Novel Role for γ-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1)

Sechler, Marybeth; Borowicz, Stanley; Scoyk, Michelle Van; Avasarala, Sreedevi; Zerayesus, Sereke; Edwards, Michael G.; Rathinam, Manoj Kumar Karuppusamy; Zhao, Xiangmin; Wu, Pei Ying; Tang, Ke; Bikkavilli, Rama Kamesh; Winn, Robert A.

doi:10.1074/jbc.m114.631820

Cited by 22 publications

(25 citation statements)

References 34 publications

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“…PG, also known as γ‐catenin,31, 32 is a component of adherens junctions and desmosomes, and it plays an important role in Wnt/β‐catenin signaling 33, 34. In several tumors, the loss of PG expression by cells has been related to tumor growth, invasive behavior and hence metastatic progression 35, 36.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Ortega-Martinez

Gardeazábal

Erramuzpe

et al. 2016

Intl Journal of Cancer

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Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I–II patients may still develop metastasis during follow‐up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow‐up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease‐free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early‐stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival.

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Section: Discussionmentioning

confidence: 99%

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Ortega-Martinez

Gardeazábal

Erramuzpe

et al. 2016

Intl Journal of Cancer

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“…Most evidence shows that reduced levels of HAI‐1/SPINT1 in carcinoma cells lead to enhanced invasiveness and metastasis (Fig. d) . In fact, relationship between the reduced HAI‐1/SPINT1 and a poorer clinical outcome of gynecological, mammary, prostatic, oral and pancreatic ductal carcinomas have been reported .…”

Section: Hai‐1/spint1 Suppresses the Epithelial To Mesenchymal Transimentioning

confidence: 98%

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

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The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells.

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“…Furthermore, plakoglobin expression in plakoglobin‐deficient and mp53‐expressing cells reduced growth, migration and invasion of these cells in vitro . Plakoglobin has also been shown to regulate the expression of HAI‐1 and to reduce migration in a p53‐dependent way in NSCLC cells . Coimmunoprecipitation experiments indicated that plakoglobin interacted with p53.…”

Section: Discussionmentioning

confidence: 98%

“…Plakoglobin is an armadillo protein family member and is a paralog of β‐catenin with similar dual cell‐cell adhesion and signaling activities . However, unlike β‐catenin that acts as an oncogene through its interaction with the transcription factors T‐cell factor/lymphoid enhancer‐binding factor (TCF/LEF), and activation of Wnt signaling pathway, plakoglobin generally acts as a tumor/metastasis suppressor . We have shown that plakoglobin can act as a tumor/metastasis suppressor by at least 3 mechanisms: regulation of stability and subcellular localization of growth regulating molecules, interaction with transcription factors involved in the regulation of cell growth and metastasis and sequestration of β‐catenin oncogenic activities; see also …”

Section: Introductionmentioning

confidence: 99%

“…20,21 However, unlike b-catenin that acts as an oncogene through its interaction with the transcription factors T-cell factor/ lymphoid enhancer-binding factor (TCF/LEF), and activation of Wnt signaling pathway, 22,23 plakoglobin generally acts as a tumor/metastasis suppressor. 20,21,[24][25][26][27] We have shown that plakoglobin can act as a tumor/metastasis suppressor by at least 3 mechanisms: regulation of stability and subcellular localization of growth regulating molecules, 19,25,28 interaction with transcription factors involved in the regulation of cell growth and metastasis [16][17][18][19]25 and sequestration of b-catenin oncogenic activities; 29 see also. [30][31][32][33][34] p53 GOF mutations can induce aberrant accumulation and increased transcriptional activation of b-catenin in cancer cells.…”

mentioning

confidence: 99%

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Plakoglobin restores tumor suppressor activity of p53^R175H mutant by sequestering the oncogenic potential of β‐catenin

2018

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Tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins have not only lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H) with well‐documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signaling protein and a paralog of β‐catenin. Unlike β‐catenin that has oncogenic function through its role in the Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor. We have shown that plakoglobin interacted with wild type and a number of p53 mutants in various carcinoma cell lines. Plakoglobin and mutant p53 interacted with the promoter and regulated the expression of several p53 target genes. Furthermore, plakoglobin interactions with p53 mutants restored their tumor suppressor/metastasis activities in vitro. GOF p53 mutants induce accumulation and oncogenic activation of β‐catenin. Previously, we showed that one mechanism by which plakoglobin may suppress tumorigenesis is by sequestering β‐catenin's oncogenic activity. Here, we examined the effects of p53R175H expression on β‐catenin accumulation and transcriptional activation and their modifications by plakoglobin coexpression. We showed that p53R175H expression in plakoglobin null cells increased total and nuclear levels of β‐catenin and its transcriptional activity. Coexpression of plakoglobin in these cells promoted β‐catenin's proteasomal degradation, and decreased its nuclear levels and transactivation. Wnt/β‐catenin targets, c‐MYC and S100A4 were upregulated in p53R175H cells and were downregulated when plakoglobin was coexpressed. Plakoglobin‐p53R175H cells also showed significant reduction in their migration and invasion in vitro.

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Novel Role for γ-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1)

Cited by 22 publications

References 34 publications

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Plakoglobin restores tumor suppressor activity of p53^R175H mutant by sequestering the oncogenic potential of β‐catenin

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Novel Role for γ-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1)

Cited by 22 publications

References 34 publications

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Plakoglobin restores tumor suppressor activity of p53R175H mutant by sequestering the oncogenic potential of β‐catenin

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Plakoglobin restores tumor suppressor activity of p53^R175H mutant by sequestering the oncogenic potential of β‐catenin