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

Cell Death Dis. 2018 Feb 15;9(3):263. doi: 10.1038/s41419-018-0333-3.

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 TGFβ receptor and activated the TGFβ-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 TGFβ-Smad signalling pathway. This study might provide a new promising strategy for CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminohydrolases / genetics
  • Aminohydrolases / metabolism*
  • Animals
  • Apoptosis
  • Binding Sites
  • Caco-2 Cells
  • Cell Cycle Checkpoints
  • Cell Proliferation*
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Promoter Regions, Genetic
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta1 / metabolism*
  • Tumor Burden

Substances

  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Aminohydrolases
  • nitrilase