The HNF1A-AS1/miR-92a-3p axis affects the radiosensitivity of non-small cell lung cancer by competitively regulating the JNK pathway

Cell Biol Toxicol. 2021 Oct;37(5):715-729. doi: 10.1007/s10565-021-09595-z. Epub 2021 Mar 23.

Abstract

Background: It has been widely reported that long non-coding RNAs (lncRNAs) could affect the varieties of tumor response to radiotherapy. LncRNA HNF1A-AS1 is transcribed from HNF1A gene cluster's antisense strand. This work focused on the mechanism of how HNF1A-AS1 participated in the radiosensitivity of non-small cell lung cancer (NSCLC).

Methods: The mRNA or protein expression of HNF1A-AS1, miR-92a-3p MAP2K4, and JNK in NSCLC cells and tissues was detected by qRT-PCR or western blotting. RNA immunoprecipitation (RIP) detection and luciferase reporting system were used to evaluate the relationship between HNFA-AS1 and miR-92a-3p or between miR-92a-3p and MAP2K4. Flow cytometry assays, colony formation, and MTT were performed to analyze the function changes in A549 and Calu-1 cells. The rescue experiment was also conducted to explore the underlying mechanisms.

Results: HNF1A-AS1 was investigated in NSCLC cells and tissues and highly related to the advanced pathological stage. HNF1A-AS1 bound with miR-92a-3p, which was downregulated in NSCLC. It showed that miR-92a-3p was negatively related to HNF1A-AS1. Knockdown of HNF1A-AS1 impacted most cell biological behaviors in NSCLC cells, including restricting the proliferation and aggravating apoptosis. Furthermore, knockdown of HNF1A-AS1 dramatically enhanced radiotherapy sensitivity of NSCLC. Moreover, miR-92a-3p was found to target MAP2K4 and could reduce MAP2K4 expression. Inhibition of HNF1A-AS1 elevated radiotherapy sensitivity and retarded the progression of NSCLC cells, followed by decreasing expression levels of MAP2K4. Besides, MAP2K4 mimic rescued the si-HNF1A-AS1 effects on the biological behavior of NSCLC cells.

Conclusion: HNF1A-AS1 is highly expressed in NSCLC. MiR-92a-3p is the target gene of HNF1A-AS1 and involved in tumor progression by regulating the MAP2K4/JNK pathway. HNF1AS1/miR-92a-3p/MAP2K4 axis plays important roles in radiotherapy resistance of NSCLC.

Keywords: HNF1A-AS1; MAP2K4; Non-small cell lung cancer; Radiosensitivity; miR-92a-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / radiotherapy
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Nuclear Factor 1-alpha
  • Humans
  • Lung Neoplasms* / genetics
  • MAP Kinase Signaling System
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Radiation Tolerance / genetics

Substances

  • Hepatocyte Nuclear Factor 1-alpha
  • MIRN92 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • long non-coding RNA HNF1A-AS1, human