The expression of hepatocyte nuclear factor-4α, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas

Kojima, Kazuhiro; Kishimoto, Takashi; Nagai, Yuichiro; Tanizawa, Toru; Nakatani, Yukio; Miyazaki, Masaru; Ishikura, Hiroshi

doi:10.1080/00313020601024011

Cited by 31 publications

(36 citation statements)

References 39 publications

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“…Forced expression of HNF4α inhibits the proliferation of HCC cells in vitro and suppresses the diethylnitrosamineinduced HCC in rats [33], suggesting its tumor suppressive roles in HCC. On the other hand, HNF4α is up-regulated in gastric intestinal metaplasia [34] and ovarian mucinus tumors [35]. Inhibition of HNF4α activity attenuates the proliferation and induces the apoptosis of colon cancer cells [36].…”

Section: Discussionmentioning

confidence: 98%

Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14

Xuan

Zhao

et al. 2015

Cancer Letters

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Section: Discussionmentioning

confidence: 98%

Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14

Xuan

Zhao

et al. 2015

Cancer Letters

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“…For instance, it has been suggested that there is an equilibrium between GATA-4 transcriptional activation and CCAAT displacement protein-mediated repression of the sucrase-isomaltase gene (13). Furthermore, it is clear that other factors, such as HNF-4␣ (35,39,59) and GATA-5 and GATA-6 (28,36,68), can also participate in the regulation of various aspects of intestinal gene expression (69). Finally, considering the nonterminal differentiated state of our model, it would also be interesting to investigate the involvement of other factors such as Id2, the PAX, Nkx, and HOX families, and the polycomb groups in the global enterocytic differentiation process (45,54,70).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between HNF-1α, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line

Benoit

Paré

Francoeur

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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In the intestinal epithelium, the Cdx, GATA, and HNF transcription factor families are responsible for the expression of differentiation markers such as sucrase-isomaltase. Although previous studies have shown that Cdx2 can induce differentiation in rat intestinal IEC-6 cells, no data are available concerning the direct implication of transcription factors on differentiation in human normal intestinal epithelial cell types. We investigated the role of Cdx2, GATA-4, and HNF-1α using the undifferentiated human intestinal epithelial crypt cell line HIEC. These transcription factors were tested on proliferation and expression of polarization and differentiation markers. Ectopic expression of Cdx2 or HNF-1α, alone or in combination, altered cell proliferation abilities through the regulation of cyclin D1 and p27 expression. HNF-1α and GATA-4 together induced morphological modifications of the cells toward polarization, resulting in the appearance of functional features such as microvilli. HNF-1α was also sufficient to induce the expression of cadherins and dipeptidylpeptidase, whereas in combination with Cdx2 it allowed the expression of the late differentiation marker sucrase-isomaltase. Large-scale analysis of gene expression confirmed the cooperative effect of these factors. Finally, although DcamKL1 and Musashi-1 expression were downregulated in differentiated HIEC, other intestinal stem cell markers, such as Bmi1, were unaffected. These observations show that, in cooperation with Cdx2, HNF-1α acts as a key factor on human intestinal cells to trigger the onset of their functional differentiation program whereas GATA-4 appears to promote morphological changes.

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“…HNFα was reported to be upregulated in human hepatocellular carcinoma (38), human gastric intestinal metaplasia (39), and ovarian mucinus tumors (40). Recent observations implied that a reduction of HNF4α activity by ligand antagonists could attenuate cell proliferation and promote apoptotic cell death in two independent CRC cell lines (41).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor-4α Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species

Darsigny

Babeu²,

Seidman³

et al. 2010

Cancer Research

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Hepatocyte nuclear factor-4α (Hnf4α) is a transcription factor that controls epithelial cell polarity and morphogenesis. Hnf4α conditional deletion during postnatal development has minor effects on intestinal epithelium integrity but promotes activation of the Wnt/β-catenin pathway without causing tumorigenesis. Here, we show that Hnf4α does not act as a tumor-suppressor gene but is crucial in promoting gut tumorigenesis in mice. Polyp multiplicity in Apc Min mice lacking Hnf4α is suppressed compared with littermate Apc Min controls.Analysis of microarray gene expression profiles from mice lacking Hnf4α in the intestinal epithelium identifies novel functions of this transcription factor in targeting oxidoreductase-related genes involved in the regulation of reactive oxygen species (ROS) levels. This role is supported with the demonstration that HNF4α is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of ROS in colorectal cancer cell lines. Analysis of a colorectal cancer patient cohort establishes that HNF4α is significantly upregulated compared with adjacent normal epithelial resections. Several genes involved in ROS neutralization are also induced in correlation with HNF4A expression. Altogether, the findings point to the nuclear receptor HNF4α as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. Cancer Res; 70(22); 9423-33. ©2010 AACR.

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The expression of hepatocyte nuclear factor-4α, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas

Cited by 31 publications

References 39 publications

Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14

Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14

Cooperation between HNF-1α, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line

Hepatocyte Nuclear Factor-4α Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species

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