Rce1 suppresses invasion and metastasis of hepatocellular carcinoma via epithelial-mesenchymal transition induced by the TGF-β1/H-Ras signaling pathway

J Cell Physiol. 2020 Mar;235(3):2506-2520. doi: 10.1002/jcp.29155. Epub 2019 Sep 11.

Abstract

Ras converting enzyme 1 (Rce1) plays an important role in invasion and metastasis of malignancy. However, the mechanism has not yet been fully explored in hepatocellular carcinoma (HCC). Primarily, we investigated the expression of Rce1 and H-Ras influence on patient prognosis through the clinical data. Further, we analyzed the regulatory effects of Rce1/H-Ras signal pathway on the epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, we screened out the protein which bonds with Rce1 by CO-IP experiment to discuss the mechanism of Rce1 in EMT of HCC. This research revealed a significantly decreased expression of Rce1 in HCC compared with noncancerous tissues (p < .05). In contrast, H-Ras expression was increased in the tumor. The expression of them was a close association with the differentiation and tumor-node-metastasis (TNM) stage of the tumor (p < .001; p = .035, respectively) and Rce1 was an independent prognostic indicator (95%Cl: 0.193-0.821; p = .013). Through targeted regulation of Rce1 by cDNA or small interfering RNA, results show that the lower expression of Rce1 facilitated EMT and promoted the invasion and metastasis of HCC (p < .05). Furthermore, the CO-IP experiment unfolded that Rce1 could bond with farnesyltransferase-β (FNTB) which mediated the expression of H-Ras. Conclusions: Rce1 inhibits EMT via target regulation H-Ras and suppress the early invasion and metastasis of HCC. It may be a potential therapeutic target and prognostic indicator for HCC.

Keywords: epithelial-mesenchymal transition; hepatocellular carcinoma; invasion and metastasis; ras converting enzyme 1; signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Endopeptidases / genetics*
  • Epithelial-Mesenchymal Transition / genetics
  • Farnesyltranstransferase / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction
  • Transforming Growth Factor beta1 / genetics*

Substances

  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Farnesyltranstransferase
  • Endopeptidases
  • RCE1 protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)