GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma

• Published in: Journal of advanced research 2023-02, Vol.44, p.173-183
• Main Authors: Tan, Wenliang, Zhang, Kelin, Chen, Xinming, Yang, Lei, Zhu, Sicong, Wei, Yingcheng, Xie, Zhiqin, Chen, Yajin, Shang, Changzhen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; beta Catenin - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Glutathione Peroxidase - metabolism; GPX2; Hepatocellular carcinoma; Humans; Lenvatinib; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Original; Reactive Oxygen Species - metabolism; ROS
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2022.03.012

[Display omitted] •Lenvatinib inhibits GPX2 expression and induces ROS related apoptosis in HCC.•High expression of GPX2 is an independent risk factor for overall survival in HCC.•Lenvatinib induces cell apoptosis through inhibiting β-catenin/GPX2 axis in HCC.•GPX2 levels could predict lenvatinib sensibility for HCC patients. Lenvatinib has recently become available as the first-line therapy for advanced hepatocellular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown. The current study aims to identify the molecular mechanisms of lenvatinib in HCC. Gene expression microarrays, flow cytometry, western blot, qRT-PCR, immunohistochemistry and immunofluorescence were used to study the response of HCC cells to lenvatinib. Xenograft tumor of Huh7 cells was also established to detect the effect of lenvatinib in vivo. Herein, we found that lenvatinib could induce apoptosis via increasing reactive oxygen species (ROS) levels in HCC cells. Then, microarray analysis and qRT-PCR results confirmed that GPX2 was a vital target for lenvatinib against HCC. Loss and gain function of experiment showed that regulating GPX2 levels markedly affected the lenvatinib-induced ROS levels and apoptosis in HCC cells. In addition, analyses of The Cancer Genome Atlas database and the qRT-PCR results in our cohort both showed that GPX2 markedly overexpressed in tumor tissues and correlated with poor overall survival in HCC. Mechanistically, our findings further demonstrated that GPX2 was a downstream gene regulated by β-catenin, while lenvatinib could prevent nuclear translocation of β-catenin and further inhibit GPX2 expression in HCC cells. More importantly, the correlation of GPX2 expression with lenvatinib response was further analyzed in 22 HCC patients who received lenvatinib therapy, and the results showed that the objective response rate (ORR) in patients with low GPX2 expression was 44.4% (4/9), while the ORR in patients with high GPX2 levels was only 7.7% (1/13). Our findings indicated that GPX2 plays an important role in lenvatinib-induced HCC cell apoptosis, which might serve as a biomarker for instruction of lenvatinib therapy in HCC patients.