MicroRNA‐30a inhibits epithelial‐to‐mesenchymal transition by targeting Snai1 and is downregulated in non‐small cell lung cancer

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expression by base-pairing to the 3 0 -UTR of the target mRNA. Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated. Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E-cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression. In the present study, we found that Snai1, a known transcriptional repressor of E-cadherin and modulator of EMT, is post-transcriptionally targeted by miRNA-30a in non-small cell lung cancer (NSCLC). Consistent with this, microRNA30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E-cadherin (epithelial marker) and negatively with N-cadherin (mesenchymal marker) expression. Forced re-introduction of miR-30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E-cadherin expression. Using a chicken embryonic metastasis assay, we found that miR-30a suppresses in vivo distant metastasis to the lungs and liver. Finally, we screened the expression of miR-30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR-30a was downregulated significantly (p < 0.0001) in tumors compared to corresponding normal tissues. These results suggest that miR-30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC.Lung cancer is the most common cancer world wide in terms of both incidence and mortality. 1 The major problem in the management of lung cancer is metastatic disease, highlighting the importance of a better understanding of the biological processes that occur in tumor cells to promote the aggressive neoplastic phenotype. The hallmarks of malignant transformation are the capabilities of invasion and metastasis. In order to acquire these traits, tumor cells must be able to detach from the primary tumor, migrate, and disseminate to distant organs to form metastases. 2 Now it is clear that a transition of tumor cells at the invasive front, which is characterized by the loss of epithelial markers and the gain of a mesenchyme-like phenotype, plays a key role to induce invasion and metastasis. This transition is called epithelial to mesenchymal transition, or EMT.Epithelial cells are generally characterized by their arrangement as a sheet of cells abutting each other in a uniform fashion. As a result of regularly spaced cell-cell junctions between neighboring cells, epithelial cells cannot move away from the monolayer. On the other hand, mesenchymal cells generally lack tight intercellular adhesions and a regimented structure. The transition of epithelial cells into mesenchymal-like cells is orchestrated by a series of events finally leading to the release of epithelial cells from the surround...

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

“…[37][38][39][40][41] For e.g., let-7, miR-30a, miR-125a-5p, miR-126, miR-183, miR-200, miR-21, miR-221, miR-222, and miR-328 have important roles in EMT, invasion, and metastasis of lung cancer. [42][43][44][45][46][47] In this study, we found that enforced expression of miR-19 (i.e., miR-19a and miR-19b-1) in lung cancer cells A549 and HCC827 cells triggered EMT, as shown by mesenchymal-like morphological changes, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1, and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, FN1, N-cadherin, or snail1), formation of stress fibers, reduced cell adhesion, and enhanced cell migration and invasion. In addition, DNA microarray results also highlighted the expression of genes involved in EMT, migration, and metastasis in miR-19-expressing A549 cells.…”

Absent expression of miR‑30a promotes the growth of lung cancer cells by targeting MEF2D

“…The majority of previous studies have shown that miR-30 family members act as tumor suppressors in various types of cancer (2)(3)(4). In addition, miR-30 family members are frequently found to be downregulated in these types of tumor tissue.…”

“…In other investigations, miR-30b and miR-30c were found to inhibit sarcoma viral oncogene homolog, which affected gefitinib-induced apoptosis and the EMT of NSCLC cells (14). miR-30a was also found to be negatively associated with the expression of N-cadherin, a mesenchymal marker (2), and miR-30d was demonstrated to inhibit tumor growth and invasion in NSCLC (15). However, the possible role of miR-30a in lung cancer remains to be elucidated.…”

“…74104; Qiagen China Co., Ltd., Shanghai, China]. According to the manufacturer's protocol The stem-loop RT-qPCR primers were as follows: miR-30a, RT primer 5'-GTC GTA TCC AGT GCA GGG TCC GAG GTA TTC GCA CTG GAT ACG ACG CTG CA-3' , forward primer 5'-CGA CGA CTT TC A-GTC GGA TGT T-3' and reverse primer 5'-GTG CAG GGT CCG AGG T-3'; U6, RT and reverse primer 5'-GTG CA-GGG TCC GAG GT-3' and forward primer, 5'-CTC GCT TCG GCA GCA CA-3' as previously described (2). The method of quantification was the 2 -ΔΔCq method (16).…”

MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways

“…Different tumor types and tumors at various differentiation stages may exhibit unique miRNA profiles (15). In nonsmall cell lung cancer (NSCLC) cells, miRNA (miR)-494, miR-30a, miR-193b, miR-101, miR-7, and miR-206 have been reported as tumor inhibitors (16)(17)(18)(19)(20)(21), whereas miR-212 is believed to promote carcinogenesis in vitro (22). In patients with NSCLC, high miR-155 and low let-7a-2 expression in tumor tissue have been reported to correlate with poor survival (23).…”