MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors

Abstract

MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normalmalignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially repressed lung cancer cell growth and tumorigenicity in a dose-dependent manner. Using a bioinformatics approach, we identified miR-31 target mRNAs and independently confirmed them as direct targets in human and mouse lung cancer cell lines. These targets included the tumor-suppressive genes large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A), and expression of each was augmented by miR-31 knockdown. Their engineered repression antagonized miR-31-mediated growth inhibition. Notably, miR-31 and these target mRNAs were inversely expressed in mouse and human lung cancers, underscoring their biologic relevance. The clinical relevance of miR-31 expression was further independently and comprehensively validated using an array containing normal and malignant human lung tissues. Together, these findings revealed that miR-31 acts as an oncogenic miRNA (oncomir) in lung cancer by targeting specific tumor suppressors for repression.

MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

“…In these cases, overexpression of miR-31 could conceivably promote oncogenesis and function as an oncomiR. Indeed it is known that miR-31 can target tumor suppressors LATS2 and PPP2R2A in lung cancer cells (58). Nonetheless, a vast majority of miR-31 targets are pro-oncogenic factors including cell cycle promoting factors such as E2Fs (52), oncogenic tyrosine kinases such as MET and SRC (50), and genes that are up-regulated in metastatic cancer cells (7,8,50,54).…”

LATS tumor suppressor: A new governor of cellular homeostasis

“…56 In addition miRNA-31 has been shown to function as an oncogene by inhibiting the expression of several tumor suppressors including LATS2. 57 In addition, PiWiL2, a regulatory protein which interacts with miRNA, and its associated Piwi-interacting RNAs (piRNAs) have been shown to modulate LATS2 expression as a mechanism in regulating the cell cycle of mesenchymal stem cells. 58 Finally, LATS2 mRNA stability is also regulated by tristetraprolin (TTP), which binds AU-rich elements within the 3'UTR to destabilize LATS2 mRNA and leads to subsequent downregulation of protein expression, 59 a possible mechanism for regulating LATS2 effects on cell proliferation.…”

Genetic and epigenetic changes in lung carcinoma and their clinical implications

“…137 Such miRNAs as miR-126, miR-31, miR-519c, Let-7a, miR-133B, miR-15a, miR-16, and miR-183 have been found to regulate lung cancer cell proliferation, migration and invasion by targeting specific molecules, including Crk, EGFL7, VEGF, LATS2, PPP2R2A, HIF-1a, NIRF, MCL-1, BCL2L2, cyclins D1, D2 and E1, and Ezrin. [138][139][140][141][142][143][144][145][146] Abnormally expressed miRNAs may have potential as markers in lung cancer diagnosis, treatment response, and prognosis. Has-miR-205, which suppresses epithelial-to-mesenchymal transition, has been identified as a highly specific marker for squamous carcinoma of the lung.…”