FOXM1 Promotes Tumor Progression by Targeting CDCA5 in Adrenocortical Carcinoma

Background: Adrenocortical carcinoma (ACC) is characterized with low incidence but poor prognosis. Though promotional effect of FOXM1 has been reported in various malignancies, the regulatory role of FOXM1 in ACC and underlying mechanism still remains unknown. Methods: The FOXM1 expression difference between ACC tumor and non-functioning adrenal adenoma tissues was evaluated by qPCR and immunohistochemistry using clinical specimens collected in West China Hospital. Bioinformatic analysis was conducted to explore differentially expressed genes between ACC and normal adrenal tissues. Venn diagram was constructed using FOXM1 co-expressed and survival related genes to identify crucial FOXM1 related genes in ACC. Co-immunoprecipitation was performed to explore the interaction of FOXM1 with CDCA5. sh-RNA was used to knock-down the expression of FOXM1 and CDCA5 respectively and their effects on ACC cell proliferation, migration and invasion were detected using experiments including CCK-8, Colony formation, EDU, Wound healing and Transwell assay. Mouse ACC Xenograft Model was used to explore the effect FOXM1 overexpression on tumor growth in vivo. Findings: We identified an upregulated FOXM1 expression in our clinical ACC specimens. High FOXM1 expression was associated with poor survival prognosis and high CDCA5 expression in ACC. CCK-8, Colony formation and EDU assay indicated FOXM1 overexpression promoted ACC cell proliferation, which was suppressed in sh-FOXM1 group. Wound healing and Transwell assays showed the migration and invasion abilities of ACC cells were significantly promoted in FOXM1 overexpression group but inhibited in FOXM1 knockdown group. However the promotional effects of FOXM1 overexpression on ACC tumor cell proliferation, invasion and migration were reversed when CDCA5 was knockdown, which indicated the effect of FOXM1 on promoting ACC progression was mediated by CDCA5. Co-immunoprecipitation results also revealed direct interaction between FOXM1 and CDCA5. Xenograft mouse model experiments indicated FOXM1 promoted tumor growth and CDCA5 expression in vivo. Interpretation: In summary, FOXM1 overexpression is confirmed in ACC tumor tissues and contributed to ACC progression via targeting CDCA5. FOXM1-CDCA5 axis in regulating tumor progression could be a promising therapeutic target in ACC.Funding Information: This paper was supported by the following grants: Funding from China Scholarship Council (Grant number: 202006240301) to Shengzhuo Liu; Sichuan Science and Technology Program [grant number 2019YJ0133]; Chengdu Science and Technology Program [grant number 2019-YF05-00084-SN]; and 1.3.5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University [grant number 2018HXFH049, ZYJC18004, ZY2016104, 2021HXFH007].Declaration of Interests: The authors declare that they have no competing interestsEthics Approval Statement: Written informed consents for sample collection and subsequent analysis were obtained from the patients. Approvement of this study was obtained from West China Hospital Ethics committee. Approval of this study was obtained from the Animal Ethics Committee of West China Hospital (Approval No:20211068A).