MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression

Xiang, Ying; Chen, Yajun; Yan, Yun-Bo; Liu, Yu; Qiu, Jiao; Tan, Rui-Qiao; Tian, Qing; Guan, Li; Niu, Sheng; Xin, Hong‐Wu

doi:10.7150/jca.41135

Cited by 18 publications

(12 citation statements)

References 29 publications

(43 reference statements)

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“…Some study suggested that Twist promotes platinum resistance in ovarian cancer via activation of collagen type XI alpha 1 (COL11A1), GAS6, L1CAM, and Akt signaling [ 35 , 116 ]. Recently, acquisition of therapeutic resistance in ovarian cancer correlated with Twist, EMT phenotype and micro-RNA [ 117 , 118 , 119 , 120 ]. Various approaches were applied to overcome the clinical challenges of metastasis and chemoresistance in OC including nanoparticle delivery of siRNA against Twist [ 121 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Bahar

Kim

et al. 2020

IJMS

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Ovarian cancer (OC) is the most lethal of the gynecologic cancers, and platinum-based treatment is a part of the standard first-line chemotherapy regimen. However, rapid development of acquired cisplatin resistance remains the main cause of treatment failure, and the underlying mechanism of resistance in OC treatment remains poorly understood. Faced with this problem, our aim in this study was to generate cisplatin-resistant (CisR) OC cell models in vitro and investigate the role of epithelial–mesenchymal transition (EMT) transcription factor Twist on acquired cisplatin resistance in OC cell models. To achieve this aim, OC cell lines OV-90 and SKOV-3 were exposed to cisplatin using pulse dosing and stepwise dose escalation methods for a duration of eight months, and a total of four CisR sublines were generated, two for each cell line. The acquired cisplatin resistance was confirmed by determination of 50% inhibitory concentration (IC50) and clonogenic survival assay. Furthermore, the CisR cells were studied to assess their respective characteristics of metastasis, EMT phenotype, DNA repair and endoplasmic reticulum stress-mediated cell death. We found the IC50 of CisR cells to cisplatin was 3–5 times higher than parental cells. The expression of Twist and metastatic ability of CisR cells were significantly greater than those of sensitive cells. The CisR cells displayed an EMT phenotype with decreased epithelial cell marker E-cadherin and increased mesenchymal proteins N-cadherin and vimentin. We observed that CisR cells showed significantly higher expression of DNA repair proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly (ADP-ribose) polymerases 1 (PARP1), with significantly reduced endoplasmic reticulum (ER) stress-mediated cell death. Moreover, Twist knockdown reduced metastatic ability of CisR cells by suppressing EMT, DNA repair and inducing ER stress-induced cell death. In conclusion, we highlighted the utilization of an acquired cisplatin resistance model to identify the potential role of Twist as a therapeutic target to reverse acquired cisplatin resistance in OC.

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Section: Discussionmentioning

confidence: 99%

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Bahar

Kim

et al. 2020

IJMS

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“…In recent years, it has become increasingly popular to study the roles played by various miRNAs in cancer chemoresistance. In OC, many miRNAs, such as miR-132 [ 10 ], miR-142 [ 11 ], miR-186 [ 12 ], and miR-195 [ 13 ] have been reported to modulate cisplatin-resistance. Studies conducted on miR-105 have mainly focused on its role as a prognostic marker and its ability to modulate cell proliferation, apoptosis, and metastasis [ 14 – 17 ].…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-105-1 Regulates Cisplatin-Resistance in Ovarian Carcinoma Cells by Targeting ANXA9

