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Predictive Value of RAD51 on the Survival and Drug Responsiveness of Ovarian Cancer Yuchen Feng1, Daoqi Wang2, Luyang Xiong3, Guohua Zhen1 and Jiahong Tan4*

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Predictive Value of RAD51 on the Survival and Drug Responsiveness of Ovarian Cancer Yuchen Feng1, Daoqi Wang2, Luyang Xiong3, Guohua Zhen1 and Jiahong Tan4* Feng et al. Cancer Cell Int (2021) 21:249 https://doi.org/10.1186/s12935-021-01953-5 Cancer Cell International PRIMARY RESEARCH Open Access Predictive value of RAD51 on the survival and drug responsiveness of ovarian cancer Yuchen Feng1, Daoqi Wang2, Luyang Xiong3, Guohua Zhen1 and Jiahong Tan4* Abstract Background: Ovarian cancer has greatly endangered and deteriorated female health conditions worldwide. Refne- ment of predictive biomarkers could enable patient stratifcation and help optimize disease management. Methods: RAD51 expression profle, target-disease associations, and ftness scores of RAD51 were analyzed in ovar- ian cancer using bioinformatic analysis. To further identify its role, gene enrichment analysis was performed, and a regulatory network was constructed. Survival analysis and drug sensitivity assay were performed to evaluate the efect of RAD51 expression on ovarian cancer prognosis. The predictive value of RAD51 was then confrmed in a validation cohort immunohistochemically. Results: Ovarian cancer expressed more RAD51 than normal ovary. RAD51 conferred ovarian cancer dependency and was associated with ovarian cancer. RAD51 had extensive target-disease associations with various diseases, including ovarian cancer. Genes that correlate with and interact with RAD51 were involved in DNA damage repair and drug responsiveness. High RAD51 expression indicated unfavorable survival outcomes and resistance to platinum, taxane, and PARP inhibitors in ovarian cancer. In the validation cohort (126 patients), high RAD51 expression indicated platinum resistance, and platinum-resistant patients expressed more RAD51. Patients with high RAD51 expression had shorter OS (HR 2.968, P < 0.0001) and poorer PFS (HR 2.838, P < 0.0001). RAD51 expression level was negatively cor- related with patients’= survival length. = Conclusions: Ovarian cancer had pronounced RAD51 expression and RAD51 conferred ovarian cancer dependency. High RAD51 expression indicated poor survival and decreased drug sensitivity. RAD51 has predictive value in ovarian cancer and can be exploited as a predictive biomarker. Keywords: Drug responsiveness, Ovarian cancer, Predictor, RAD51, Survival Background regimen for ovarian cancer patients [7, 8]. Te late 1980s Among the malignancies threatening women’s health, witnessed the introduction of carboplatin and taxane [7, ovarian cancer is the most lethal and represents a sali- 8]. Since 1996, the landmark combination regimen of cis- ent public health concern [1–3]. Epithelial ovarian can- platin and paclitaxel following surgical cytoreduction has cer comprises 95% of ovarian cancer and contributes to been a mainstay in the treatment of ovarian cancer [7, 8]. the death of more 230,000 women worldwide annually Aiming to specifcally kill cancer cells, targeted therapy [4–6]. In the late 1970s, cisplatin arose as a therapeutic has ushered a new era for ovarian cancer treatment [4, 5]. Poly-(ADP-ribose)-polymerase (PARP) inhibitors dis- play promising antitumor efects by leveraging synthetic *Correspondence: [email protected] lethality and ameliorate some concerns in handling ovar- 4 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, ian cancer [9]. Despite steady advance in research, the Wuhan 430030, People’s Republic of China disconcerting situation faced by ovarian cancer patients Full list of author information is available at the end of the article has persisted, and the 5-year survival rate has remained © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Feng et al. Cancer Cell Int (2021) 21:249 Page 2 of 13 at approximately 40% for decades [1, 8]. Realization of in ovarian cancer. Genes that correlate with or interact individualized precision medicine requires refnement of with RAD51 were further analyzed. Te efect of RAD51 predictive biomarkers, which would enable patient strati- expression on survival and drug responsiveness in ovar- fcation and selection and could help optimize disease ian cancer was examined in online databases. Finally, the management [4, 