The role of Hes genes in intestinal development, homeostasis and tumor formation

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Development (Impact Factor: 6.27). 03/2012; 139(6):1071-82. DOI: 10.1242/dev.069070
Source: PubMed

ABSTRACT Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.

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    • "Hes1 also induces differentiation of absorptive enterocytes. Absorptive enterocytes are poorly developed in E47-like factor 3 (Elf3) knock-out (KO) mice indicating Elf3's importance in enterocyte development [16] [17]. Notch signaling pathways play a very important role in intestinal epithelial cell differentiation, and both Atoh1 and Hes1 activity are regulated by Notch ligands such as Dll1 and Dll4. "
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    ABSTRACT: Necrotizing enterocolitis is a disease entity with multiple proposed pathways of pathogenesis. Various combinations of these risk factors, perhaps based on genetic predisposition, possibly lead to the mucosal and epithelial injury that is the hallmark of NEC. Intestinal epithelial integrity is controlled by a tightly regulated balance between proliferation and differentiation of epithelium from intestinal epithelial stem cells and cellular loss by apoptosis. various signaling pathways play a key role in creating and maintaining this balance. The aim of this review article is to outline intestinal epithelial barrier development and structure and the impact of these inflammatory signaling and regulatory pathways as they pertain to the pathogenesis of NEC.
    Pathophysiology 02/2014; 21(1). DOI:10.1016/j.pathophys.2014.01.001
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    • "HES1 acts either as an oncogene or as a tumour suppressor, depending on the tumour context. Implicated mechanisms include regulation of proliferation, EMT, metastasis and chemoresistance (Hughes, 2009; Meng et al, 2009; Kannan et al, 2011; Zage et al, 2011; Ueo et al, 2012). Clinical studies of HES1 overexpression in cancer have shown poorer prognosis in ovarian malignancy, either no impact or a modest trend towards poorer overall survival in two small CRC cohorts and no prognostic association in biliary tract cancer (Reedijk et al, 2008; Wang et al, 2010; Mazur et al, 2012). "
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    ABSTRACT: Background: The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance. Methods: Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables. Results: The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19). Conclusion: The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.
    British Journal of Cancer 07/2013; 109(4). DOI:10.1038/bjc.2013.431 · 4.82 Impact Factor
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    ABSTRACT: The small and large intestines are tubular organs composed of several tissue types. The columnar epithelium that lines the inner surface of the intestines distinguishes the digestive physiology of each region of the intestine and consists of several distinct cell types that are rapidly and continually renewed by intestinal stem cells that reside near the base of the crypts of Lieberk├╝hn. Notch signaling controls the fate of intestinal stem cells by regulating the expression of Hes genes and by repressing Atoh1. Alternate models of Notch pathway control of cell fate determination are presented. Roles for Notch signaling in development of the intestine, including mesenchymal and neural cells, are discussed. The oncogenic activities of Notch in colorectal cancer, as well as the tumor suppressive activities of Atoh1, are reviewed. Therapeutic targeting of the Notch pathway in colorectal cancers is discussed, along with potential caveats. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see for revised estimates.
    Annual Review of Physiology 11/2012; DOI:10.1146/annurev-physiol-030212-183741 · 14.70 Impact Factor
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