LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals

Cell Death Differ. 2017 Sep;24(9):1502-1517. doi: 10.1038/cdd.2017.74. Epub 2017 Jun 23.

Abstract

While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment.

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Chromatin Immunoprecipitation
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / physiology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • MicroRNAs
  • RNA, Long Noncoding
  • Receptors, Androgen
  • long noncoding SARCC, human