Oct4 Regulates the Transition of Cancer Stem-Like Cells to Tumor Endothelial-Like Cells in Human Liver Cancer.

Hong-Lin Liu,Hong-Ting Tang,Xiao-Yan Kuang,Qin-Shan Li,Zai Wang,Shi-Qing Xu,Ting-Ting Deng,Qing Fang,Ya-Ping Xu,Liang Peng,Han-Lin Yang

doi:10.3389/fcell.2020.563316

Abstract

Octamer-binding transcription factor 4 (Oct4) has been recently implicated as a proangiogenic regulator in several induced pluripotent stem cells (iPSCs), however, its role in cancer stem-like cells (CSCs) remain unclear. We report here that Oct4 participates in tumor vasculogenesis in liver CSCs (LCSCs). We identify that LCSCs possess the potential of endothelial trans-differentiation under endothelial induction, present endothelial specific markers and their functions in vitro, and participate in neovasculogenesis in vivo. The knockdown of the Oct4A by short hairpin RNA (shRNA) in LCSCs represses endothelial trans-differentiation potential, but induces endothelial lineage-restricted differentiation, the latter is positively regulated by Oct4B1. Furthermore, Oct4 regulates vasculogenesis in LCSCs may be via the AKT-NF-κB-p65 signaling pathway. This work reveals Oct4, which is a crucial regulator, plays a critical role in tumor endothelial-like cells transition of LCSCs through Oct4A and Oct4B1 by different ways. The simultaneous inhibition of both the isoforms of Oct4 is hence expected to help regress neovascularization derived from CSCs. Our findings may provide insights to the possible new mechanisms of tumor vasculogenesis for primary liver cancer.

Highlights

Primary liver cancer is the third leading cause of mortality due to cancer across the world (Bray et al, 2018)
We previously discovered that a single cell-cloned liver CSCs (LCSCs), T3A-A3, has the potential to transdifferentiate into various tumor cells under given conditions and that Oct4A plays the pivotal role in these events (Liu et al, 2013)
To investigate the relationship between Octamer-binding transcription factor 4 (Oct4) and vasculogenesis in hepatoma, we examined 20 Hepatocellular Carcinoma (HCC) specimens by performing Oct4 and CD31 double-labeled immunohistochemistry (IHC) assay

Summary

Introduction

Primary liver cancer is the third leading cause of mortality due to cancer across the world (Bray et al, 2018). Antiangiogenic strategies of inhibiting tumor endothelial cells (TECs) are considered critical for optimizing the therapeutic effect in liver cancers. Oct Regulates Neovasculogenesis of LCSCs therapeutic effects of anti-VEGF/VEGFRs agents are transient and, eventually, bring about drug resistance in a substantial patient population, including that of liver cancer patients (Sampat and O’Neil, 2013; Haibe et al, 2020). It is urgent to elucidate the novel molecular mechanisms of tumor neovascularization and the origin of TECs toward making a breakthrough against the limitations of anti-angiogenic therapy. Whether LCSCs possess the potential to transit into vascular endothelial cells remains unclear. The exploration of the endothelial transition potential of LCSCs and its molecular mechanism is expected to open new avenues toward the development of anti-vasculogenic therapy against liver cancer

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Results

Conclusion