Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A

Hua Guo; Chunfang Ha; Hui Dong; Zhijuan Yang; Yuan Ma; Yonghui Ding

doi:10.1186/s12935-019-1051-3

Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A

Cancer Cell Int. 2019 Dec 21:19:347. doi: 10.1186/s12935-019-1051-3. eCollection 2019.

Authors

Hua Guo^#¹, Chunfang Ha^#¹, Hui Dong², Zhijuan Yang¹, Yuan Ma¹, Yonghui Ding¹

Affiliations

¹ 1Department of Gynecology, General Hospital of Ningxia Medical University, No. 804, Shengli South Street, Xingqing District, Yinchuan, 750004 Ningxia Hui Autonomous Region People's Republic of China.
² 2Scientific Research Equipment Management Center, General Hospital of Ningxia Medical University, Yinchuan, 750004 People's Republic of China.

^# Contributed equally.

Abstract

Background: Ovarian cancer (OC) is a gynecological malignancy with a high mortality. Cisplatin-based treatment is the typical treatment regimen for OC patients; however, it may cause unfavorable resistance. The current study intends to explore the function of cancer-associated fibroblast (CAF)-derived exosomal microRNA-98-5p (miR-98-5p) in cisplatin resistance in OC, and the participation of CDKN1A.

Methods: Bioinformatics analysis was employed in order to obtain cisplatin resistance-related differential genes in OC as well as possible upstream regulatory miRs. After gain- and loss-of-function assays in OC cells, RT-qPCR and western blot analysis were employed to measure CDKN1A and miR-98-5p expression. Dual luciferase reporter assay was applied to verify the targeting relationship between miR-98-5p and CDKN1A. CAFs were treated with miR-98-5p inhibitor, and then exosomes were isolated and co-cultured with OC cells. CCK-8, colony formation and flow cytometry assays were conducted to assess cell proliferation, cell colony formation, cell cycle distribution and cell apoptosis, respectively. At last, xenograft tumor in nude mice was carried out to test whether exosomal miR-98-5p could affect cisplatin resistance in OC in vivo.

Results: CDKN1A was highly expressed in cisplatin-sensitive OC cell lines, and silencing CDKN1A significantly promoted proliferation and cell cycle entry but decreased apoptosis in cisplatin-sensitive OC cells. miR-98-5p targeted CDKN1A to inhibit CDKN1A expression. CAF-derived exosomal miR-98-5p increased OC cell proliferation and cell cycle entry, but suppressed cell apoptosis. Furthermore, exosomal miR-98-5p promoted cisplatin resistance and downregulated CDKN1A in nude mice.

Conclusion: Collectively, CAF-derived exosomes carrying overexpressed miR-98-5p promote cisplatin resistance in OC by downregulating CDKN1A.

Keywords: CDKN1A; Cancer-associated fibroblasts; Cisplatin resistance; Exosomes; Ovarian cancer; microRNA-98-5p.