Epigenetic and genetic inactivation of tumor suppressor miR-135a in non-small-cell lung cancer

Jin Eun Choi, Hyo Sung Jeon, Hyun Jung Wee, Ji Yun Lee, Won Kee Lee, Shin Yup Lee, Seung Soo Yoo, Sun Ha Choi, Dong Sun Kim, Jae Yong Park

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Despite therapeutic advances, lung cancer prognosis remains poor. Loss of heterozygosity (LOH) in the 3p21 region is well documented in lung cancer, but the specific causative genes have not been identified. Materials and Methods: Here, we aimed to examine the clinical impact of miR-135a, located in the 3p21 region, in lung cancer. miR-135a expression was assessed using quantitative real-time polymerase chain reaction. LOH was analyzed at microsatellite loci D3S1076 and D3S1478, and promoter methylation status was determined by pyrosequencing of resected samples of primary non-small-cell lung cancer (NSCLC). The regulation of telomerase reverse transcriptase (TERT) was evaluated in lung cancer cells H1299 by luciferase report assays after treatment with miR-135a mimics. Results: miR-135a was significantly downregulated in squamous cell cancer (SCC) tumor tissues compared to normal tissues (p = 0.001). Low miR-135a expression was more frequent in patients with SCC (p = 2.9 × 10−4) and smokers (p = 0.01). LOH and hypermethylation were detected in 27.8% (37/133) and 17.3% (23/133) of the tumors, respectively. Overall, 36.8% (49/133) of the NSCLC cases harbored either miR-135a LOH or promoter hypermethylation. The frequencies of LOH and hypermethylation were significantly associated with SCCs (p = 2 × 10−4) and late-stage (p = 0.04), respectively. MiR-135a inhibited the relative luciferase activity of psiCHECK2-TERT-3'UTR. Conclusion: These results suggest that miR-135a may act as a tumor suppressor to play an important role in lung cancer carcinogenesis, which will provide a new insight into the translational value of miR-135a. Further large-scale studies are required to confirm these findings.

Original languageEnglish
Pages (from-to)1012-1020
Number of pages9
JournalThoracic Cancer
Volume14
Issue number11
DOIs
StatePublished - Apr 2023

Keywords

  • DNA methylation
  • loss of heterozygosity
  • methylation prediction region
  • miR-135a
  • non-small-cell lung cancer

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