Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line

Cancer Sci. 2015 Aug;106(8):1000-7. doi: 10.1111/cas.12703. Epub 2015 Jul 14.


Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colorectal cancer (CAC). CAC cells often develop chemoresistance, resulting in a poorer prognosis than that of sporadic colorectal cancer (CRC). The mechanism by which CAC enhances malignant potential remains unknown. We have previously reported that the proteasomal degradation of the transcription factor Atonal homolog 1 (Atoh1) protein results in the non-mucinous form of CRC. It also remains unknown whether Atoh1 protein is expressed in CAC. Therefore, in the present study, we investigated whether Atoh1 protein stabilizes in CAC. Consequently, the treatment with TNF-α stabilized Atoh1 protein through the inactivation of GSK-3β via Akt, resulting in the mucinous form of CRC cell lines. Atoh1 protein also enriched cancer stem cells with upregulated Lgr5 expression and cells in G0/G1 cell cycle phase, resulting in both the chemoresistance to 5-fluorouracil and oxaliplatin and the promotion of cell migration. Immunofluorescence of the human mucinous CAC specimens showed the accumulation of NF-κB p65 at nuclei with the expression of Atoh1 in mucinous cancer. In conclusion, the inflammation associated with carcinogenesis may preserve the differentiation system of intestinal epithelial cell (IEC), resulting in the acquisition of both the mucinous phenotype and high malignant potential associated with the enrichment of cancer stem cell.

Keywords: Atonal homolog 1; cancer stem cells; colitis-associated cancer; inflammatory bowel disease; signet ring cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blotting, Western
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Female
  • Humans
  • Inflammatory Bowel Diseases / complications
  • Intestinal Mucosa / pathology
  • Male
  • Middle Aged
  • Neoplastic Stem Cells / pathology*
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism*


  • ATOH1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Tumor Necrosis Factor-alpha