A Role for Hath1, a bHLH Transcription Factor, in Colon Adenocarcinoma

Leow, Ching Ching; Polakis, Paul; Gao, Wei‐Qiang

doi:10.1196/annals.1339.048

Cited by 22 publications

(17 citation statements)

References 38 publications

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“…We and others have reported that ATOH1 is a tumor suppressor that is silenced by genetic and epigenetic mechanisms in most human colon cancers. 16,27 In our previous studies, we showed that Atoh1 is required for Spdef expression in normal mouse intestine. 4,7 Here, we report microarray analysis showing a tight correlation between ATOH1 and SPDEF loss in human colonic adenoma and adenocarcinoma (Figure 1 A ).…”

Section: Discussionmentioning

confidence: 96%

SPDEF Functions as a Colorectal Tumor Suppressor by Inhibiting β-Catenin Activity

Noah

Price

et al. 2013

Gastroenterology

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BACKGROUND & AIMS Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC). METHODS We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. Spdef−/− and wild-type mice (controls) were either bred with ApcMin/+ mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of Spdef also was induced transiently by administration of tetracycline to Spdefdox-intestine mice with established tumors, induced by the combination of AOM and DSS or by breeding with ApcMin/+ mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells. RESULTS In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. Spdef−/−; ApcMin/+ mice developed approximately 3-fold more colon tumors than Spdef+/+; ApcMin/+ mice. Likewise, Spdef−/− mice developed approximately 3-fold more colon tumors than Spdef+/+ mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in Spdef−/− mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from Spdefdox-intestine; ApcMin/+ mice and in Spdefdox-intestine mice after administration of AOM + DSS. SPDEF inhibited the expression of β-catenin–target genes in mouse colon tumors, and interacted with β-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC. CONCLUSIONS SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.

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Section: Discussionmentioning

confidence: 96%

SPDEF Functions as a Colorectal Tumor Suppressor by Inhibiting β-Catenin Activity

Noah

Price

et al. 2013

Gastroenterology

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“…Expression of Hath1 in colon cancer cell line HT29 inhibits proliferation, anchorage-independent growth and expression of MUC2. Thus, Math1 and Hath1 may be repressed by the Wnt signaling pathway (Leow et al, 2004(Leow et al, , 2005.…”

Section: Modifier Genes Of Apc Intestinal Polyposismentioning

confidence: 99%

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Taketo

2006

Oncogene

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The canonical Wnt signaling plays important roles in embryonic development and tumorigenesis. For the latter, induced mutations in mice have greatly contributed to our understanding of the molecular mechanisms of cancer initiation and progression. Here, I will review recent reports on gastrointestinal cancer model mice, with an emphasis on the roles of the Wnt signal pathway. They include: mouse models for familial adenomatous polyposis; modifying factors that affect mouse intestinal polyposis, including the genes that help cancer progression; Wnt target genes that affect mouse intestinal polyposis; and a mouse model of gastric cancer that mimics Helicobacter pyroli infection.

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“…Mucus overlies epithelial cells of colon and acts as a physical barrier that prevents the invasion of colonic bacteria and thus inflammation [7]. The mucus-secreting goblet cells protect the epithelial layer, and the depletion of these cells is a common characteristic of multiple models of murine intestinal inflammation [5, 8], UC patients [9], and colon cancer [10]. The goblet cells are derived from the multipotent stem cells, and the Notch signaling pathway has been shown to play a major role in their differentiation [11].…”

Section: Introductionmentioning

confidence: 99%

Mucus and adiponectin deficiency: role in chronic inflammation-induced colon cancer

Saxena

Baliga

Venkatesh³

et al. 2013

Int J Colorectal Dis

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Purpose This study aims to define the role of adiponectin (APN) in preventing goblet cell apoptosis and in differentiation of epithelial cells to goblet cell lineage resulting in greater mucus production and hence greater protection from chronic inflammation-induced colon cancer (CICC). Methods Six- to eight-week-old male APNKO and C57BL/6 (WT) mice were randomly distributed to three treatment groups: DSS, DMH, DSS+DMH and control. Chronic inflammation was induced in DSS and DSS+ DMH group by administrating 2 % DSS in drinking water for 5 days followed by 5 days of normal drinking water and this constitutes one DSS cycle. Three cycles of DSS were administered to induce chronic inflammation. Cancer was induced in both APNKO and WT mice in DMH and DSS+ DMH groups by intraperitoneal injections of DMH (20 mg/kg body weight) once for DSS+DMH group and once per week for 12 weeks for DMH group. On day 129, the colon tissue was dissected for mucus thickness measurements and for genomic studies. HT29-Cl.16E and Ls174T cells were used for several genomic and siRNA studies. Results APNKO mice have more tumors and tumor area in DSS+DMH group than WT mice. APN deficiency down-regulated goblet to epithelial cell ratio and enhanced the colonic mucosal erosion with reduced mucus thickness. APN increases Muc2 production with no affect on Muc1 production. APN abated goblet cell apoptosis, while APN deficiency reduced epithelial to goblet cell differentiation. Conclusion APN may be involved in reducing the severity of CICC by preventing goblet cell apoptosis and increasing epithelial to goblet cell differentiation.

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A Role for Hath1, a bHLH Transcription Factor, in Colon Adenocarcinoma

Cited by 22 publications

References 38 publications

SPDEF Functions as a Colorectal Tumor Suppressor by Inhibiting β-Catenin Activity

SPDEF Functions as a Colorectal Tumor Suppressor by Inhibiting β-Catenin Activity

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Mucus and adiponectin deficiency: role in chronic inflammation-induced colon cancer

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