Abstract
ObjectivesDown syndrome critical region 1 (DSCR1) is associated with carcinogenesis and tumor growth in several types of malignancy. However, little is known about the role of DSCR1 in CRC progression. The present study aimed to elucidate the clinicopathological significance, prognostic, and function roles of DSCR1 in CRC.MethodsFirstly, we analyzed DSCR1 expression in 58 paired CRC samples and Oncomine database. Then, we analyzed DSCR1 expression in two independent CRC cohorts (test cohort: n = 70; validation cohort: n = 58) and tested its overall survival (OS) by Kaplan-Meier survival analyses. Finally, we overexpressed DSCR1 in two CRC cell lines DLD1 and LoVo and analyzed its effect on cell cycle and senescence.ResultsDSCR1 expression was significantly decreased in CRC samples and associated with clinicopathologic features of CRC patients, such as tumor size, lymph node metastasis, and TNM stage. CRC patients with low expression of DSCR1 had shorter overall survival (OS). Kaplan-Meier survival analyses showed that the expression of DSCR1 was significant factor for OS in both cohorts. Multiple Cox regression analysis showed that DSCR1 expression was an independent prognostic marker for OS in test cohort. Overexpression of DSCR1 isoform 4 (DSCR1-4) increased p21, p16, p-NFAT1, and p-NFAT2, while decreased CDK2, CDK4, and Cyclin D1 in CRC cells. In addition, overexpression of DSCR1-4 prevented proliferation and colony formation, and induced senescence in vitro. Moreover, overexpression of DSCR1-4 inhibited tumor growth and tumor angiogenesis in vivo.ConclusionsOur study found high expression of DSCR1 contributes to favorable prognosis of CRC patients and prevents cell cycle and proliferation of CRC cells, indicating a critical tumor suppressive role in CRC progression.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and one of the leading death causes of cancer patients worldwide [1]
Down syndrome critical region gene 1 (DSCR1) was downregulated in CRC tissues To investigate the role of DSCR1 in CRC progression, we firstly analyzed expression of DSCR1 in Oncomine database
The results showed that DSCR1 level was significantly decreased in CRC tissues compared to normal colon tissues in Oncomine dataset (Fig. 1a, b)
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and one of the leading death causes of cancer patients worldwide [1]. Control of dietary and lifestyle, such as reducing intake of highenergy snack foods and high-energy drinks, was reported to associate to the incidence of CRC [6]. These approaches are far from improving the damage of this global malignancy. It has been reported that syngeneic DSCR1 knockout mice has hyperactivated calcineurin and precocious endothelial apoptosis, which leads to inhibiting formation of an effective tumor vasculature and suppressing tumorigenesis of colon cancer [16]. Another study indicated that DSCR1 may function as a tumor suppressor in early stage transformation of colon cancer by negatively regulating PPARgamma signaling [17]. We investigated the expression of CRC and evaluated its prognostic significance and function in CRC
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