NF-κB-induced WIP1 expression promotes colorectal cancer cell proliferation through mTOR signaling

Biomed Pharmacother. 2018 Mar;99:402-410. doi: 10.1016/j.biopha.2018.01.075.


Colorectal cancer (CRC) is one of the major causes of cancer deaths worldwide. Wild-type p53-induced protein 1 (WIP1) is overexpressed in multiple human cancers and acted as an oncogene. This study was aimed to investigate the effect of WIP1 in colorectal cancer growth and analyzed underlying mechanisms. Herein, we determined WIP1 expression in CRC tissues and cell lines, as well as evaluated its detailed function in CRC cell proliferation. Several factors have been reported to mediate WIP1 effects; herein, we examined the involvement of mTOR and p21 in WIP1 regulation of CRC cell proliferation. Moreover, NF-κB has been regarded as a positive transcriptional regulator of WIP1 to activate its expression. NF-κB knockdown suppressed CRC cell proliferation, which could be reversed by WIP1 overexpression, through p21 and mTOR. Further, we examined the binding of NF-κB to the promoter region of WIP1. In CRC tissues, NF-κB expression was significantly up-regulated, and positively correlated with WIP1 expression, suggesting that inhibiting NF-κB expression to attenuate its activating effect on WIP1 expression presented a promising strategy of controlling excess proliferation of CRC cell. In summary, WIP1 promotes CRC proliferation through p21 and mTOR, both downstream targets of p53; NF-κB served as a positive transcriptional regulator of WIP1 to activate its expression and affect its function in CRC cells. Our finding provided a novel strategy for treatment for CRC.

Keywords: Cell proliferation; Colorectal cancer (CRC); NF-κB; Wild-type p53-induced protein 1 (WIP1); mTOR; p21.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • NF-kappa B / metabolism*
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Proportional Hazards Models
  • Protein Binding
  • Protein Phosphatase 2C / genetics
  • Protein Phosphatase 2C / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation / genetics


  • Cyclin-Dependent Kinase Inhibitor p21
  • NF-kappa B
  • TOR Serine-Threonine Kinases
  • PPM1D protein, human
  • Protein Phosphatase 2C