MiR-149-3p promotes the cisplatin resistance and EMT in ovarian cancer through downregulating TIMP2 and CDKN1A

Abstract

Background Ovarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs (miRNAs) playing essential roles in it. However, the clinical significance of miRNAs and their molecular mechanisms in OC are mostly unknown. Methods miR-149-3p expression was predicted through Gene Expression Omnibus (GEO) data in OC and confirmed by q-PCR in various OC cells and tissues from patients with different clinical characteristics. Moreover, its roles in terms of proliferation, migration and invasion were measured by CCK-8, colony formation, wound healing and transwell assays in OC cells including cisplatin-resistant and cisplatin-sensitive cells. And its effect on epithelial-mesenchymal transition was also assessed through detecting related protein expression. Additionally, its potential targets were verified by dual luciferase assay and Ago-RIP assay. Finally, its oncogenic functions were explored in vivo. Results In data from GSE79943, GSE131790, and TCGA, miR-149-3p was found to be highly expressed in OC tissues and associated with poor survival. In metastasis and chemoresistant tissues and cisplatin-resistant OC cells, its high expression was confirmed. In terms of tumorigenic effects, miR-149-3p knockdown in cisplatin-resistant OC cells inhibited its cisplatin resistance and other malignant phenotypes, while miR-149-3p overexpression in cisplatin-resistant OC cells led to contrary results. Mechanistically, miR-149-3p targeted 3’UTR of CDKN1A and TIMP2 to function as an oncogenic miRNA. Conclusion In brief, miR-149-3p promoted cisplatin resistance and EMT in OC by downregulating CDKN1A and TIMP2, which might provide a potential therapeutic target for OC treatment.

Exosomal miR-483-5p in Bone Marrow Mesenchymal Stem Cells Promotes Malignant Progression of Multiple Myeloma by Targeting TIMP2

“…TIMP2 was a kind of matrix metalloproteinases (MMP) inhibitor, while MMPs were intriguing genes frequently up-regulated in most cancers ( Gobin et al, 2019 ). Consistent with theoretical expectations, as an MMP inhibitor, TIMP2 was downregulated in many cancer types, and its high expression may indicate a better prognosis ( Stetler-Stevenson and Gavil, 2014 ; Wang et al, 2021 ; Wang and Liu, 2021 ). In our research, we found that both TIMP2 mRNA and protein expression were negatively correlated with miR-483-5p.…”

RETRACTED ARTICLE: Protein tyrosine phosphatase receptor type Z1 inhibits the cisplatin resistance of ovarian cancer by regulating PI3K/AKT/mTOR signal pathway

“…Cells were cultured in Dulbecco modified Eagle’s culture medium containing 10% fetal bovine serum (Gibco, Carlsbad, California) in an incubator with 5% carbon dioxide at 37°C. Drug-resistant cell lines SKOV3 and A2780 were constructed by treating the proliferated cell cultures using DDP (Meilun Biotech, Dalian, China) at a concentration of 8 μM for consecutive 12 weeks [ 14 ].…”

Overcoming therapeutic resistance to platinum-based drugs by targeting Epithelial–Mesenchymal transition

“…The expression of miR-363 was also decreased, promoting EMT by attenuating the direct inhibitory effect on Snail (83, 84). In contrast, the expression of miR-149-3p was increased, promoting EMT by downregulating TIMP2 and CDKN1A expression (85). Notably, in OC cells, there is a miR-374b-5p-FOXP1 feedback loop in which miR-374b-5p can negatively regulate FOXP1 by binding to the 3'UTR of FOXP1, which can also repress miR-374b-5p transcription.…”