Involvement of microRNA-551a in the response mechanism of sorafenib in patients with advanced hepatocellular carcinoma

Abstract

Abstract: Objective: Sorafenib is one of the standard first-line therapies for patients with advanced hepatocellular carcinoma (HCC) disease. This study aimed to explore the role of microRNAs (miRNAs) in sorafenib response mechanisms.
Method: HCC-related miRNAs expression profiles were analyzed, and a comprehensive bioinformatics approach identified sorafenib response miRNAs and their associated molecular mechanisms. A total of 24 patients with advanced HCC admitted to our hospital for treatment between February 2021 and February 2022 were selected. During the same period, 18 patients with cirrhosis admitted for treatment were selected as the control group. To verify the expression characteristics and prognostic value of sorafenib-responsive miRNAs.
Result: HCC patients with high miRNA-551a expression had a poorer prognosis, and expression was suppressed by sorafenib, which is involved in HCC progression and sorafenib response mechanisms through multiple pro-oncogenic pathways and autophagic pathways. In the clinical validation cohort, serum miRNA-551a expression was higher in advanced HCC patients before sorafenib treatment than in controls (P<0.05) and decreased after treatment (P<0.05). Patients with advanced HCC with high pre-treatment serum miRNA-551a expression benefited from sorafenib treatment (P<0.05). Univariate and multivariate Cox proportional regression models also confirmed that pre-treatment serum miRNA-551a levels could predict the prognosis of advanced HCC patients treated with sorafenib independently of clinicopathological features (P<0.05). Molecular docking and kinetic modeling confirmed that sorafenib directly binds pre-miRNA-551a and prevents cleavage of pre-miRNA-551a from maturing miRNA-551a by the endoribonuclease Dicer. The Nomogram model based on the combination of miRNA-551a expression characteristics and clinicopathological features effectively predicted the prognosis of HCC patients at survival rates at 1-, 3- and 5- years and, ideally, screening of sorafenib-responsive patients.
Conclusion: miRNA-551a, as a pro-oncogene, can be suppressed by sorafenib expression involved in its response mechanism. The assessment and targeting of miRNA-551a expression characteristics can help personalize the treatment of HCC patients.

Key words: Advanced hepatocellular carcinoma, Sorafenib, microRNA, Response, Prognosis

Bian Tao, Qin Feng, Wang Shengjie, Wang Hui, Han Shanshan. Involvement of microRNA-551a in the response mechanism of sorafenib in patients with advanced hepatocellular carcinoma[J]. Electronic Journal of Liver Tumor, 2023, 10(2): 16-26.

References

[1] SUNG H, FERLAY J, SIEGEL R L, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] ROAYAIE S, JIBARA G, TABRIZIAN P, et al.The role of hepatic resection in the treatment of hepatocellular cancer[J]. Hepatology, 2015, 62(2): 440-451.
[3] LIU L J, LV Z, XUE X, et al.Canonical WNT Signaling Activated by WNT7B Contributes to L-HBs-Mediated Sorafenib Resistance in Hepatocellular Carcinoma by Inhibiting Mitophagy[J]. Cancers (Basel), 2022, 14(23): 5781.
[4] KUDO M, FINN R S, QIN S, et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173.
[5] TANG W, CHEN Z, ZHANG W, et al.The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects[J]. Signal Transduct Target Ther, 2020, 5(1): 87.
[6] PRATAMA M Y, PASCUT D, MASSI M N, et al.The role of microRNA in the resistance to treatment of hepatocellular carcinoma[J]. Ann Transl Med, 2019, 7(20): 577.
[7] KOHNO T, MORISHITA A, IWAMA H, et al.Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma[J]. Oncol Lett, 2020, 20(2): 1727-1733.
[8] 成炳祥, 方煊, 朱承良, 等. 索拉非尼对肝癌患者血清中肿瘤相关miRNAs的影响[J]. 中国医药导报, 2014, 11(9): 4.
[9] HAN T, ZHANG Y, YANG X, et al.miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance[J]. Mol Ther Nucleic Acids, 2020, 19: 1073-1085.
[10] NISHIDA N, ARIZUMI T, HAGIWARA S, et al.MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma[J]. Liver Cancer, 2017, 6(2): 113-125.
[11] FARZANEH Z, VOSOUGH M, AGARWAL T, et al.Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches[J]. Cancer Cell Int, 2021, 21(1): 208.
[12] CHEN X, XIE B, CAO L, et al.Direct binding of microRNA-21 pre-element with Regorafenib: An alternative mechanism for anti-colorectal cancer chemotherapy?[J]. J Mol Graph Model, 2017, 73: 48-53.
[13] PATIL M D, RATHOD V P, BIHADE U R, et al.Purification and characterization of arginine deiminase from Pseudomonas putida: Structural insights of the differential affinities of l-arginine analogues[J]. J Biosci Bioeng, 2019, 127(2): 129-137.
[14] KUDO M, UESHIMA K, IKEDA M, et al.Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma[J]. Liver Cancer, 2022, 11(4): 354-367.
[15] HEQING Y, BIN L, XUEMEI Y, et al.The role and mechanism of autophagy in sorafenib targeted cancer therapy[J]. Crit Rev Oncol Hematol, 2016, 100: 137-140.
[16] LAI Y, FENG B, ABUDOUREYIMU M, et al.Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma[J]. Front Oncol, 2019, 9: 1156.
[17] DONG Z B, WU H M, HE Y C, et al.MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1[J]. Cell Death Dis, 2022, 13(1): 35.
[18] KANG H, KIM C, JI E, et al.The MicroRNA-551a/MEF2C Axis Regulates the Survival and Sphere Formation of Cancer Cells in Response to 5-Fluorouracil[J]. Mol Cells, 2019, 42(2): 175-182.
[19] STIUSO P, POTENZA N, LOMBARDI A, et al.MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib[J]. Mol Ther Nucleic Acids, 2015, 4: e233.
[20] LIU L, HAN S, XIAO X, et al.Glucocorticoid-induced microRNA-378 signaling mediates the progression of pancreatic cancer by enhancing autophagy[J]. Cell Death Dis, 2022, 13(12): 1052.
[21] LÜNSE C E, MICHLEWSKI G, HOPP C S, et al. An aptamer targeting the apical-loop domain modulates pri-miRNA processing[J]. Angew Chem Int Ed Engl, 2010, 49(27): 4674-4677.
[22] 黄桂荣, 吴德平, 陈方鹏, 等. NRS-2002和CONUT评分与中晚期肝细胞癌患者预后分析及Nomogram模型构建[J/CD]. 肝癌电子杂志, 2021, 8(2): 62-68.
[23] HUANG S, LI D, ZHUANG L, et al.A meta-analysis of the efficacy and safety of adjuvant sorafenib for hepatocellular carcinoma after resection[J]. World J Surg Oncol, 2021, 19(1): 168.