MUS81 Participates in the Progression of Serous Ovarian Cancer Associated With Dysfunctional DNA Repair System

Renquan Lu; Suhong Xie; Yanchun Wang; Hui Zheng; Hongqin Zhang; Minjie Deng; Weizhong Shi; Ailing Zhong; Miaomiao Chen; Meiqin Zhang; Xiaofeng Xu; Masood A Shammas; Lin Guo

doi:10.3389/fonc.2019.01189

MUS81 Participates in the Progression of Serous Ovarian Cancer Associated With Dysfunctional DNA Repair System

Front Oncol. 2019 Nov 15:9:1189. doi: 10.3389/fonc.2019.01189. eCollection 2019.

Authors

Renquan Lu^{1

2}, Suhong Xie^{1

2}, Yanchun Wang¹, Hui Zheng¹, Hongqin Zhang^{1

2}, Minjie Deng¹, Weizhong Shi³, Ailing Zhong^{1

2}, Miaomiao Chen^{1

2}, Meiqin Zhang⁴, Xiaofeng Xu¹, Masood A Shammas⁵, Lin Guo^{1

2}

Affiliations

¹ Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Clinical Laboratory, Shanghai Proton and Heavy Ion Center, Shanghai, China.
⁴ Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁵ Department of Medical Oncology, Dana Farber (Harvard) Cancer Institute, Boston, MA, United States.

Abstract

Objective: Methyl methanesulfonate ultraviolet sensitive gene clone 81 (MUS81) is a structure-specific endonuclease that plays a pivotal role in the DNA repair system of cancer cells. In this study, we aim to elucidate the potential association between the dysfunction of MUS81 and the progression of Serous Ovarian Cancer (SOC). Methods: To investigate the association between MUS81 and prognosis of SOC, immunohistochemistry technology and qPCR were used to analyze the level of MUS81 expression, and transcriptional profile analysis and protein interaction screening chip were used to explore the MUS81 related signal pathways. Random amplified polymorphic DNA (RAPD) analysis, immunofluorescence and comet assays were further performed to evaluate genomic instability and DNA damage status of transduced SOC cells. Experiments both in vitro and in vivo were conducted to verify the impact of MUS81 silencing on chemotherapeutic drug sensitivity of SOC. Results: The overexpression of MUS81 in SOC tissues was related to poor clinical outcomes. The transcriptional chip data showed that MUS81 was involved in multiple pathways associated with DNA repair. Deficiency of MUS81 intensified the genome instability of SOC cells, promoted the emergence of DSBs and restrained the formation of RAD51 foci in SOC cells with exposure to UV. Furthermore, downregulation of MUS81 enhanced the sensitivity to Camptothecin and Olaparib in SOC cell lines and xenograft model. Conclusions: MUS81 is involved in the progression of SOC and inhibition of MUS81 could augment the susceptibility to chemotherapeutic agents. MUS81 might represent a novel molecular target for SOC chemotherapy.

Keywords: DNA damage; MUS81; chemotherapy; homologous recombination (HR); ovarian cancer.