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: 6.46). 03/2012; 139(6):1071-82. DOI: 10.1242/dev.069070
Source: PubMed


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.
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    • "The Hes/Hey family of bHLH transcription factors is a major target of the Notch signaling pathway (Artavanis-Tsakonas et al., 1999; Imayoshi and Kageyama, 2011; Ueo et al., 2012). They are expressed in NSCs and progenitor cells in vitro and in vivo, where they repress the expression of genes involved in differentiation, making them critical mediators of fate choice (Sasai et al., 1992; Lobe, 1997; Allen and Lobe, 1999; Hirata et al., 2001; Hatakeyama et al., 2004; Androutsellis-Theotokis et al., 2006, 2008a,b, 2009, 2010a,b; Basak and Taylor, 2007, 2009; Rueger et al., 2010; Imayoshi and Kageyama, 2011; Masjkur et al., 2012; Pacioni et al., 2012). "
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    ABSTRACT: Stem cells, by definition, are able to both self-renew (give rise to more cells of their own kind) and demonstrate multipotential (the ability to differentiate into multiple cell types). To accommodate this unique dual ability, stem cells interpret signal transduction pathways in specialized ways. Notable examples include canonical and non-canonical branches of the Notch signaling pathway, with each controlling different downstream targets (e.g., Hes1 vs. Hes3) and promoting either differentiation or self-renewal. Similarly, stem cells utilize STAT3 signaling uniquely. Most mature cells studied thus far rely on tyrosine phosphorylation (STAT3-Tyr) to promote survival and growth; in contrast, STAT3-Tyr induces the differentiation of neural stem cells (NSCs). NSCs use an alternative phosphorylation site, STAT3-Ser, to regulate survival and growth, a site that is largely redundant for this function in most other cell types. STAT3-Ser regulates Hes3, and together they form a convergence point for several signals, including Notch, Tie2, and insulin receptor activation. Disregulation and manipulation of the STAT3-Ser/Hes3 signaling pathway is important in both tumorigenesis and regenerative medicine, and worthy of extensive study.
    Full-text · Article · Oct 2013 · Frontiers in Physiology
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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.
    Full-text · Article · Jul 2013 · British Journal of Cancer
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