10]. predictive value of RAD51 was confrmed in the valida- Ovarian cancer shows a predisposition to genomic tion phase. instability, which is a pervasive characteristic feature of most solid tumors [11]. Te devastating genomic instabil- Methods ity drives disease progression and the potential for drug cBioPortal resistance but also highlights the possibility for treatment As an open-source resource for interactive exploration [12]. Defects in cancer genome have already been recog- of multidimensional cancer genomics datasets, cBioPor- nized in many commonly used treatment regimens [13]. tal (https:// www. cbiop ortal. org) provides high-quality For example, platinum agents induce DNA inter- and access to molecular profles and clinical attributes from intrastrand crosslink lesions, which cannot be repaired large-scale cancer genomic projects [20]. By exploring efciently by ovarian cancer cells with impaired genomes cBioPortal, we obtained the mutation profle and expres- [11]. DNA damage repair acts as a brake and protects sion patterns of RAD51. In addition, clinicopathological against genomic instability and can afect the response to characteristics of involved patients were also retrieved DNA-damaging anticancer therapy [11, 12]. DNA dam- from cBioPortal. Te efect of RAD51 expression on dis- age repair pathways could be exploited as ideal targets for ease-free months of ovarian cancer patients was evalu- therapeutic intervention [11, 12]. Te TCGA network has ated in survival analysis, and log-rank test was used. allowed for a characterization of the genetic signatures of ovarian cancer by integrated genomic analysis, laying the foundation for the discovery of potential predictive bio- Gene Expression Profling Interactive Analysis (GEPIA) markers [14]. To facilitate data mining and a deeper understand- RAD51 or RAD51 recombinase, also known as ing of gene functions, GEPIA (http:// gepia. cancer- pku. RAD51A, which catalyzes the recognition of homology cn) delivers fast and customizable functionalities based and strand exchange and enables timely DNA damage on TCGA and GTEx data [21]. Te profle plotting and repair, is essential for the maintenance of genome integ- comparison of RAD51 expression between various tumor rity [15]. RAD51 has a multifaceted role in carcinogen- tissues and matched normal tissues were performed in esis, cancer progression, and anticancer drug resistance GEPIA using one-way ANOVA test. Correlation analysis [15, 16]. Epithelial–mesenchymal transition-associated concerning RAD51 was implemented using GEPIA, and drug resistance, hypoxia-mediated drug tolerance, and Pearson’s correlation coefcient was calculated. drug resistance in cancer stem cells all involve RAD51 [15, 16]. RAD51 can also upregulate prometastatic gene The Human Protein Atlas expression [16]. RAD51 is a crucial component and func- tions at the core of homologous recombination, which Aiming to map all human proteins in cells, tissues, and recruits and allocates various mediators or regulators organs, the Human Protein Atlas (https:// www. prote inatl or interactors, such as BRCA2, PALB2, and TOPBP1 as. org) has created a genome-wide map of the human [15, 16]. RAD51 overexpression leads to excessive and proteome with integration of various omics technologies improper recombination, thereby triggering genomic [22]. We assessed RAD51 expression in the major tissues instability, which successively drives malignant trans- and organs by using the Human Protein Atlas. formation, contributes to tumor progression, and even induces anticancer drug tolerance [15–17]. Under expo- Kaplan–Meier plotter sure to exogenous insults, formation of RAD51 foci in Integrating gene expression data and clinical informa- cell nucleus represents the assembly and initiation of tion from GEO, EGA, and TCGA, Kaplan–Meier plot- DNA damage repair [18]. Recently, RAD51 was reported ter (https:// kmplot. com/ analy sis/) can analyze the to be a reliable surrogate marker capable of predicting the prognostic value of a particular gene, which enables dis- capacity for homologous recombination repair [18, 19]. covery and validation of survival biomarkers [23]. Ovar- Here, we explored the predictive value of RAD51 in ian cancer patients were divided into two groups based ovarian cancer. RAD51 expression in cancers was pro- on RAD51 expression. Using Kaplan–Meier plotter, the fled to get a general insight and
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