南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (9): 1388-1393.doi: 10.12122/j.issn.1673-4254.2021.09.14

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癌旁circWDR25与肝细胞癌根治性切除术后的预后相关

刘 磊，杜成友，魏续福，廖 锐   

  1. 重庆医科大学附属第一医院肝胆外科，重庆 400016
  • 出版日期:2021-09-20 发布日期:2021-09-30

Correlation of peritumoral circWDR25 expression with the prognosis of patients with hepatocellular carcinoma after curative resection

LIU Lei, DU Chengyou, WEI Xufu, LIAO Rui   

  1. Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
  • Online:2021-09-20 Published:2021-09-30

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摘要： ：目的 探讨癌旁组织中肝星状细胞（HSCs）分泌表达的circWDR25（hsa-circRNA-0004310）与肝细胞癌（HCC）患者行根治性切除术后的预后关系。方法 肝星状细胞系LX-2分别与3种肝癌细胞系Hep3B、SMMC-7721、HCCLM3行transwell小室法共培养，建立肿瘤细胞活化的HSCs，收集HSCs上清分离外泌体，提取RNA后检测circRNA基因表达谱；收集2014年1月~2015年10月在重庆医科大学附属第一医院肝胆外科接受根治性切除手术的288例HCC患者的癌旁肝组织，行原位杂交，检测circWDR25与α-SMA的阳性表达量，预后单因素分析和多因素分析分别采用Log-rank检验和Cox回归分析。结果 基因表达谱发现肿瘤活化的LX-2所分离出的外泌体中circWDR25表达上调最显著；癌旁circWDR25和HSCs呈正相关（r=0.156，P=0.008）。术前AST>36 g/L、肿瘤多发、肿瘤>5 cm、HSC>70、circWDR25>190为影响HCC患者根治性切除术后总体生存率的独立危险因素；术前AST>36、肿瘤多发、肿瘤>5 cm、有癌栓、HSC>70、circWDR25>190为肝癌患者无瘤生存的独立危险因素。结论 癌旁circWDR25和HSCs是HCC患者根治性肝切除术后预后的影响因素，二者在癌旁组织中的高表达与预后差密切相关。

关键词: 肝细胞癌；肝星状细胞；外泌体；环状RNA；circWDR25

Abstract: Objective To study the association between the expression of peritumoral circWDR25 (hsa-circRNA-0004310) secreted by hepatic stellate cells (HSCs) and the prognosis of the patients with hepatocellular carcinoma (HCC) after curative resection. Methods HSCs cell line LX-2 was co-cultured separately with 3 liver cancer cell lines (Hep3B, SMMC-7721, and HCCLM3) in Transwell chambers to obtain tumor cell-activated HSCs. The supernatants of HSC cultures were collected to isolate the exosomes, from which total RNA was extracted to detect circRNA expression profile. We also collected specimens of paracancerous liver tissues from 288 HCC patients undergoing radical resection in our department from January, 2014 to October, 2015, and the expression levels of circWDR25 and α-SMA were detected with in situ hybridization. Log-rank test and Cox regression analysis were used for univariate and multivariate analysis of the factors affecting the patients' prognosis, respectively. Results Gene expression profiling revealed that the expression of circWDR25 was the most obviously up-regulated in the exosomes isolated from tumor-activated LX-2 cells. The expression of peritumoral circWDR25 was positively correlated with HSCs adjacent to the cancer loci (r=0.156, P=0.008). Multivariate analysis showed that a preoperative AST level >36 g/L, multiple tumors, a tumor diameter >5 cm, HSC>70, and circWDR25>190 were independent risk factors affecting the overall survival of HCC patients after radical resection; a preoperative AST level >36 g/L, multiple tumors, a tumor diameter >5 cm, presence of tumor thrombus, HSC>70, and circWDR25>190 were all independent risk factors for tumor-free survival in patients with liver cancer. Conclusion Peritumoral circWDR25 and HSCs are factors affecting the prognosis of HCC patients after radical hepatectomy, and their high expression in the adjacent tissues is closely related to a poor prognosis of the patients.

Key words: hepatocellular carcinoma; hepatic stellate cells; exosomes; circRNA; circWDR25