IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin.
IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin.
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DOI：
10.1016/j.tranon.2021.101059
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发表时间：
2021-06
影响因子：
5
通讯作者：
Geller DA
中科院分区：
文献类型：
--
作者：
Guo Y;Xu J;Du Q;Yan Y;Geller DA
IRF 2和β-catenin在HCC组织中高表达。IRF 2上调β-catenin促进HCC细胞增殖。IRF 2增强HCC细胞中的乐伐替尼耐药性。肝细胞癌（HCC）是全球第三大癌症相关死亡原因。乐伐替尼口服化疗被批准作为不可切除HCC患者的一线治疗。乐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。IRF 2是通过调节癌细胞生长、凋亡和耐药性与各种癌症的发展相关的组成型转录因子。然而，IRF 2在HCC中乐伐替尼耐药中的潜在作用尚未探索。在这项研究中，我们发现IRF 2通过调节β-catenin表达促进肝癌细胞增殖，抑制凋亡，并增加Lenvatinib耐药性。沉默IRF 2下调β-catenin的表达，而过表达IRF 2上调β-catenin。β-catenin与IRF 2在HCC组织中的表达呈正相关。用XAV-939抑制β-catenin可有效消除乐伐替尼治疗引起的β-catenin表达。这些发现确定了IRF 2在HCC中的重要功能，并证明了HCC细胞的乐伐替尼耐药机制。靶向IRF 2可能是提高乐伐替尼治疗HCC疗效的潜在策略。
IRF2 and β-catenin are highly expressed in HCC tissues. IRF2 upregulation of β-catenin promotes HCC cell proliferation. IRF2 enhances lenvatinib resistance in HCC cells. 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.
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影响因子：
11.2
作者：
Castellone MD;De Falco V;Rao DM;Bellelli R;Muthu M;Basolo F;Fusco A;Gutkind JS;Santoro M
通讯作者：
Santoro M
影响因子：
3.4
作者：
Fu, Rongdang;Jiang, Shaotao;Zhang, Xiaohong
通讯作者：
Zhang, Xiaohong
影响因子：
4.8
作者：
Brodrick, Brooks;Vidrich, Alda;Cohn, Steven M.
通讯作者：
Cohn, Steven M.
影响因子：
2.9
作者：
Sakai, Toshitaka;Mashima, Hirosato;Ohnishi, Hirohide
通讯作者：
Ohnishi, Hirohide
DOI：
10.1161/atvbaha.119.313179
发表时间：
2019-10-01
影响因子：
8.7
作者：
Kim, Koung Li;Seo, Songyi;Suh, Wonhee
通讯作者：
Suh, Wonhee