MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis

Cell Oncol (Dordr). 2021 Aug;44(4):821-834. doi: 10.1007/s13402-021-00605-0. Epub 2021 May 11.

Abstract

Purpose: Lenvatinib is a long-awaited alternative to Sorafenib for first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to Lenvatinib results in tumor progression and has become a major obstacle to improving the prognosis of HCC patients. Exploring the mechanisms underlying Lenvatinib resistance is considered essential for the treatment of advanced HCC.

Methods: Lenvatinib resistant HCC (LR-HCC) cells were generated and potential long non-coding RNAs (Lnc-RNAs) upregulated in LR-HCC cells were identified by RNA sequencing. The effects of upregulated Lnc-RNAs were evaluated in vitro in cell models and in vivo in experimental animals using quantitative cell viability and apoptosis assays.

Results: We found that Lnc-RNA MT1JP (MT1JP) was upregulated in LR-HCC cells and inhibited the apoptosis signaling pathway. In addition, we found that sponging of microRNA-24-3p by MT1JP released Bcl-2 like 2 (BCL2L2), an anti-apoptotic protein, thereby forming a positive-feedback loop. The role of this feedback loop was validated using rescue assays. Additionally, we found that upregulation of MT1JP and BCL2L2 impaired the sensitivity of HCC cells to Lenvatinib both vitro and vivo.

Conclusions: Our results suggest a novel molecular feedback loop between MT1JP and apoptosis signaling in Lenvatinib sensitive HCC cells.

Keywords: Apoptosis; Hepatocellular carcinoma; Lenvatinib; Resistance; Sorafenib.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Nude
  • Mice, SCID
  • MicroRNAs / genetics*
  • Phenylurea Compounds / therapeutic use*
  • Quinolines / therapeutic use*
  • RNA, Long Noncoding / genetics*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L2 protein, human
  • MIRN24 microRNA, human
  • MicroRNAs
  • Phenylurea Compounds
  • Quinolines
  • RNA, Long Noncoding
  • lenvatinib