PAX3 and ETS1 synergistically activate MET expression in melanoma cells

Kubic, Jennifer D.; Little, Elizabeth C.; Lui, Jason W.; Iizuka, Takumi; Lang, Deborah

doi:10.1038/onc.2014.420

Cited by 30 publications

(32 citation statements)

References 46 publications

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“…A functional study on the role of ETS1 revealed that it exacerbates melanomagenesis through the activation of ETS1-MET axis in combination with or without PAX3. Majority of ETS1 was expressed in cytoplasm while PAX3 is only expressed in nucleus (Kubic 2015). In concordat with this study, Potu et al reported that Ets1 upregulation amplifies NRAS activity via its overexpression which leads to a malignant phenotype.…”

Section: Dusp6 Ets1 and Brn2 Expression In Human Nevi And Thin Melsupporting

confidence: 64%

The Role of Microenvironment in Development of Skin Cancer and Metastasis

Chitsazan¹

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The overarching aim of this thesis is to study the mechanisms by which giant congenital nevi form and to study if such mechanisms are targetable. Virtually nothing is known about genes conferring susceptibility to the development of giant congenital nevi, largely untreatable lesions which increase the risk of patients for development of neurocutaneous melanocytoma and malignant melanoma. To discover such genes, we utilized a nevusprone transgenic mouse model together with the Collaborative Cross (CC), a genetic resource for discovery of genes for complex diseases. It not only allows gene discovery, but also a systems genetics approach that enabled us to determine how the gene functions in vivo to modify the nevogenesis.We also show that the identity of somatic oncogenic mutation (e.g. in NRAS) does not always define the histopathological subtype of nevus, as is generally thought. In sum, we have performed an unbiased genetic screen and discovered a novel gene (Cdon), a dependence receptor of sonic hedgehog (Shh) as the modifier gene for nevus exacerbation. We then used three different mouse models to validate it as the causal gene and determine its mechanism of action. We also show that Shh pathway components are active in the epidermis adjacent to human congenital nevi (Chapter 2 and 3). In summary this is the first time a gene has been successfully mapped and functionally validated using CC. In Chapter 4 we discuss the result from an unbiased genetic screen to map the modifier gene for development of sub-cutaneous (hypodermis) metastasis using 45 CC strains. Gja1 which encodes a gap junction subunit connexion 43 (Cx43) is the best candidate. Our gene expression and protein expression studies suggest that Gja1 could be a strong candidate for further study of sub-cutaneous metastasis.In Chapter 5 we went on to study the gene expression of normal skin, melanocytoma and malignant melanoma samples from our NRAS-Cdk4 mouse model to study the transformation and progression of melanocytic lesions. Dusp6 a negative regulator of MAPK pathway was highly upregulated with transformation and progression. Our protein expression study validated this result on murine and human nevi versus malignant melanoma samples.3

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Section: Dusp6 Ets1 and Brn2 Expression In Human Nevi And Thin Melsupporting

confidence: 64%

The Role of Microenvironment in Development of Skin Cancer and Metastasis

Chitsazan¹

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“…This finding is supported by Gambarotta et al . (1996) as well as by Kubic et al ., (2015), who both described transcriptional regulation of MET by C‐ets‐1, however, not in a TGFβ1‐dependent context. C‐ets‐1 overexpression has been shown to strongly promote malignant invasiveness of breast cancer cells, which is in line with our findings (Furlan et al ., 2008).…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

et al. 2018

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Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal‐like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal‐like breast cancer cell lines, as well as in triple‐negative breast cancer tumor tissues, compared to other subtypes. Using real‐time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)‐induced and MET‐dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C‐ets‐1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1‐induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR‐128‐3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR‐128‐3p reduced MET expression and abrogated HGF‐induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF‐induced and MET‐mediated cell migration, through positive regulation of C‐ets‐1 and negative regulation of miR‐128‐3p expression in basal‐like breast cancer cell lines and in triple‐negative breast cancer tissue.

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“…In melanoma patient specimens, increased MET expression has been implicated in tumor progression, with receptor expression correlating with melanoma growth and metastasis [38,39]. Recent studies have revealed the concomitant overexpression of transcription factors ETS1, PAX3, and SOX10 that drive up-regulation of Met in melanoma cell lines and primary tumors [35,40]. We report herein that increased Met expression mediates the generation of NRAS resistant melanoma in vivo , while inhibition of Met overcomes this resistance, indicating that combination strategies that suppress RTK signaling with MAPK pathway inhibition may be therapeutically beneficial.…”

Section: Discussionmentioning

confidence: 99%

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

et al. 2017

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Targeted therapies have revolutionized cancer care but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice but 40% of tumors recurred. Analysis of resistant tumors revealed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed enhanced efficacy of cytotoxicity with combined RTK and MEK inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.

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PAX3 and ETS1 synergistically activate MET expression in melanoma cells

Cited by 30 publications

References 46 publications

The Role of Microenvironment in Development of Skin Cancer and Metastasis

The Role of Microenvironment in Development of Skin Cancer and Metastasis

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

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