title: Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.
abstract: 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.
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Advanced Therapeutics for Gastrointestinal Diseases, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.|Department of Laboratory Medicine and Pathobiology, Faculty of Medicine University of Toronto, Toronto, Canada.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kano
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Horita
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Hibiya
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.|Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Pathology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kitagaki
authors.affiliation: Pathology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Negi
authors.affiliation: Pathology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Eisaku
authors.initials: E
authors.lastname: Itoh
authors.affiliation: Pathology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Akashi
authors.affiliation: Pathology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagaishi
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.|Center for Stem Cell and Regenerative Medicine, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Advanced Therapeutics for Gastrointestinal Diseases, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014409:Tumor Necrosis Factor-alpha; C500942:ATOH1 protein, human
keywords: Atonal homolog 1; cancer stem cells; colitis-associated cancer; inflammatory bowel disease; signet ring cell