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.
Highlights
Serous Ovarian Cancer (SOC) is a common gynecological malignancy that has increasing numbers of new diagnoses each year in China [1]
The level of methane sulfonate ultraviolet sensitive gene clone 81 (MUS81) expression in SOC was upregulated in our previous work [11]
There was a trend of abnormal MUS81 expression in ovarian cancer according to TCGA (Figure 1A)
Summary
Serous Ovarian Cancer (SOC) is a common gynecological malignancy that has increasing numbers of new diagnoses each year in China [1]. The most challenging aspect of SOC is its striking genomic instability, which is associated with abnormal DNA damage repair (DDR) pathways [2]. Methyl methane sulfonate ultraviolet sensitive gene clone 81 (MUS81) plays an important role in maintaining genome stability and replication fork integrity [5]. Previous evidence has indicated that MUS81 activity was required for cell survival under DNA damage, such as endogenous agents or anti-cancer compounds [9, 10]. Our previous findings revealed that MUS81 was involved in the evolution and promotion of SOC, and that deficiency of MUS81 enhanced the effects of DNA-damaging agents [11]. The roles of MUS81 could be associated with DNA repair systems and genomic instability; whether MUS81 contributes to cellular adaptations to genotoxic stress in SOC progression remains largely unexplored
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