CDKN3 promotes tumor progression and confers cisplatin resistance via RAD51 in esophageal cancer

Cancer Management and Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Cancer Management and Research downloaded from https://www.dovepress.com/ For personal use only. CDKN3 promotes tumor progression and confers cisplatin resistance via RAD51 in esophageal cancer This article was published in the following Dove Press journal: Cancer Management and Research Jiansong Wang 1 Wencheng Che 2 Weimin Wang 1 Gongzhang Su 3 Tianchang Zhen 3 Zhongmin Jiang 3 1 Graduate Department, Weifang Medical University, Weifang, Shandong 261031, People’s Republic of China; 2Department of Thoracic Surgery, Zibo Central Hospital, Zibo, Shandong 255022, People’s Republic of China; 3Department of Thoracic Surgery, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, People’s Republic of China Purpose: Esophageal cancer (ESCA) progression and chemoresistance are critical factors that impact the survival of patients with esophageal cancer. Cyclin dependent kinase inhibitor 3 (CDKN3) is an important regulator of the cell cycle that has received little attention, therefore the purpose of this study was to investigate CDKN3 involvement in ESCA. Methods: We first explored the public database in addition to our cohort to evaluate the expression of CDKN3 in ESCA patients. We performed bioinformative analysis on specific processes regulated by CDKN3, then we investigated the role of CDKN3 in ESCA progression and chemoresistance in vitro and in vivo. Finally, we sought to elucidate the mechanism of CDKN3 regulation of chemoresistance in ESCA. Results: We discovered that CDKN3 was highly expressed in ESCA and serves as an independent prognostic factor of this disease. Bioinformatic analysis showed CDKN3 involvement in DNA replication, the cell cycle G2/M phase transition, DNA damage repair (DDR) signaling pathways, et al Functional experiments in vitro and in vivo demonstrated that CDKN3 promoted ESCA progression and enhanced cisplatin resistance. Furthermore, CDKN3 inhibition resulted in reduced expression of RAD51, which plays a pivotal role in DDR. Overexpression of RAD51 reversed cisplatin-induced DNA damage and chemosensitivity in CDKN3 inhibited ESCA cell lines. Conclusion: The present research indicated that CDKN3 promoted ESCA progression and enhanced cisplatin resistance via RAD51, thereby influencing overall patient survival. Keywords: esophageal cancer, chemoresistance, CDKN3, RAD51, DNA damage repair Introduction Correspondence: Zhongmin Jiang Department of Thoracic Surgery, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan, Shandong 250014, People’s Republic of China Tel +8 605 318 926 8344 Fax +8 605 318 926 8344 Email Esophageal cancer (ESCA) is a clinically challenging disease that requires extensive medical attention. ESCA is ranked as the sixth leading cause of mortality (508,585 deaths per year) and accounts for 6.6% of all cancer-related deaths.1 ESCA progression and chemoresistance are important factors that influence patient survival. In patients with locally advanced ESCA, whose 5-year survival is about 20%, the standard treatment consists of chemotherapy or chemoradiotherapy with surgery.2 Cisplatin belongs to the platinum-based drug category, which is the most prevalent first-line treatment for ESCA. Unfortunately, cisplatin resistance has become increasingly more common and is a major cause of treatment failure in ESCA.2 Thus, it is imperative to elucidate the mechanisms involved in tumor progression and cisplatin resistance in ESCA. 3253 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 3253–3264 DovePress © 2019 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://doi.org/10.2147/CMAR.S193793 Dovepress Wang et al Cyclin dependent kinase inhibitor 3 (CDKN3), a member of the dual-specificity protein phosphatase family, plays a significant role in cell division and cancer progression. CDKN3 has inhibitory effects on the CDKdriven cell cycle, which is a major event for the progression of cancer cells. Binding of CDKN3 to CDK1/CDK2 results in dephosphorylation of the activated residues and an inhibition of CDK activities.3 Despite the negative regulatory effects of CDKN3 on CDK1 and CDK2, aberrant overexpression of CDKN3 has been implicated in numerous human cancers including prostate cancer,4 gastric cancer,5 and nasopharyngeal carcinoma,6 et al CDKN3 promotes tumor growth, migration, invasion and other aggressive biological processes,5 but its precise mechanism in the regulation of ESCA progression remains unknown. Therefore, this study aimed to explore the role of CDKN3 in ESCA. In the pilot study, we demonstrated that the CDKN3 expression was significantly increased in both esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC) in comparison with normal esophageal epithelial tissues. Elevated levels of CDKN3 is associated with a poor prognosis in ESCA. Interestingly, bioinformatic analysis of The Cancer Genome Atlas (TCGA) database revealed CDKN3 involvement in numerous biological processes including cell cycle transformation, DNA replication and DNA damage repair (DDR), et al Therefore, we hypothesized that CDKN3 promotes tumor progression through cell cycle regulation and contributes to chemoresistance through DDR. We also found that CDKN3 expression was positively correlated with RAD51 expression, which mediates homologous pairing and strand exchange reactions between single and double stranded DNA during repair.7 In all, we determined that CDKN3 can promote cell proliferation by facilitating the cell cycle G2/M transition and influencing chemosensitivity by interacting with RAD51 in ESCA. Material and methods ESCA clinical specimens Patients with pathologically confirmed ESCA who underwent surgery followed by platinum-based adjuvant chemotherapy between September 2016 and September 2017 were enrolled in this study. Patients who received neoadjuvant chemoradiotherapy were excluded. Chemoresistance refers to the occurrence of tumor recurrence or metastasis within one year after 3254 submit your manuscript | www.dovepress.com DovePress surgery, and patients without tumor progression are included in the sensitive group.8 Twenty-three pairs of ESCA and normal tissues were gathered in the Qianfoshan hospital. Th (...truncated)