Tumor-associated mesenchymal stem cells promote hepatocellular carcinoma metastasis via a DNM3OS/KDM6B/TIAM1 axis

Cancer Lett. 2021 Apr 10:503:19-31. doi: 10.1016/j.canlet.2021.01.011. Epub 2021 Jan 17.

Abstract

Tumor-associated mesenchymal stem cells (MSCs) play a critical role in the growth and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the crosstalk between MSCs and HCC cells is not completely understood. Here, HCC cells were treated with or without conditioned medium of MSCs (CM-MSC), and examined for differential expression of long non-coding RNAs (lncRNAs). Knockdown and overexpression experiments were conducted to explore the function of the lncRNA DNM3OS in MSC-induced HCC growth and metastasis. CM-MSC treatment led to a concentration-dependent induction of DNM3OS in HCC cells. DNM3OS was significantly upregulated in HCC compared to adjacent liver tissues. High DNM3OS expression was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Silencing of DNM3OS inhibited HCC cell proliferation and invasion in vitro and tumorigenesis and metastasis in vivo. Overexpression of DNM3OS enhanced HCC cell proliferation, invasion, and metastasis. Biochemically, DNM3OS was mainly localized in the nucleus and physically interacted with KDM6B. The association of DNM3OS with KDM6B induced the expression of TIAM1 through reduction of H3K27me3 at the TIAM1 promoter. TIAM1 overexpression restored the proliferation and invasion of DNM3OS-depleted HCC cells. Our data delineate a mechanism by which MSCs accelerate HCC growth and metastasis through a DNM3OS/KDM6B/TIAM1 axis.

Keywords: DNM3OS; Hepatocellular carcinoma; KDM6B; Mesenchymal stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology*
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Culture Media, Conditioned / chemistry
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / chemistry*
  • RNA, Long Noncoding / genetics*
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1 / genetics*

Substances

  • Culture Media, Conditioned
  • RNA, Long Noncoding
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • TIAM1 protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • KDM6B protein, human