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NIT1 suppresses tumour proliferation by activating the TGF?1-Smad2/3 signalling pathway in colorectal cancer.

ABSTRACT: NIT1 protein has been reported to be a potential tumour suppressor in tumour progression. However, little is known about the specific role of NIT1 in tumour development and progression. In this study, we confirmed the specific effects of NIT1 in the regulation of colorectal carcinoma cell proliferation. Here, we showed that NIT1 was significantly downregulated in colorectal cancer tissues compared with that in adjacent normal tissues. The decreased expression of NIT1 was significantly correlated with poor differentiation and more serosal invasion. Functional experiments showed that NIT1 inhibited CRC cell growth both in vitro and in vivo. NIT1 induced cell cycle arrest and apoptosis. Furthermore, NIT1 recruited Smad2/3 to the TGF? receptor and activated the TGF?-Smad2/3 pathway by interacting with SARA and SMAD2/3 in CRC. Further study has shown that SMAD3 directly binds to the promoter regions of NIT1 and enhances the transcription of NIT1. Together, our findings indicate that NIT1 suppresses CRC proliferation through a positive feedback loop between NIT1 and activation of the TGF?-Smad signalling pathway. This study might provide a new promising strategy for CRC.

SUBMITTER: Lin C

PROVIDER: S-EPMC5833788 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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NIT1 suppresses tumour proliferation by activating the TGFβ1-Smad2/3 signalling pathway in colorectal cancer.

Lin Chun C Zhang Jianming J Lu Yanxia Y Li Xiaomin X Zhang Wenjuan W Zhang Wei W Lin Weihao W Zheng Lin L Li Xuenong X

Cell death & disease 20180215 3

NIT1 protein has been reported to be a potential tumour suppressor in tumour progression. However, little is known about the specific role of NIT1 in tumour development and progression. In this study, we confirmed the specific effects of NIT1 in the regulation of colorectal carcinoma cell proliferation. Here, we showed that NIT1 was significantly downregulated in colorectal cancer tissues compared with that in adjacent normal tissues. The decreased expression of NIT1 was significantly correlated ...[more]

PMID: 29449642

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Project description:BackgroundNew effective drugs for prostate cancer (PCa) treatment are urgently needed. Avasimibe was recently identified as a promising drug for anticancer therapies. The main purpose of this study was to explore the effects and the underlying mechanisms of avasimibe in prostate cancer.MethodsIn this study, MTT and clonogenic survival assays were performed to detect cell proliferation after avasimibe treatment. The effect of avasimibe on cell migration was measured by wound healing and transwell migration assays. Cell cycle distribution and apoptosis were detected by flow cytometry. Immunofluorescence staining and western blot analysis were used to detect the expression of cell cycle-related proteins and epithelial-mesenchymal transition (EMT)-related proteins. In vivo, the antitumour effects of avasimibe were evaluated using a xenograft model and pulmonary metastasis model.ResultsThe study found that avasimibe suppresses tumour growth and triggers G1 phase arrest. Moreover, the expression of the cell cycle-related proteins CDK2/4/6, Cyclin D1 and Cyclin A1 + A2 was significantly increased and p21 expression was decreased after avasimibe treatment. The migration of PCa cells was attenuated after treatment with avasimibe, followed by the downregulation of the expression of the EMT-related proteins N-cadherin, β-catenin, vimentin, Snail and MMP9 and upregulation of E-cadherin expression. Moreover, E2F-1 was elevated after treatment with avasimibe. After knockdown of E2F-1 expression, the inhibition of cell proliferation and migration caused by avasimibe was significantly recovered. The results of the xenograft model showed that avasimibe suppressed tumour growth in vivo. Immunofluorescence staining revealed lower levels of Ki67 and higher levels of E2F-1 in tumour tissues of the avasimibe group than those of the control group. A pulmonary metastasis model also confirmed the inhibition of PCa metastasis by avasimibe. The number of lung metastatic foci in the avasimibe group was significantly decreased compared with that in the control group.ConclusionsOur results suggest that avasimibe can suppress tumour proliferation and metastasis via the E2F-1 signalling pathway. These findings demonstrate the potential of avasimibe as a new effective drug for PCa treatment.

Dataset Information

NIT1 suppresses tumour proliferation by activating the TGF?1-Smad2/3 signalling pathway in colorectal cancer.

Publications

NIT1 suppresses tumour proliferation by activating the TGFβ1-Smad2/3 signalling pathway in colorectal cancer.

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