<p>Down-Regulation of ZEB1 by miR-199a-3p Overexpression Restrains Tumor Stem-Like Properties and Mitochondrial Function of Non-Small Cell Lung Cancer</p>

Abstract

Objective: ) targeting of 3ʹ-UTR of ZEB1 was characterized as an important way to inhibit invasion and metastases in nonsmall cell lung cancer (NSCLC), one of the most common cancers around the world. Here we aimed to investigate the tumor-suppressive role of miR-199a-3p targeted ZEB1. Materials and Methods: A549 cells were transfected with ZEB1 and/or miR-199a-3p. Then, tumor growth was investigated in xenograft mice. Stem-like property, proliferation and mitochondria injury were further validated in vitro. Results: Overexpression of miR-199a-3p with premiRNAs significantly reduced tumor growth inhibited CD44 and Ki67 and increased Caspase-3 in A549 xenograft mice. Sphere formation and protein expression of stem-like markers showed that miR-199a-3p inhibited stemness of A549 cell. miR-199a-3p reduced proliferation of A549 cells, as showed with EdU staining and reduced expression of Ki67. Transfection of miR-199a-3p also promoted apoptosis, as indicated with increased apoptotic cells with flow cytometry, and increased cleaved Caspase-3/Caspase3 and Bcl-2/Bax. Apoptosis was further validated to be induced with mitochondria dysfunction, which indicated with JC-1 labeled loss of mitochondrial membrane potential, reduced activity of SOD, and increased MDA and LDH. All these effects were inverted with overexpression of ZEB1. Conclusion: Altogether, the findings suggested that the up-regulation of miR-199a-3p significantly inhibited NSCLC growth in vivo, and reduced A549 cell proliferation and promoted mitochondrial-mediated apoptosis, through down-regulation of ZEB1. The findings supported ZEB1 down-expression with miR-199a-3p as a novel therapeutic target for NSCLC treatment.

miR-199a-3p plays an anti-tumorigenic role in lung adenocarcinoma by suppressing anterior gradient 2

“…Furthermore, AGR2 forced expression almost abolished the inhibitory effect of miR-199a-3p on LUAD cell proliferation and apoptosis. In addition to our findings, Bai et al demonstrated that the upregulation of miR-199a-3p inhibited ZEB1 expression in lung cancer cells and further confirmed this effect in xenograft mice [ 20 ]. MiR-199a-3p is considered to target different genes to interfere with the progression of lung cancer.…”

“…Moreover, there is increased expression of miR-199a-3p in patients with lung cancer, and this miRNA could serve as a biomarker for diagnosing lung cancer [ 36 , 37 ]. Bai et al demonstrated that the upregulation of miR-199a-3p inhibited ZEB1 inhibited lung cancer growth in vitro and in vivo [ 20 ]. Therefore, miR-199a-3p plays a tumor-suppressing role during cancer progression.…”

“…MiR-199a-3p is an important indicator for evaluating the prognosis of patients with muscle-invasive bladder cancer after radical cystectomy [ 19 ]. Upregulation of miR-199a-3p inhibits the expression of zinc‐finger E‐box-binding homeobox 1 (ZEB1) to restrain the tumor stem-like properties in non-small cell lung carcinoma (NSCLC) cells [ 20 ]. Nonetheless, the potential mechanism of action of miR-199a-3p in LUAD needs to be further investigated.…”

LncRNA TUG1 promotes Ewing's sarcoma cell proliferation, migration, and invasion via the miR-199a-3p-MSI2 signaling pathway

“…A recent study suggested that miR-199a-3p overexpression halted the carcinogenesis process of esophageal squamous cell carcinoma [36]. In non-small cell lung cancer, miR-199a-3p was found to inhibit stemness and induce mitochondria dysfunction-mediated apoptosis of A549 cells via targeting ZEB1 [37]. Similarly, this study found that the expression level of miR-199a-3p in Ewing's sarcoma tissues and cell lines was significantly lower than that in adjacent non-tumorous tissues and human normal osteoblast cell line, and overexpression of miR-199a-3p could inhibit Ewing's sarcoma cell proliferation, migration and invasion.…”

Circular RNA _NLRP1 targets mouse microRNA-199b-3p to regulate apoptosis and pyroptosis of hippocampal neuron under oxygen-glucose deprivation exposure

“…A research reported that cerebral microvascular endothelial cells displayed less apoptosis levels through microRNA-199b-3p via downregulating MAPK/ERK/EGR1 axis in ischemic stroke [ 14 ]. In addition, microRNA-199b-3p upregulation induced apoptosis mediated by mitochondria pathway through targeting ZEB1 [ 28 ]. Then, MAPK pathway was further investigated in hippocampus neurons under OGD conditions where mmu-miR-199b-3p inhibitor or shRNA-circ_NLRP1 was introduced.…”