Osteopontin‑c isoform inhibition modulates ovarian cancer cell cisplatin resistance, viability and plasticity

Abstract

Osteopontin (OPN) is upregulated in several types of tumor and has been associated with chemoresistance. However, the contribution of OPN splicing isoforms (OPN-SIs) to chemoresistance requires further investigation. The present study aimed to evaluate the expression patterns of each tested OPN-SI in cisplatin (CDDP)-resistant ovarian carcinoma cell lines, focusing on the role of the OPN-c isoform (OPNc) in drug resistance. ACRP ovarian cancer cells resistant to CDDP, as well as their parental cell line A2780, were used. Analyses of the transcriptional expression of OPN-SIs, epithelial-mesenchymal transition (EMT) markers and EMT-related cytokines were performed using reverse transcription-quantitative PCR. OPNc was silenced in ACRP cells using anti-OPNc DNA oligomers and stably overexpressed by transfecting A2780 cells with a mammalian expression vector containing the full length OPNc cDNA. Functional assays were performed to determine cell proliferation, viability and colony formation. The results demonstrated that among the three tested OPN-SIs, OPNc was the most upregulated transcript in the ACRP cells compared with the parental A2780 cells. In addition, the expression levels of P-glycoprotein multidrug transporter were upregulated in CDDP-resistant ACRP cells compared with those in A2780 cells. OPNc knockdown sensitized ACRP cells to CDDP treatment and downregulated P-gp expression levels compared with those in the negative control group. Additionally, silencing of OPNc impaired cell proliferative and colony formation abilities, as well as reversed the expression levels of EMT markers and EMT-related cytokines compared with those in the negative control cells. Notably, although stable OPNc overexpression resulted in increased A2780 cell proliferation, it notably increased CDDP sensitivity compared with that in the cells transfected with a control vector. These results suggested that OPNc silencing may represent a putative approach to sensitize resistant ovarian cancer cells to chemotherapeutic agents.

Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate

“…Remarkably, the shape of attached A549 p21– cells demonstrate elongation absent in the A549 WT cells ( Figure 1G ). The morphological change is reminiscent of epithelial-mesenchymal transition, known to reduce cisplatin sensitivity ( Deng et al, 2019 ; Bahar et al, 2020 ; Brum et al, 2020 ; Chen et al, 2020 ; Siraj et al, 2020 ), which is also observed in our experiments ( Figure 1E ).…”

Osteopontin Splicing Isoforms Contribute to Endometriotic Proliferation, Migration, and Epithelial-Mesenchymal Transition in Endometrial Epithelial Cells

“…In esophageal adenocarcinoma, OPNb cells exhibit significantly increased cell adhesion, while OPNc cells show enhanced cell detachment [ 48 ]. In ovarian cancer, OPNc, but not OPNb, contributes to cancer progression by modulating cancer cell viability, plasticity, and cisplatin resistance [ 19 , 49 ]. The pathogenesis of endometriosis is complicated and possesses multiple characteristics typically attributed to tumors.…”

Prospects for the Use of Pathological Biomineralization in the Diagnosis of Ovarian Cancer

“…The transcription factors Runx2 and Osterix provide OPN control. Also, they have a necessary role in the differentiation and maturation of osteoblasts, regulating their proliferation [72]. Runx2 takes a direct role in early osteogenic differentiation and Osterix in the late stages of osteogenic differentiation.…”