Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.
Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.
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DOI：
10.1111/cas.12703
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发表时间：
2015-08
期刊：
影响因子：
5.7
通讯作者：
Watanabe M
中科院分区：
文献类型：
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作者：
Fukushima K;Tsuchiya K;Kano Y;Horita N;Hibiya S;Hayashi R;Kitagaki K;Negi M;Itoh E;Akashi T;Eishi Y;Oshima S;Nagaishi T;Okamoto R;Nakamura T;Watanabe M
炎症性肠病(IBD)患者患结肠炎相关性结直肠癌(CAC)的风险增加。CAC细胞常常产生化疗耐药，导致比散发性结直肠癌(CRC)预后更差。CAC增强恶性潜能的机制尚不清楚。我们以前曾报道，转录因子无性同源1(Atoh1)蛋白的蛋白酶体降解导致了非粘液性形式的结直肠癌。Atoh1蛋白是否在CAC中表达也尚不清楚。因此，在本研究中，我们研究了Atoh1蛋白在CAC中是否稳定。因此，肿瘤坏死因子-α通过AKT使β失活，从而稳定Atoh1蛋白，从而形成粘液性结直肠癌细胞系。Atoh1蛋白还通过上调Lgr5的表达来丰富肿瘤干细胞和处于G0/G1期的细胞，导致对5-氟尿嘧啶和奥沙利铂的化疗耐药，并促进细胞迁移。免疫荧光染色显示粘液性癌组织中NF-κB p65在细胞核内聚集，并伴有Atoh1的表达。总之，与癌变相关的炎症可能保留了肠上皮细胞(IEC)的分化系统，导致获得了与肿瘤干细胞浓缩相关的粘液表型和高恶性潜能。
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.