Long noncoding RNA SPRY4-IT1 promotes proliferation and metastasis of hepatocellular carcinoma via mediating TNF signaling pathway

J Cell Physiol. 2020 Nov;235(11):7849-7862. doi: 10.1002/jcp.29438. Epub 2020 Jan 13.

Abstract

Our previous studies have indicated that long noncoding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4-IT1) was highly expressed in hepatocellular carcinoma (HCC). However, it still remained unclear how SPRY4-IT1 worked in tumorgenesis in HCC. In this study, we tested the overexpression of SPRY4-IT1 in HCC tissues and cells through a quantitative real-time polymerase chain reaction. Statistical analyses showed that the upregulation had an association with the tumor node metastasis stage, thrombin time, and alkaline phosphatase. Furthermore, SPRY4-IT1 could be involved in cell proliferation, metastasis, and the epithelial-to-mesenchymal transition (EMT) process in HCC in vitro and in vivo. RNA-sequencing and transcriptome analysis were carried out to explore the mechanism of SPRY4-IT1 in HCC. With SPRY4-IT1 being knocked down or overexpressed, the level of proteins in the tumor necrosis factor (TNF) signaling pathway changed. We detected the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a SPRY4-IT1 interacting protein through RNA pull-down assay and liquid chromatography-mass spectrometry, then verified through RNA immunoprecipitation. Downregulation of HNRNPL induced the change of proteins observed on SPRY4-IT1 downregulation revealing the SPRY4-IT1: HNRNPL complex in the TNF signaling pathway and EMT process in HCC. In general, our experimental data and analysis demonstrated the role of SPRY4-IT1 in promoting progress and metastasis of HCC by the TNF signaling pathway.

Keywords: TNF signaling pathway; hepatocellular carcinoma; long noncoding RNA SPRY4-IT1; metastasis; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Proliferation / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Ribonucleoproteins / genetics*
  • Ribonucleoproteins / metabolism
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • HNRNPL protein, human
  • RNA, Long Noncoding
  • Ribonucleoproteins
  • Tumor Necrosis Factor-alpha
  • long noncoding RNA SPRY4-IT1, human