Upregulation of lncRNA DARS-AS1 accelerates tumor malignancy in cervical cancer by activating cGMP-PKG pathway

J Biochem Mol Toxicol. 2021 Jun;35(6):1-11. doi: 10.1002/jbt.22749. Epub 2021 Feb 25.

Abstract

This paper investigates the function of lncRNA DARS-AS1 in cervical cancer (CC) as well as its in-depth mechanism. The differential expression of DARS-AS1 and ATP1B2 were analyzed based on The Cancer Genome Atlas and the Genotype-Tissue Expression databases, and the survival rate was measured using Kaplan-Meier survival analysis. Biological function experiments were performed to detect cell proliferation, invasion, and migration. Quantitative real-time polymerase chain reaction was carried out to detect the expression of DARS-AS1 and ATP1B2. Western blot analysis was utilized to assess the protein levels of ATP1B2 and cGMP-PKG pathway-related proteins. DARS-AS1 was expressed at high levels in CC tissues and cell lines, and high expression of DARS-AS1 indicated a lower survival rate. CCK-8 and colony formation assays revealed that the overexpression of DARS-AS1 promoted the proliferation of CC cells. Furthermore, bioinformatics analysis suggested that the cGMP-PKG pathway ranks as the first pathway enriched by the differential genes that correlated with DARS-AS1 (|r| > 0.4). ATP1B2, as a cGMP-PKG pathway-related gene, was significantly correlated with the overall survival of CC patients. We further confirmed that ATP1B2 was lowly expressed in CC and negatively correlated with the DARS-AS1 expression. Then, biological function experiments exhibited that the promotion of cell proliferation, invasion, and migration resulted due to the upregulation of DARS-AS1 could be canceled by ATP1B2 overexpression. Finally, Western blot revealed that upregulation of DARS-AS1 could activate the cGMP-PKG pathway, while overexpression of ATP1B2 reversed this activation. Our study revealed that DARS-AS1/ATP1B2 contributes to regulating the progression of CC at least partially by modulating the cGMP-PKG pathway.

Keywords: ATP1B2; DARS-AS1; cGMP-PKG pathway; cervical cancer; expression.

MeSH terms

  • Cyclic GMP / genetics
  • Cyclic GMP / metabolism*
  • Cyclic GMP-Dependent Protein Kinases / genetics
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Female
  • Humans
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Second Messenger Systems*
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Neoplasm Proteins
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP