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

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 - Cancer Sci. (2015)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.

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Atonal homolog 1 (Atoh1) protein was expressed in colitis-associated colorectal cancer (CAC) with NF-κB signal activation. (a) HE-staining of colonic specimen taken from patients with colorectal cancer (CRC) or CAC with ulcerative colitis (UC). Scale bar, 100 μm. Muc, mucinous adenocarcinoma; Tub, tubular adenocarcinoma. (b) Immunofluorescence staining of Atoh1 showed Atoh1 protein expression in mucinous carcinoma (MC) of CAC. Scale bar, 50 μm. Lower right frame shows a high-magnified image merged with DAPI. (c) Immunofluorescence analysis of NF-κB p65. The nuclear localization of p65 is shown in both the inflamed and cancer region of colon in patients with UC. The white arrow head indicates a cell with nuclear localization of p65. Scale bar, 50 μm. The lower right frame shows a high-magnified image merged with DAPI. (d) Immunofluorescence staining of HD6 showed the expression of HD6 only in CAC of the colon. Scale bar, 20 μm. The lower right frame shows a high-magnified image merged with DAPI.
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fig05: Atonal homolog 1 (Atoh1) protein was expressed in colitis-associated colorectal cancer (CAC) with NF-κB signal activation. (a) HE-staining of colonic specimen taken from patients with colorectal cancer (CRC) or CAC with ulcerative colitis (UC). Scale bar, 100 μm. Muc, mucinous adenocarcinoma; Tub, tubular adenocarcinoma. (b) Immunofluorescence staining of Atoh1 showed Atoh1 protein expression in mucinous carcinoma (MC) of CAC. Scale bar, 50 μm. Lower right frame shows a high-magnified image merged with DAPI. (c) Immunofluorescence analysis of NF-κB p65. The nuclear localization of p65 is shown in both the inflamed and cancer region of colon in patients with UC. The white arrow head indicates a cell with nuclear localization of p65. Scale bar, 50 μm. The lower right frame shows a high-magnified image merged with DAPI. (d) Immunofluorescence staining of HD6 showed the expression of HD6 only in CAC of the colon. Scale bar, 20 μm. The lower right frame shows a high-magnified image merged with DAPI.

Mentions: We assessed the expression of Atoh1 in CAC in the patients with UC. Immunofluorescence analysis showed that Atoh1 protein was expressed in mucinous carcinoma (MC) lesions of CAC, whereas Atoh1 was not detected in tubular adenocarcinoma in CRC (Fig.5a,b). NF-κB p65 was located, in part, at the nuclei of the intestinal epithelial cell in patients with UC. NF-κB p65 was also located at the nuclei of the MC in CAC, whereas NF-κB p65 was located in the cytoplasm of both noncancerous and cancerous lesions in patients with CRC (Fig.5c). We also assessed the expression of human α-defensin 6 (HD6) in CAC. HD6 was not detected in the colon because HD6 was secreted from Paneth cells in the small intestine. HD6 was expressed only in the mucinous form of CAC (Fig.5d). Moreover, HD6 was highly expressed in the cancer cells of all CAC patients (n = 6) (Fig. S1).


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

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 - Cancer Sci. (2015)

Atonal homolog 1 (Atoh1) protein was expressed in colitis-associated colorectal cancer (CAC) with NF-κB signal activation. (a) HE-staining of colonic specimen taken from patients with colorectal cancer (CRC) or CAC with ulcerative colitis (UC). Scale bar, 100 μm. Muc, mucinous adenocarcinoma; Tub, tubular adenocarcinoma. (b) Immunofluorescence staining of Atoh1 showed Atoh1 protein expression in mucinous carcinoma (MC) of CAC. Scale bar, 50 μm. Lower right frame shows a high-magnified image merged with DAPI. (c) Immunofluorescence analysis of NF-κB p65. The nuclear localization of p65 is shown in both the inflamed and cancer region of colon in patients with UC. The white arrow head indicates a cell with nuclear localization of p65. Scale bar, 50 μm. The lower right frame shows a high-magnified image merged with DAPI. (d) Immunofluorescence staining of HD6 showed the expression of HD6 only in CAC of the colon. Scale bar, 20 μm. The lower right frame shows a high-magnified image merged with DAPI.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4556389&req=5

fig05: Atonal homolog 1 (Atoh1) protein was expressed in colitis-associated colorectal cancer (CAC) with NF-κB signal activation. (a) HE-staining of colonic specimen taken from patients with colorectal cancer (CRC) or CAC with ulcerative colitis (UC). Scale bar, 100 μm. Muc, mucinous adenocarcinoma; Tub, tubular adenocarcinoma. (b) Immunofluorescence staining of Atoh1 showed Atoh1 protein expression in mucinous carcinoma (MC) of CAC. Scale bar, 50 μm. Lower right frame shows a high-magnified image merged with DAPI. (c) Immunofluorescence analysis of NF-κB p65. The nuclear localization of p65 is shown in both the inflamed and cancer region of colon in patients with UC. The white arrow head indicates a cell with nuclear localization of p65. Scale bar, 50 μm. The lower right frame shows a high-magnified image merged with DAPI. (d) Immunofluorescence staining of HD6 showed the expression of HD6 only in CAC of the colon. Scale bar, 20 μm. The lower right frame shows a high-magnified image merged with DAPI.
Mentions: We assessed the expression of Atoh1 in CAC in the patients with UC. Immunofluorescence analysis showed that Atoh1 protein was expressed in mucinous carcinoma (MC) lesions of CAC, whereas Atoh1 was not detected in tubular adenocarcinoma in CRC (Fig.5a,b). NF-κB p65 was located, in part, at the nuclei of the intestinal epithelial cell in patients with UC. NF-κB p65 was also located at the nuclei of the MC in CAC, whereas NF-κB p65 was located in the cytoplasm of both noncancerous and cancerous lesions in patients with CRC (Fig.5c). We also assessed the expression of human α-defensin 6 (HD6) in CAC. HD6 was not detected in the colon because HD6 was secreted from Paneth cells in the small intestine. HD6 was expressed only in the mucinous form of CAC (Fig.5d). Moreover, HD6 was highly expressed in the cancer cells of all CAC patients (n = 6) (Fig. S1).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Gastroenterology and Hepatology, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus