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Open Access 12-04-2024 | Hepatocellular Carcinoma | Research

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration

Authors: Chen-Yang Tao, Xiao-Ling Wu, Shu-Shu Song, Zheng Tang, Yu-Fu Zhou, Meng-Xin Tian, Xi-Fei Jiang, Yuan Fang, Gui-Qi Zhu, Run Huang, Wei-Feng Qu, Jun Gao, Tian-Hao Chu, Rui Yang, Jia-Feng Chen, Qian-Fu Zhao, Zhen-Bin Ding, Zhi Dai, Jian Zhou, Wei-Ren Liu, Ying-Hong Shi, Jia Fan

Published in: Cellular Oncology

Abstract

Purpose

GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown.

Methods

Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry.

Results

The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8.

Conclusion

The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

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Title: Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration
Authors: Chen-Yang Tao
Xiao-Ling Wu
Shu-Shu Song
Zheng Tang
Yu-Fu Zhou
Meng-Xin Tian
Xi-Fei Jiang
Yuan Fang
Gui-Qi Zhu
Run Huang
Wei-Feng Qu
Jun Gao
Tian-Hao Chu
Rui Yang
Jia-Feng Chen
Qian-Fu Zhao
Zhen-Bin Ding
Zhi Dai
Jian Zhou
Wei-Ren Liu
Ying-Hong Shi
Jia Fan
Publication date: 12-04-2024
Publisher: Springer Netherlands
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Cellular Oncology
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-024-00934-w

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