Notch1 Signaling Promotes Primary Melanoma Progression by Activating Mitogen-Activated Protein Kinase/Phosphatidylinositol 3-Kinase-Akt Pathways and Up-regulating N-Cadherin Expression

Liu, Zhao Jun; Xiao, Min; Balint, Klara; Smalley, Keiran S.M.; Brafford, Patricia; Qiu, Ruihua; Pinnix, Chelsea C.; Li, Xueli; Herlyn, Meenhard

doi:10.1158/0008-5472.can-05-3589

Cited by 239 publications

(174 citation statements)

References 41 publications

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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%

“…2f). Using over-expression and knock-down of Notch signaling by siRNA or inhibitors, activated Notch1 signaling has been reported to be involved in tumor development, 32 tumor growth, 33 tumor angiogenesis, 34 chemotherapy sensitivity 35 and invasion of tumor cells by limiting the migration of tumor cells. 17,19,20,36 For the first time, our study demonstrated that knocking-down Notch1 was able to inhibit liver tumor metastasis in vivo in a mouse model.…”

Section: Targeting Notch1 Decreases Metastatic Hcc Cell Motility In Vmentioning

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: Targeting Notch1 Decreases Metastatic Hcc Cell Motility In Vmentioning

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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“…The Notch pathway could be either oncogenic or tumor suppressive (Yin et al, 2010). We have previously shown that Notch activation in melanoma has a critical role in driving tumor progression (Balint et al, 2005;Liu et al, 2006), and defined an oncogenic role for Notch signaling in melanocytic transformation (Pinnix et al, 2009). Additionally, Notch and Notch ligands, for example, Delta-like 4 (Dll4), are robustly expressed in tumor endothelial cells in comparison with that in neighboring, normal tissue vessels (Mailhos et al, 2001), and vascular endothelial growth factor, which can be predominately produced by tumor cells, can induce endothelial cells to express Notch1 and Dll4 (Liu et al, 2003;Noguera-Troise et al, 2006;Ridgway et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1

et al. 2011

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“…Intriguingly, a recent study has shown that Notch2 protein is significantly up regulated in dysplastic nevi and melanomas but not in common melanocytic nevi (Massi et al, 2006). Notch proteins are transmembrane receptors that are activated by specific ligands and increase signaling via the MAPK and PI3K pathways in melanoma cells (Liu et al, 2006). Wellknown oncogenes such as MDM2, CCNE1 and BRAF were each found amplified in single samples.…”

Section: G Jönsson Et Almentioning

confidence: 99%

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

et al. 2007

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Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.

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Notch1 Signaling Promotes Primary Melanoma Progression by Activating Mitogen-Activated Protein Kinase/Phosphatidylinositol 3-Kinase-Akt Pathways and Up-regulating N-Cadherin Expression

Abstract: Cellular signaling mediated by Notch receptors results in coordinated regulation of cell growth, survival, and differentiation.

Cited by 239 publications

References 41 publications

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

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

Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

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