49. Sohn W, Kim J, Kang SH, et al. Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma. Exp Mol Med, 2015, 47: e184.
50. Liu WH, Yeh SH, Lu CC, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology, 2009, 136(2): 683-693.
51. Pineau P, Volinia S, McJunkin K, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A, 2010, 107(1): 264-269.
52. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med, 2012, 4(3): 143-159.
53. Reclusa P, Taverna S, Pucci M, et al. Exosomes as diagnostic and predictive biomarkers in lung cancer. J Thorac Dis, 2017, 9(Suppl 13): S1373-S1382.
54. Cheng L, Wu S, Zhang K, et al. A comprehensive overview of exosomes in ovarian cancer: emerging biomarkers and therapeutic strategies. J Ovarian Res, 2017, 10(1): 73.

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