Kou

Ding

et al. 2021

Analytical Cellular Pathology

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Purpose. Cisplatin is one of the most effective drugs for treating ovarian carcinoma (OC), which is among the most lethal types of carcinoma. However, the chemoresistance to cisplatin that develops over time leads to a poor clinical outcome for many OC patients. Therefore, it is necessary to clearly understand the molecular mechanisms of chemoresistance. In this study, we examined how Hsa-miR-105-1 functions in cisplatin-resistant OC cells. Methods. The levels of Hsa-miR-105-1 expression in cisplatin-sensitive and resistant OC cell lines were detected by qRT-PCR. The target gene of Hsa-miR-105-1 was predicted by using the TargetScan and Starbase databases and verified by the double luciferase reporter gene assay. The target gene of Hsa-miR-105-1 was identified as ANXA9, and ANXA9 expression was evaluated by qRT-PCR, western blotting, and immunofluorescence. To validate the function of Hsa-miR-105-1 in OC cells, we silenced or overexpressed Hsa-miR-105-1 in cisplatin-sensitive or resistant OC cell lines, respectively. Furthermore, the expression levels of several apoptosis-related proteins, including P53, P21, E2F1, Bcl-2, Bax, and caspase-3, were examined by western blot analysis. Results. The levels of Hsa-miR-105-1 expression were abnormally downregulated in cisplatin-resistant OC cells, while ANXA9 expression was significantly upregulated in those cells. Treatment with an Hsa-miR-105-1 inhibitor promoted the expression of ANXA9 mRNA and protein, enhanced the resistance to cisplatin, and attenuated the cell apoptosis induced by cisplatin in cisplatin-sensitive OC cells. Moreover, treatment with Hsa-miR-105-1 mimics inhibited ANXA9 expression, which further increased the levels of P53, P21, and Bax expression and decreased the levels of E2F1 and Bcl-2 expression, finally resulting in an increased sensitivity to cisplatin in cisplatin-resistant OC cells. Conclusion. We found that a downregulation of Hsa-miR-105-1 expression enhanced cisplatin-resistance, while an upregulation of Hsa-miR-105-1 restored the sensitivity of OC cells to cisplatin. The Hsa-miR-105-1/ANXA9 axis plays an important role in the cisplatin-resistance of OC cells.

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“…MiRNAs function as chemoresistant modulators and can be considered as potential therapeutic targets during cisplatin therapy. 38,39 Among these cancer-related miRNAs, miR-183 has been reported to be responsible for tumorigenesis and drug resistance in cancers including EC. 26,27,40,41 Consistent with these previous reports, we observed significant upregulation of miR-183 in EC cell lines and patients' tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

<p>Knockdown of miR-183 Enhances the Cisplatin-Induced Apoptosis in Esophageal Cancer Through Increase of FOXO1 Expression</p>

Chen

Zheng

Xue

et al. 2020

OTT

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Background: As an important member of platinum-based chemotherapeutic drugs, cisplatin is effective and is commonly used in the treatment of esophageal cancer. However, repeated use of cisplatin usually causes severe side-effects on patients. Novel approaches should be explored to increase the sensitivity of cancer cells to cisplatin. Methods: The expression level of miR-183 in esophageal cancer tissues and cell lines was measured by quantitative reverse transcriptase real-time PCR (qRT-PCR). The sensitivity of EC cell lines to cisplatin was evaluated by CCK-8 assay and flow cytometry. Luciferase reporter assay was used to confirm the association between miR-183 and FOXO1. The apoptosis pathway of EC cells was tested by Western blot assay. Results: The expression level of miR-183 was increased in esophageal cancer patients' tumor tissues and esophageal cancer cell lines. However, knockdown of miR-183 was found to enhance the effect of cisplatin on inducing the apoptotic cell death of esophageal cancer cells. In the mechanism research, we proved that FOXO1 was the target of miR-183 in esophageal cancer cells. Inhibition of miR-183 increased the expression of FOXO1 to promote the expression of Bim and Noxa. As Bim and Noxa acted as key pro-apoptotic proteins in mitochondrial apoptosis, inhibition of miR-183 enhanced the cisplatin-induced apoptosis pathway in esophageal cancer. Conclusion: Knockdown of miR-183 enhanced the cisplatin-induced apoptosis in esophageal cancer through an increase of FOXO1 expression.

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MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression

Cited by 18 publications

References 29 publications

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Hsa-miR-105-1 Regulates Cisplatin-Resistance in Ovarian Carcinoma Cells by Targeting ANXA9

<p>Knockdown of miR-183 Enhances the Cisplatin-Induced Apoptosis in Esophageal Cancer Through Increase of FOXO1 Expression</p>

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