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GLIPR1 promotes proliferation, metastasis and 5-fluorouracil resistance in hepatocellular carcinoma by activating the PI3K/PDK1/ROCK1 pathway

Abstract

Hepatocellular carcinoma (HCC) contributes to a heavy disease burden for its high prevalence and poor prognosis, with limited effective systemic therapies available. In the era of precision medicine, treatment efficacy might be improved by combining personalized systemic therapies. Since oncogenic activation is one of the primary driving forces in HCC, characterization of these oncogenes can provide insights for developing new targeted therapies. Based on RNA sequencing of epithelial-mesenchymal transition (EMT)-induced HCC cells, this study discovers and characterizes glioma pathogenesis-related protein 1 (GLIPR1) that robustly drives HCC progression and can potentially serve as a prognostic biomarker and therapeutic target with clinical utility. GLIPR1 serves opposing roles and involves distinct mechanisms in different cancers. However, based on integrated in-silico analysis, in vitro and in vivo functional investigations, we demonstrate that GLIPR1 plays a multi-faceted oncogenic role in HCC development via enhancing tumor proliferation, metastasis, and 5FU resistance. We also found that GLIPR1 induces EMT and is actively involved in the PI3K/PDK1/ROCK1 singling axis to exert its oncogenic effects. Thus, pre-clinical evaluation of GLIPR1 and its downstream factors in HCC patients might facilitate further discovery of therapeutic targets, as well as improve HCC chemotherapeutic outcomes and prognosis.

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Fig. 1: GLIPR1 upregulation in HCC is associated with EMT.
Fig. 2: GLIPR1 promotes in vitro proliferation, foci formation and 5FU resistance in HCC.
Fig. 3: GLIPR1 promotes in vivo HCC growth and 5FU resistance.
Fig. 4: GLIPR1 promotes metastatic potential of HCC cells.
Fig. 5: GLIPR1 upregulates the PI3K/PDK/ROCK1 signaling axis.
Fig. 6: GLIPR1 promotes proliferation, metastasis and 5FU resistance in HCC via PI3K/PDK1/ROCK1 signaling axis and EMT.

Data availability

Data generated in this study are included within the manuscript and the supplementary information; or are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from the Hong Kong Research Grant Council (RGC) grants including Collaborative Research Funds (C7065-18GF, C7026-18GF, and C4039-19GF), Theme-based Research Scheme (T12-704/16-R), Research Impact Funds (R4017-18, R1020-18F, and R7022-20), National Natural Science Foundation of China (81772554 and 82072738), and The Shenzhen Peacock team project (KQTD20180411185028798). Xin-Yuan Guan is the Sophie YM Chan Professor in Cancer Research.

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XYG designed and supervised the study. YCT and LG wrote the manuscript. YCT, LG, YZ, JL, YY, and YT performed the experiments. YCT, LG, and YZ analyzed the data. AWL contributed to the clinical interpretation of the results and provided important suggestions. All of the authors have read and approved the manuscript.

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Correspondence to Xin-Yuan Guan.

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Tiu, Y.C., Gong, L., Zhang, Y. et al. GLIPR1 promotes proliferation, metastasis and 5-fluorouracil resistance in hepatocellular carcinoma by activating the PI3K/PDK1/ROCK1 pathway. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00490-1

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