Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer

Gajek, Arkadiusz; Gralewska, Patrycja; Marczak, Agnieszka; Rogalska, Aneta

doi:10.3390/cancers13112690

Cited by 6 publications

(3 citation statements)

References 164 publications

(180 reference statements)

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“…It is worth mentioning that the functional role of miR-206 and miR-26b in the setting of tumors appears to be inversely related to their endogenous expression levels, as previously highlighted by others. 41,53 Indeed, several reports showed that ovarian cancer features DNA hypermethylation and miRNA levels could be increased by demethylating agents. 26,54 Understanding the mechanisms involved in the regulation of miR-206 levels and the role of estrogenic agents in this process 55 warrants further research.…”

Section: Discussionmentioning

confidence: 99%

Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

et al. 2022

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Few studies explored the role of microRNAs (miRNAs) in the post‐transcriptional regulation of glycolytic proteins and downstream effectors in ovarian cancer cells. We recently showed that the functional activation of the cytoskeletal regulator FAK in endothelial cells is fostered by the glycolytic enhancer 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3). We tested the hypothesis that miR‐206 and mir‐26b, emerging onco‐suppressors targeting PFKFB3 in estrogen‐dependent tumors, would regulate proliferation and migration of serous epithelial ovarian cancer (EOC) cells via common glycolytic proteins, i.e., GLUT1 and PFKFB3, and downstream FAK. PFKFB3 was overexpressed in SKOV3, and its pharmacological inhibition with 3‐(3‐pyridinyl)‐1‐(4‐pyridinyl)‐2‐propen‐1‐one (3PO) significantly reduced cell proliferation and motility. Both miR‐206 and miR‐26b directly targeted PFKFB3 as evaluated by a luciferase reporter assay. However, endogenous levels of miR‐26b were higher than those of miR‐206, which was barely detectable in SKOV3 as well as OVCAR5 and CAOV3 cells. Accordingly, only the anti‐miR‐26b inhibitor concentration‐dependently increased PFKFB3 levels. While miR‐206 overexpression impaired proliferation and migration by downregulating PFKFB3 levels, the decreased PFKFB3 protein levels related to miR‐26 overexpression had no functional consequences in all EOC cell lines. Finally, consistent with the migration outcome, exogenous miR‐206 and miR‐26b induced opposite effects on the levels of total FAK and of its phosphorylated form at Tyr576/577. 3PO did not prevent miR‐26b‐induced SKOV3 migration. Overall, these results support the inverse relation between endogenous miRNA levels and their tumor‐suppressive effects and suggest that restoring miR‐206 expression represents a potential dual anti‐PFKFB3/FAK strategy to control ovarian cancer progression.

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Section: Discussionmentioning

confidence: 99%

Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

et al. 2022

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“…1A). Evidences showed that miR-NAs own great potentials in combination cancer therapy [29][30][31]. For example, targeting miR-21 could enhance conventional chemotherapeutic efficacy, together with overcoming drug resistance and cancer recurrence [32].…”

Section: Mir-138-1-3p Expression Was Reduced In Sorafenib-resistant Cells and May Participate In Resistance Developmentmentioning

confidence: 99%

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

Mou

Pan

et al. 2021

J Biomed Sci

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Background Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. Methods In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. Results We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. Conclusions PAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.

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“…miRs can be detected in biological fluids, allowing non-invasive diagnosis to discriminate malignant lesions from benign lesions. Gajek et al [ 11 ] summarize the latest findings on the utility of miRs as potential biomarkers for ovarian cancer diagnosis and prognosis as circulating miR profiles reflect the tumor profiles. Furthermore, by modulating the sensitivity of the cancer cells to chemotherapeutic agents they might serve as promising therapeutic for multidrug-resistance ovarian cancer [ 11 ].…”

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confidence: 99%

The Role of microRNAs in Cancer: Functions, Biomarkers and Therapeutics

Tucci

2022

Cancers

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Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer

Cited by 6 publications

References 164 publications

Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

The Role of microRNAs in Cancer: Functions, Biomarkers and Therapeutics

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