The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer

Rustighi, Alessandra; Tiberi, Luca; Soldano, Alessia; Napoli, Marco; Nuciforo, Paolo; Rosato, Antonio; Kaplan, Fred F.; Capobianco, Anthony A.; Pece, Salvatore; Fiore, Pier Paolo P.P. Di; Sal, Giannino Del

doi:10.1038/ncb1822

Cited by 155 publications

(168 citation statements)

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“…Moreover, alterations of Notch signaling that function in tumor initiation, progression, angiogenesis and metastasis have been found to be mediated through the activation of several important downstream pathways. Until now, b-catenin, 17 AKT, 32,33,38 Pin1, 39 Snail, 22 MMP9 19 and HES1 36 have been reported to either function as the downstream targets or be associated with Notch signaling in cancers. Notch signaling induces EMT Figure 4.…”

Section: Discussionmentioning

confidence: 99%

“…during normal development, and tumor metastasis has been reported to occur through the control of Slug (Snail2) 39,40 and Snail1 under hypoxic conditions. 37,40 Our results show that Snail1 is the downstream target gene of Notch1 and further regulates E-cadherin expression in the following evidence: (i) knocking-down Notch1 reduced and abolished Snail1 expression in metastatic HCC cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the reestablishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and is ranked second amongst all cancer deaths in Hong Kong. HCC is correlated with an increased likelihood of vascular invasion, metastasis and recurrence (even after surgical resection), leading to poor prognosis. 1 Metastasis, both intrahepatic and extrahepatic, is of particular concern and occurs in more than half of HCC cases. 2 The incidence of high grade HCC that metastasize to distant sites is high. 2 However, the detailed mechanisms of metastasis are yet to be revealed.The process that converts adherent epithelial cells into migratory cells to invade the extracellular matrix is called the epithelial-mesenchymal transition (EMT). This process plays fundamental roles in tissue and organ formation during embryonic development and in wound healing and tissue repair during adult life. 3,4 However, the abnormal activation of EMT programs can be disadvantageous to cancer patients. 3 EMT can allow carcinoma cells to acquire mesenchymal cell gene expression profiles and properties, 5 leading to the transformation of the cells from being coherent and displaying apicobasal polarity to become nonpolarized cells that can move through the extracellular media. This transformation enables the spread of tumor cells to distant sites. 6,7 Although EMT is considered to be the first step in the metastatic progression of migratory cancer cells, EMT has not been confirmed to exist in vivo. 3...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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“…As expected, treatment of SKBR3 cells with EGF caused an increase in NOTCH1 ϩ NICD, which was suppressed by ATRA. To determine the amounts of NICD specifically, we used an antibody targeting Val-1744 (42). The data indicate that the surge of NICD in SKBR3 cells exposed to EGF is also blocked by ATRA.…”

Section: Atra-dependent Suppression Of Emt-associated Notch1mentioning

confidence: 99%

All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells

Zanetti

Affatato

Centritto

et al. 2015

Journal of Biological Chemistry

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Background: All-trans-retinoic acid is a promising therapeutic agent in breast cancer. Results: All-trans-retinoic acid modulates mammary tumor cell epithelial-to-mesenchymal-transition via the TGF␤ and NOTCH pathways. Conclusion:The present study unveils a new aspect of all-trans-retinoic acid activity (i.e. regulation of phenotypic cell plasticity). Significance: Our results indicate that all-trans-retinoic acid is endowed with anti-metastatic properties that could be exploited at the therapeutic level.

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“…Lineage commitment and cell differentiation that are highly relevant in the context of stem cells are also dramatically influenced by Pin1. Pin1 maintains the balance between stem cell pluripotency, stemness, and commitment by stabilizing and activating molecules controlling self-renewal and differentiation (15)(16)(17). These provocative roles of Pin1 in the areas of proliferation, survival, senescence, and cell fate determination have tremendous impact on stem cell biology that remains unexplored in the context of CPCs.…”

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confidence: 99%