Guo Yarong, Xu Jun, Du Qiang, Yan Yihe, Geller David A
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, United States; Department of Oncology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China.
Department of Surgery, The First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China.
Transl Oncol. 2021 Jun;14(6):101059. doi: 10.1016/j.tranon.2021.101059. Epub 2021 Mar 15.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Lenvatinib oral chemotherapy is approved as a first-line treatment of patients with unresectable HCC. The efficacy and therapeutic duration of lenvatinib are limited by drug resistance, and the mechanism is unclear. IRF2 is a constitutive transcription factor associated with the development of various cancers by regulating cancer cell growth, apoptosis, and drug resistance. However, the potential role of IRF2 in lenvatinib resistance in HCC has not been explored. In this study, we found that IRF2 promoted proliferation, inhibited apoptosis, and increased lenvatinib resistance of HCC cells by regulating β-catenin expression. Silencing IRF2 downregulated the expression of β-catenin, while overexpressing IRF2 upregulated β-catenin. Moreover, the expression of β-catenin and IRF2 was positively correlated in HCC tissues. Inhibiting β-catenin with XAV-939 effectively abrogated β-catenin expression caused by lenvatinib treatment. These findings identify an important function of IRF2 in HCC and demonstrate a mechanism of lenvatinib resistance of HCC cells. Targeting IRF2 may be a potential strategy to improve the therapeutic effect of lenvatinib on HCC.
肝细胞癌（HCC）是全球癌症相关死亡的第三大主要原因。仑伐替尼口服化疗被批准作为不可切除HCC患者的一线治疗方法。仑伐替尼的疗效和治疗持续时间受到耐药性的限制，其机制尚不清楚。IRF2是一种组成型转录因子，通过调节癌细胞的生长、凋亡和耐药性，与各种癌症的发生发展相关。然而，IRF2在HCC对仑伐替尼耐药中的潜在作用尚未得到探索。在本研究中，我们发现IRF2通过调节β-连环蛋白的表达促进HCC细胞增殖、抑制凋亡并增加其对仑伐替尼的耐药性。沉默IRF2可下调β-连环蛋白的表达，而过表达IRF2则上调β-连环蛋白。此外，HCC组织中β-连环蛋白和IRF2的表达呈正相关。用XAV-939抑制β-连环蛋白可有效消除仑伐替尼治疗引起的β-连环蛋白表达。这些发现确定了IRF2在HCC中的重要功能，并揭示了HCC细胞对仑伐替尼耐药的机制。靶向IRF2可能是提高仑伐替尼对HCC治疗效果的潜在策略。
