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

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.

Emodin exerts antitumor effects in ovarian cancer cell lines by preventing the development of cancer stem cells via epithelial mesenchymal transition

“…4C and D , the protein expression level of E-cadherin was increased following treatment with emodin, whereas the expression level of N-cadherin was decreased, suggesting that emodin inhibited EMT. In addition, the stemness of the tumors in the emodin treatment groups was significantly suppressed, as evidenced by the decrease in protein expression level of OCT4, which has been validated as a master regulator in the maintenance of the cancer stem-like phenotype ( 37 ).…”

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…In head and neck squamous cell carcinoma, Oct4-high cells tend to display more stem cell-like characteristics such as self-renewal, chemoresistance and invasion capacity compared to Oct4-low ones [ 159 ]. A recent study on liver cancer explored the role of Oct4 in tumor vasculogenesis and revealed the differential role of two Oct4 variants, Oct4A and Oct4B1, in mediating endothelial reprogramming of liver cancer stem cells (LCSCs) into tumor endothelial cells (TECs) in vitro [ 160 ]. Accumulating evidence suggests that Sox family members are upregulated in breast cancer and are involved in promoting tumor progression, invasion, metastasis and chemoresistance.…”

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development

“…Similar to CRC and gastric cancer, dysregulated expression in pathways such as the Wnt, Notch, and TGF-β pathways has been found to contribute to the stemness of HCC CSCs [ 99 , 100 , 101 ]. As a result, surface markers that have been used to identify other CSCs—such as CD24, CD44, CD90, CD133, and EpCAM—have been used to identify HCC CSCs, and intracellular markers, such as NANOG, OCT-3/4, and SOX2, have been used to identify HCC CSCs as well [ 23 , 38 , 98 , 99 , 101 , 102 ].…”