MicroRNA-15a induces cell apoptosis and inhibits metastasis by targeting BCL2L2 in non-small cell lung cancer

Abstract

MicroRNAs (miRNAs) play a critical role in cancer development and progression. Aberrant expression of miR-15a has recently been reported in several cancers, but its role in non-small cell lung cancer (NSCLC) still remains obscure. We investigated the effects of miR-15a on proliferation, apoptosis, and metastasis in A549 cells. Eighteen paired NSCLC and adjacent non-tumor lung tissues were surgically removed and immediately snap frozen until total RNA was extracted and confirmed by two independent pathologists. The targets of miR-15a were predicted by bioinformatics tools. RNA isolation and quantitative real-time PCR (qRT-PCR), Western blot analysis, cell proliferation assay, cell cycle analysis, cell apoptosis assay, and migration and invasion assays were done. The wild type (WT) or mutant type (MT) 3'-untranslated region (UTR) vectors were co-transfected with miR-15a or negative control into A549 cells, and after 24 h of transfection, luciferase activity was measured using the Dual-Glo luciferase assay kit. Statistical analysis was performed using SPSS 13.0 software (SPSS, Chicago, IL, USA). P values of less than 0.05 were considered statistically significant. miR-15a was significantly downregulated in NSCLC than in adjacent non-cancerous tissues. miR-15a overexpression remarkably inhibited cell viability, invasion, and migration and promoted the apoptosis of NSCLC cells. Additionally, inhibition of miR-15a expression had the opposite effects on tumor progression, while cell cycle remained unaltered. Furthermore, we identified that BCL2L2 was a target of miR-15a and negatively regulated by miR-15a at the translational level. miR-15a acts as a tumor suppressor in NSCLC by directly targeting BCL2L2 and may serve as a potential diagnostic biomarker and therapeutic target for NSCLC.

BCL-W has a fundamental role in B cell survival and lymphomagenesis

“…Furthermore, our data revealed that a transcriptionally competent MYC was required for the reduction in BCL-W expression. However, there was no evidence of direct transcriptional activation by MYC, suggesting that MYC was indirectly regulating the expression of BCL-W. We (here) and others (27)(28)(29) have shown that Bcl-w is a target of the miR-15 family, which is known to be regulated by MYC (40). In addition, we recently demonstrated that MYC downregulates the expression of BCL-2 and BCL-XL by transcriptionally upregulating the levels of the miR-15 and let-7 families, respectively (22,23).…”

“…Therefore, we postulated that MYC may be indirectly altering Bcl-w expression through miR. As we (Supplemental Figure 7) and others (27)(28)(29) have shown, Bcl-w mRNA is targeted and negatively regulated by the miR-15 family. Recently, we reported that MYC transcriptionally upregulates this miR family as a mechanism to downregulate Bcl-2 expression (22,23).…”

MicroRNA‑335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2

“…The expression of specific miRNAs may be upregulated in particular types of cancer and downregulated in others; this conflicting observation is predominantly a result of differences in the mechanisms of oncogenesis between tumor types (22,23). Upregulated miRNAs in cancer act as oncogenes by negatively regulating tumor suppressor genes, whereas downregulated miRNAs act as tumor suppressors via the blockade of oncogenes in tumor progression (24,25). Therefore, identifying the targets of miRNAs is essential for understanding the functions of miRNAs in cancer.…”

Epigallocatechin-3-gallate inhibits paclitaxel-induced apoptosis through the alteration of microRNA expression in human dermal papilla cells

“…Additionally, EGCG-regulated miRNAs targeted FOXO1, BCL2L1, BCL2L2, PTEN, BBC3, and MDM2 which are the regulator genes against cell growth, proliferation, and cell death. When FOXO1 is overexpressed, cell proliferation and growth is inhibited by upregulating caspase-3 and caspase-9 and inducing G2/M arrest and (Yang et al 2015). BCL2L1 and BCL2L2, BCL2 family, are pro-oncogene and repress intrinsic pathwaymediated cell death (Denoyelle et al 2014;Zhang et al 2015).…”