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Regulation of the tumor suppressor homeogene Cdx2 by HNF4α in intestinal cancer
T Saandi1, F Baraille, L Derbal-Wolfrom
1Inserm, Unité 682, Strasbourg, France.
Abstract:
The gut-specific homeotic transcription factor Cdx2 is a crucial regulator of intestinal development and homeostasis, which is downregulated in colorectal cancers (CRC) and exhibits a tumor suppressor function in the colon. We have previously established that several endodermal transcription factors, including HNF4α and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4α in the mechanism of deregulation of Cdx2 in colon cancers. Crossing Apc(Δ14/+) mice prone to spontaneous intestinal tumor development with pCdx2-9LacZ transgenic mice containing the LacZ reporter under the control of the 9.3-kb Cdx2 promoter showed that this promoter segment contains sequences recapitulating the decrease of Cdx2 expression in intestinal cancers. Immunohistochemistry revealed that HNF4α, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apc(min/+) and Apc(Δ14/+)) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4α and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4α and Cdx2 in several experimental models of human colon cancer cell lines: xenografts in nude mice, wound healing and glucose starvation. Furthermore, Cdx2 decreased by knocking down HNF4α in human colon cancer cells using siRNA and in the colon of mice conditionally knocked out for the Hnf4α gene in the adult intestine (Hnf4α(f/f);VilCre(ERT2) mice). Finally, the conditionally knocked out mice Hnf4α(f/f);VilCre(ERT2) treated with the carcinogen AOM developed colorectal tumors earlier than wild-type mice, as previously reported for mice with a reduced Cdx2 expression. In conclusion, this study provides evidence that the downregulation of HNF4α is an important determinant of the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers. Consistently, similar to Cdx2, HNF4α exerts a tumor suppressor function in the colon in that its loss of function facilitates tumor progression.
Insights
Downregulation of hepatocyte nuclear factor 4-alpha (HNF4α) contributes to reduced Cdx2 expression in colorectal cancers (CRC). Loss of HNF4α function accelerates intestinal tumor progression, indicating its tumor suppressor role in the colon.
Area of Science:
- Gastroenterology
- Molecular Biology
- Oncology
Background:
- Caudal type homeobox 2 (Cdx2) is a key regulator of intestinal development and homeostasis, acting as a tumor suppressor in the colon.
- Cdx2 expression is reduced in colorectal cancers (CRC).
- Hepatocyte nuclear factor 4-alpha (HNF4α) and GATA binding protein 6 (GATA6) are endodermal transcription factors involved in Cdx2 regulation in the normal gut.
Purpose of the Study:
- To investigate the role of HNF4α in the downregulation mechanism of Cdx2 in colon cancers.
- To explore the potential tumor suppressor function of HNF4α in the colon.
Main Methods:
- Utilized Apc(Δ14/+) and pCdx2-9LacZ transgenic mice models for studying Cdx2 promoter activity.
- Employed immunohistochemistry to assess HNF4α and Cdx2 expression in various mouse models of intestinal tumors and human CRC.
- Investigated Cdx2 expression changes following HNF4α knockdown via siRNA in human colon cancer cells and conditional knockout of Hnf4α in mice.
Main Results:
- HNF4α expression decreased concurrently with Cdx2 in genetic and chemically induced mouse models of intestinal tumors, as well as in human CRC.
- HNF4α and Cdx2 showed correlated expression patterns in experimental models of human colon cancer cells.
- Knocking down HNF4α led to decreased Cdx2 levels, and mice with conditional Hnf4α knockout developed tumors earlier after carcinogen treatment.
Conclusions:
- Downregulation of HNF4α is a significant factor in the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers.
- HNF4α functions as a tumor suppressor in the colon, and its loss of function promotes tumor progression, similar to Cdx2.
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