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

Introduction: Lenvatinib has recently become available as the first-line therapy for advanced hepatocel-lular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown.Objectives: The current study aims to identify the molecular mechanisms of lenvatinib in HCC.Methods: 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.Results: 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, anal-yses 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 B-catenin, while lenvatinib could prevent nuclear translocation of B-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).Conclusion: 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.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study revealed that Lenvatinib can induce apoptosis in HCC cells by increasing reactive oxygen species levels, with GPX2 identified as a crucial target for Lenvatinib against HCC. It was found that GPX2 was highly expressed in tumor tissues and correlated with poor overall survival in HCC patients. Furthermore, Lenvatinib was shown to inhibit GPX2 expression in HCC cells by preventing the nuclear translocation of β-catenin. These findings suggest that GPX2 may play an important role in Lenvatinib-induced HCC cell apoptosis and can serve as a biomarker for guiding Lenvatinib therapy in HCC patients.