Epigenetic Inactivation of microRNA-34b/c Predicts Poor Disease-Free Survival in Early-Stage Lung Adenocarcinoma

Abstract

Purpose The microRNA-34b/c (miR-34b/c) has been considered a tumor suppressor in different tumor types and it is a known transcriptional target of the tumor suppressor gene TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in early stage lung adenocarcinoma (AC) patients and to determine the functional role of miR-34b/c re-expression in lung AC cell lines. Experimental Design Aberrant methylation and expression of miR-34b/c were assessed in 15 lung AC cell lines and a cohort of 140 early stage lung AC. Lung AC cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion and apoptosis were investigated. Results Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung AC cell lines and 64 out of 140 (46%) primary lung adenocarcinomas. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially in those harboring a TP53 mutation. Patients with high levels of miR-34b/c methylation had significantly shorter disease-free survival and overall survival as compared to patients with unmethylated miR-34b/c or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung AC cell lines decreased cell proliferation, migration and invasion. Conclusions Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in early stage lung AC patients with surgically resected tumors. Re-expression of miR-34b/c leads to a less aggressive phenotype in lung AC cell lines.

A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

“…miR-210, which was highly expressed in heavy smokers, has been associated with hypoxia in lung cancer and positively regulates HIF-1a (41). Certain miRNAs negatively correlated with smoking status (such as miR-342-5p and miR-34b) may act as tumor suppressor miRNAs, and their expression may be regulated by epigenetic mechanisms (42).…”

Epigenetically regulatedMIR941andMIR1247target gastric cancer cell growth and migration

“…MIR127, MIR9, MIR148, MIR203, MIR340, MIR18, and MIR34b/c are several examples of DNA methylation regulated miRNAs. 14,23,[31][32][33] In the case of MIR34b/c, this locus has been reported to be epigenetically regulated in several cancers 31,34 Recently, MIR34b/c was shown to be a tumor suppressor mediating p53 activation in both colon and gastric cancers. 23,33,35 In addition, methylation of MIR124 families was initially described in colorectal cancer and was subsequently reported in tumors or other origins.…”

MicroRNA-206 inhibits the viability and migration of human lung adenocarcinoma cells partly by targeting MET

“…Aberrant expression of miRNAs has been observed in lung cancer, including upregulation of miR-21, miR-17-92, miR-155 and miR-367 (6)(7)(8) and downregulation of let-7, miR-34b/c, miR-449a, miR-1 and miR-145 (8)(9)(10)(11)(12). This indicates that miRNAs can function as tumor suppressors and oncogenes in tumor development.…”