Rodilla V, Villanueva A, Obrador-Hevia A et al.Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA 106:6315-6320

Institut d'Investigació Biomèdica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'Investigacions Mèdiques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2009; 106(15):6315-20. DOI: 10.1073/pnas.0813221106
Source: PubMed


Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.

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    • "In mammalian skin, alterations in TH levels influence the Shh pathway, which in turn controls TH availability (Dentice et al., 2007). Notably, several components of the Notch pathway, including Hes1 and Jag1, have been described as targets of Wnt (Fre et al., 2009; Peignon et al., 2011; Rodilla et al., 2009; Estrach et al., 2006). Given that, in studies involving analysis of the whole mucosa, TRα1 activates the Wnt pathway in intestinal crypts (Plateroti et al., 2006; Kress et al., 2009), we cannot exclude the possibility that some of the responses observed for Notch also depend on Wnt activity. "
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    ABSTRACT: Thyroid hormones control various aspects of gut development and homeostasis. The best-known example is in gastrointestinal tract remodeling during amphibian metamorphosis. It is well documented that these hormones act via the TR nuclear receptors, which are hormone-modulated transcription factors. Several studies have shown that thyroid hormones regulate the expression of several genes in the Notch signaling pathway, indicating a possible means by which they participate in the control of gut physiology. However, the mechanisms and biological significance of this control have remained unexplored. Using multiple in vivo and in vitro approaches, we show that thyroid hormones positively regulate Notch activity through the TRα1 receptor. From a molecular point of view, TRα1 indirectly controls Notch1, Dll1, Dll4 and Hes1 expression but acts as a direct transcriptional regulator of the Jag1 gene by binding to a responsive element in the Jag1 promoter. Our findings show that the TRα1 nuclear receptor plays a key role in intestinal crypt progenitor/stem cell biology by controlling the Notch pathway and hence the balance between cell proliferation and cell differentiation. © 2015. Published by The Company of Biologists Ltd.
    Development 08/2015; 142(16). DOI:10.1242/dev.121962 · 6.46 Impact Factor
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    • "Cell lines expressing dominant-negative TCF4 (Ls174T/dnTCF4) and ICN1 (Ls174T/dnTCF4/ICN1) have been previously described (Rodilla et al., 2009; van de Wetering et al., 2002) and were maintained in Dulbecco's media with 10% fetal bovine serum (FBS). Doxycycline (Sigma) was used at 1 µg/ml. "
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    ABSTRACT: Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal. © 2015. Published by The Company of Biologists Ltd.
    Development 01/2015; 142:41-50. DOI:10.1242/dev.107714 · 6.46 Impact Factor
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    • "However, recent studies showed that Notch1 was correlated with poor survival in HCC as well [13] [16]. Apart from the functions mentioned above, the Notch signaling pathway is also critical for endothelial progenitor cells to develop new blood vessels [31] [32]. So far as VM is concerned, tumor cells with such capacity bear close resemblance to endothelial progenitor cells phenotypically and functionally. "
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    ABSTRACT: Background and aims: According to recent findings, some tumor cells function as endothelial progenitor cells to initiate tumor vasculogenesis, known as "vasculogenic mimicry" (VM). Notch1, the key regulator of vasculogenesis and embryonic differentiation, has shown a correlation with a poor prognosis in hepatocellular carcinoma (HCC). We attempted to elucidate the relationship between Notch1 and the vascularization of HCC. Materials and methods: HCC cell lines were assayed for tube formation and low-density lipoprotein (LDL) absorption. The translation level of targets of interest was verified using western blot. Notch1 was silenced in HepG2, BEL-7402 and HCCLM6 using lentivirus shRNA. A hypoxic culture was conducted in an anaerobic culture chamber to induce VM in HepG2. Samples from 53 patients with HCC, i.e., 5 with metastasis and 48 without were tested for Notch1(+) cells and CD34 negative plus Periodic Acid-Schiff (PAS) positive structures, respectively. Results: BEL-7402 and HCCLM6 were capable of tube formation and LDL absorption in vitro, while HepG2 was negative for both. Notch1 down-regulation suppressed endothelial marker expression and greatly impaired tube formation. After hypoxic culture, the tube formation capacity of HepG2 was significantly enhanced, along with an increase in Notch1 expression. Notch1 was strongly and profusely expressed in all 5 cases of distant metastasis, while 19 of the 48 cases without metastasis were sparsely positive (P < 0.05). Notch1 positivity was mainly seen in the cytoplasm and nuclei. VM structures were only found in 2 cases from the metastasis group (P < 0.05). Conclusions: HCC is capable of VM. Notch1 might serve as a potential target for VM development in HCC.
    International journal of clinical and experimental pathology 10/2014; 7(9):5782-91. · 1.89 Impact Factor
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