The expression change of stemness-related markers in recurrent hepatocellular carcinoma and relationship with clinicopathologic characteristics_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 WANG Haiqing ¹ , FENG Xielin ¹ , LI Lei ¹ , HAO Jingcheng ² , GONG Chen ¹

1. Department of Hepato-Biliary-Pancreatic Surgery, Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, P. R. China;
2. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, P. R. China;

Corresponding author：

WANG Haiqing, Email: 541026814@qq.com

Keywords：

hepatocellular carcinoma; stemness; telomere length; recurrence

DOI：

10.7507/1007-9424.202007121

Video：

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Objective To investigate the expression change characteristic of stemness-related markers for recurrent hepatocellular carcinoma (HCC), and to discuss the relationship between stemness-related markers and clinicopathologic characteristics of HCC.Methods We collected 25 recurrent HCC patients who also had the first liver resection for HCC in Sichuan Cancer Hospital from Jan. 2010 to Oct. 2018. Immunohistochemistry was used to compare expressions of CD133, CD90, CD117, and epithelial cell adhesion molecule (EpCAM) in HCC tissues. Fluorescence in situ hybridization was used to detect telomere length.Results The primary HCC had higher platelet count, larger tumor, less microvascular invasion (MVI), and less multiple HCC than the recurrent HCC (P<0.05), but the expressions of CD90, CD133, CD117, and EpCAM were not significantly differed after recurrence (P>0.05). The expressions of CD90, CD133, CD117, and EpCAM were not associated with tumor size, tumor number, Barcelona Clinic Liver Cancer Staging (BCLC staging), satellite nodules, and differentiation (P>0.05). The MVI-positive group had a significantly higher expression level of EpCAM (P=0.016) and longer telomere length (P=0.001). The telomere length was longer for tumors diameter less than 5 cm (P=0.038) and poor differentiation (P=0.046). Correlation analysis found that there was no relationship between telomere length and expression levels of EpCAM (r=–0.092, P=0.513), CD90 (r=–0.235, P=0.100), CD133 (r=0.024, P=0.867), and CD117 (r=–0.277, P=0.052), but an apparent positive correlation between expression levels of EpCAM and CD133 was found (r=0.358, P=0.011). Survival analysis found that poor differentiation (P=0.003) and BCLC B–C staging (P=0.040) were the risk factors of disease-free survival for patients after first HCC resection, and BCLC B–C staging (P=0.017) and tumor diameter more than 5 cm (P=0.035) were the risk factors for recurrent HCC.Conclusions Recurrent HCC had similar stemness-related markers expression and longer telomere length. Expression level of EpCAM and telomere length were associated with MVI.

Citation： WANG Haiqing, FENG Xielin, LI Lei, HAO Jingcheng, GONG Chen. The expression change of stemness-related markers in recurrent hepatocellular carcinoma and relationship with clinicopathologic characteristics. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(5): 587-594. doi: 10.7507/1007-9424.202007121 Copy

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2.	Govaere O, Roskams T. Pathogenesis and prognosis of hepatocellular carcinoma at the cellular and molecular levels. Clin Liver Dis, 2015, 19(2): 261-276.
3.	Marquardt JU, Thorgeirsson SS. Stem cells in hepatocarcinogenesis: evidence from genomic data. Semin Liver Dis, 2010, 30(1): 26-34.
4.	Kim H, Choi GH, Na DC, et al. Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis. Hepatology, 2011, 54(5): 1707-1717.
5.	Chan AW, Tong JH, Chan SL, et al. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology, 2014, 64(7): 935-950.
6.	Yamamoto N, Okano K, Kushida Y, et al. Clinicopathology of recurrent hepatocellular carcinomas after radiofrequency ablation treated with salvage surgery. Hepatol Res, 2014, 44(11): 1062-1071.
7.	Heidenreich B, Rachakonda PS, Hemminki K, et al. TERT promoter mutations in cancer development. Curr Opin Genet Dev, 2014, 24: 30-37.
8.	Rachakonda PS, Hosen I, de Verdier PJ, et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci U S A, 2013, 110(43): 17426-17431.
9.	Borah S, Xi L, Zaug AJ, et al. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science, 2015, 347(6225): 1006-1010.
10.	Chen YL, Jeng YM, Chang CN, et al. TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection. Int J Surg, 2014, 12(7): 659-665.
11.	Kim H, Yoo JE, Cho JY, et al. Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing “stemness”-related markers. J Hepatol, 2013, 59(4): 746-752.
12.	Lo RC, Leung CO, Chok KS, et al. Variation of stemness markers expression in tumor nodules from synchronous multi-focal hepatocellular carcinoma - an immunohistochemical study. Diagn Pathol, 2017, 12(1): 56.
13.	Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis, 2014, 32(6): 778-785.
14.	Yamashita T, Forgues M, Wang W, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res, 2008, 68(5): 1451-1461.
15.	Govaere O, Komuta M, Berkers J, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut, 2014, 63(4): 674-685.
16.	Tsujikawa H, Masugi Y, Yamazaki K, et al. Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness. Hum Pathol, 2016, 50: 24-33.
17.	Durnez A, Verslype C, Nevens F, et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology, 2006, 49(2): 138-151.
18.	邢龙彬, 高英堂. 肝癌干细胞表面标志物研究进展. 世界华人消化杂志, 2016, 24(31): 4231-4237.
19.	Zhao X, Parpart S, Takai A, et al. Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma. Oncogene, 2015, 34(39): 5095-5104.
20.	Seino S, Tsuchiya A, Watanabe Y, et al. Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers. Oncotarget, 2018, 9(31): 21844-21860.
21.	Gurzu S, Kobori L, Fodor D, et al. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. Biomed Res Int, 2019, 2019: 2962580.
22.	Aizarani N, Saviano A, Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature, 2019, 572(7768): 199-204.
23.	Zhou L, Zhu Y. The EpCAM overexpression is associated with clinicopathological significance and prognosis in hepatocellular carcinoma patients: a systematic review and meta-analysis. Int J Surg, 2018, 56: 274-280.
24.	Lei J, Yan L, Wang W. Donor safety in living donor liver transplantation: a single-center analysis of 300 cases. PLoS One, 2013, 8(4): e61769.

1. Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 2007, 132(7): 2542-2556.
2. Govaere O, Roskams T. Pathogenesis and prognosis of hepatocellular carcinoma at the cellular and molecular levels. Clin Liver Dis, 2015, 19(2): 261-276.
3. Marquardt JU, Thorgeirsson SS. Stem cells in hepatocarcinogenesis: evidence from genomic data. Semin Liver Dis, 2010, 30(1): 26-34.
4. Kim H, Choi GH, Na DC, et al. Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis. Hepatology, 2011, 54(5): 1707-1717.
5. Chan AW, Tong JH, Chan SL, et al. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology, 2014, 64(7): 935-950.
6. Yamamoto N, Okano K, Kushida Y, et al. Clinicopathology of recurrent hepatocellular carcinomas after radiofrequency ablation treated with salvage surgery. Hepatol Res, 2014, 44(11): 1062-1071.
7. Heidenreich B, Rachakonda PS, Hemminki K, et al. TERT promoter mutations in cancer development. Curr Opin Genet Dev, 2014, 24: 30-37.
8. Rachakonda PS, Hosen I, de Verdier PJ, et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci U S A, 2013, 110(43): 17426-17431.
9. Borah S, Xi L, Zaug AJ, et al. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science, 2015, 347(6225): 1006-1010.
10. Chen YL, Jeng YM, Chang CN, et al. TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection. Int J Surg, 2014, 12(7): 659-665.
11. Kim H, Yoo JE, Cho JY, et al. Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing “stemness”-related markers. J Hepatol, 2013, 59(4): 746-752.
12. Lo RC, Leung CO, Chok KS, et al. Variation of stemness markers expression in tumor nodules from synchronous multi-focal hepatocellular carcinoma - an immunohistochemical study. Diagn Pathol, 2017, 12(1): 56.
13. Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis, 2014, 32(6): 778-785.
14. Yamashita T, Forgues M, Wang W, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res, 2008, 68(5): 1451-1461.
15. Govaere O, Komuta M, Berkers J, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut, 2014, 63(4): 674-685.
16. Tsujikawa H, Masugi Y, Yamazaki K, et al. Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness. Hum Pathol, 2016, 50: 24-33.
17. Durnez A, Verslype C, Nevens F, et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology, 2006, 49(2): 138-151.
18. 邢龙彬, 高英堂. 肝癌干细胞表面标志物研究进展. 世界华人消化杂志, 2016, 24(31): 4231-4237.
19. Zhao X, Parpart S, Takai A, et al. Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma. Oncogene, 2015, 34(39): 5095-5104.
20. Seino S, Tsuchiya A, Watanabe Y, et al. Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers. Oncotarget, 2018, 9(31): 21844-21860.
21. Gurzu S, Kobori L, Fodor D, et al. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. Biomed Res Int, 2019, 2019: 2962580.
22. Aizarani N, Saviano A, Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature, 2019, 572(7768): 199-204.
23. Zhou L, Zhu Y. The EpCAM overexpression is associated with clinicopathological significance and prognosis in hepatocellular carcinoma patients: a systematic review and meta-analysis. Int J Surg, 2018, 56: 274-280.
24. Lei J, Yan L, Wang W. Donor safety in living donor liver transplantation: a single-center analysis of 300 cases. PLoS One, 2013, 8(4): e61769.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The expression change of stemness-related markers in recurrent hepatocellular carcinoma and relationship with clinicopathologic characteristics

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