Open AccessAtonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line
Author(s) -
Fukushima Keita,
Tsuchiya Kiichiro,
Kano Yoshihito,
Horita Nobukatsu,
Hibiya Shuji,
Hayashi Ryohei,
Kitagaki Keisuke,
Negi Mariko,
Itoh Eisaku,
Akashi Takumi,
Eishi Yoshinobu,
Oshima Shigeru,
Nagaishi Takashi,
Okamoto Ryuichi,
Nakamura Tetsuya,
Watanabe Mamoru
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12703
Subject(s) - cancer research , colorectal cancer , carcinogenesis , lgr5 , cancer , cancer stem cell , cell , tumor necrosis factor alpha , cell cycle , biology , medicine , immunology , genetics
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.