Abstract
Colorectal cancer (CRC) is a common human malignancy worldwide and increasing studies have attributed its malignant progression to abnormal molecular changes in cancer cells. Nuclear division cycle 80 (NDC80) is a newly discovered oncoprotein that regulates cell proliferation and cycle in numerous malignancies. However, its clinical significance and biological role in CRC remain unclear. Therefore, in this study, we firstly analyze its expression in a retrospective cohort enrolling 224 CRC patients and find its overexpression is significantly correlated with advanced tumor stage and poor prognosis in CRC patients. In addition, our result reveals it is an independent adverse prognostic factor affecting CRC‐specific and disease‐free survival. The subgroup analysis indicates NDC80 expression can stratify the clinical outcome in stage II and III patients, but fails in stage I and IV patients. In cellular assays, we find knockdown of NDC80 dramatically inhibits the proliferative ability, apoptosis resistance, cell cycle progression, and clone formation of CRC cells in vitro. Using xenograft model, we further prove knockdown of NDC80 also inhibits the tumorigenic ability of CRC cells in vivo. Finally, the microarray analysis is utilized to preliminarily clarify the oncogenic molecular mechanisms regulated by NDC80 and the results suggest it may promote CRC progression partly by downregulating tumor suppressors such as dual specificity phosphatase 5 and Forkhead box O1. Taken together, our study provides novel evidences to support that NDC80 is not only a promising clinical biomarker but also a potential therapeutical target for CRC precise medicine.
Highlights
Colorectal cancer (CRC) is the third most common human malignancy in the United States, accounting for an estimated 135,430 newly diagnosed cases and 50,260 cancer- related deaths in 2017 [1]
Nuclear division cycle 80 (NDC80) expression is significantly correlated with tumor invasion, lymph node and distant metastasis (P = 0.041, P = 0.013 and P = 0.015), but not with other features including gender, age, tumor location, colon tumor location, tumor size, and tumor differentiation (P = 0.678, P = 0.520, P = 0.733, P = 0.381, P = 0.602, and P = 0.264)
After silencing NDC80 in SW620 cells, we found the protein expression of Dual specificity phosphatase 5 (DUSP5) and Forkhead box O1 (FOXO1) was significantly increased, whereas the opposite was for that of Dual specificity phosphatase 1 (DUSP1), which is somewhat inconsistent with PCR detection (Fig. 6F)
Summary
Colorectal cancer (CRC) is the third most common human malignancy in the United States, accounting for an estimated 135,430 newly diagnosed cases and 50,260 cancer- related deaths in 2017 [1]. Increased screening and improved treatment have been found to effectively reduce CRC mortality during the past decade, significant prognostic disparities still exist in patients within the same pathological stage [2]. This challenging situation may largely reflect the shortage of reliable biomarkers used for precise diagnosis and treatment. Recent studies have strongly supported the clinical applicability of molecular classification in characterizing CRC patients, such as microsatellite instability, chromosome instability, and deficient mismatch repair [3]. Tremendous efforts are still essential for further clarifying CRC-r elated molecular events and identifying more promising molecular biomarkers used for clinical management
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