Abstract
BackgroundN-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure.MethodsImmunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay.ResultsNDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation.ConclusionOur study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.
Highlights
N-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis
Results showed that NDRG1 expression was significantly lower in Colorectal cancer (CRC) tissues compared to their corresponding nontumorous tissues (Fig. 1a, p < 0.0001)
The data showed a negative correlation between NDRG1 expression and local invasion, as well as lymphatic metastasis (Table 1)
Summary
N-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; the mechanisms underlying these effects remain obscure. NDRG1 has been proved to play a key role in tumor proliferation, metastasis, differentiation, cell adhesion, cellcycle modulation, and autophagy [7,8,9,10,11,12]. Evidences have demonstrated that NDRG1 expression was significantly decreased in several malignant diseases, including gastric, colorectal, prostate, and breast cancer [13,14,15,16]. Recent studies have shown NDRG1 could induce cancer cell G0/G1 arrest, inhibiting tumor proliferation [13, 25].
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