Suppression of Anoikis by <i>SKP2</i> Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma

Wang, Xiaochun; Wu, Yupeng; Ye, Bo; Lin, De–Chen; Feng, Yan–Bin; Zhang, Ziqiang; Xu, Xin; Han, Yaling; Cai, Yan; Dong, Jin‐Tang; Zhan, Qimin; Wu, Min; Wang, Ming-Rong

doi:10.1158/1541-7786.mcr-08-0092

Cited by 48 publications

(48 citation statements)

References 31 publications

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“…43,[45][46][47] We found a significant increase in Skp2 protein levels already in preneoplastic prostate lesions (high-grade PIN), in agreement with a previous study, 48 and a pattern of expression that was inversely related to BRCA2 protein during prostate neoplastic transformation. Skp2 exhibited both a nuclear and a cytoplasmic pattern of expression in PCa glands and human prostate cell lines, in agreement with previous findings.…”

Section: Brca2 Expression In Prostate Cancer 2373supporting

confidence: 92%

Skp2 Overexpression Is Associated with Loss of BRCA2 Protein in Human Prostate Cancer

Arbini

Greco

Yao

et al. 2011

The American Journal of Pathology

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BRCA2 (breast cancer 2, early onset) is a tumor suppressor gene that confers increased susceptibility for prostate cancer (PCa). Previous in vitro experiments demonstrated that Skp2, an E3 ubiquitin ligase aberrantly overexpressed in PCa, is involved in the proteolytic degradation of BRCA2 in PCa cells, suggesting that the BRCA2-Skp2 interaction may play a role in prostate tumorigenesis. Herein, we investigated BRCA2 and Skp2 expression during PCa development using a prostate TMA. Although luminal and basal benign prostate epithelium exhibited moderate to strong nuclear BRCA2 immunostaining, the intensity and number of positive nuclei decreased significantly in high-grade prostatic intraepithelial neoplasia and PCa. Decreased frequency and intensity of nuclear BRCA2 labeling were inversely correlated with Skp2 expression in high-grade prostatic intraepithelial neoplasia and PCa. To functionally assess the effects of BRCA2 and Skp2 expression on prostate malignant transformation, we overexpressed Skp2 in normal immortalized prostate cells. Skp2 overexpression reduced BRCA2 protein and promoted cell growth and migration. A similar phenotype was observed after reduction of BRCA2 protein levels using specific BRCA2 smallinterfering RNA. Forced BRCA2 expression in Skp2-overexpressing stable transfectants inhibited the migratory and growth properties by >60%. These results show that loss of BRCA2 expression during prostate tumor development is strongly correlated with both migratory behavior and cancer growth and include Skp2 Prostate cancer (PCa) is a leading cause of morbidity and mortality among men in the Western world. Despite increased awareness and improved methods for early detection, many patients succumb to disseminated cancer that is resistant to conventional therapies.1 The identification of early molecular events in PCa represents the first step in devising early diagnostic tools and new anticancer therapies aimed at preventing disease progression and dissemination.BRCA2 (breast cancer 2, early onset) is a tumor suppressor gene that, when mutated, confers an increased susceptibility to developing PCa.2,3 The inheritance of one defective allele confers PCa predisposition; and neoplastic cells from predisposed individuals frequently exhibit loss of heterozygosity in the remaining wild-type allele, 4 consistent with a critical role of BRCA2 in prostate tumor suppression. The major identified function of the BRCA2 protein is to form complexes with Rad51 in the nuclei, which orchestrate homologous recombinational repair of double-stranded DNA breaks.5 In addition to its role in mediating DNA repair, BRCA2 plays a role in the stabilization of stalled DNA replication forks, centrosome duplication, mammalian gametogenesis, cytokinesis, telomere replication, and transcriptional regulation. 6 -8 In addition to cancer predisposition, recent clinical evidence suggests that patients with PCa who carry germline BRCA2 mutations display a more aggressive phenotype with worse survival rates than noncarrier patients 9 -14...

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Section: Brca2 Expression In Prostate Cancer 2373supporting

confidence: 92%

Skp2 Overexpression Is Associated with Loss of BRCA2 Protein in Human Prostate Cancer

Arbini

Greco

Yao

et al. 2011

The American Journal of Pathology

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“…In addition, a functional study showed that decreased expression of SKP2 in ESCC cells could inhibit the migration, invasion, colony formation of ESCC cells in vitro, and tumorigenesis in mouse models by inactivating the PI3k-Akt pathway. 37 In the present study, the overexpression of SKP2 was also found in ESCC tissues. In addition, the correlation analysis showed that the expression level of SKP2 was significantly correlated with differentiation grade, TNM stage, and lymph node metastasis of ESCC.…”

Section: Discussionsupporting

confidence: 69%

microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2

Jiao

Zhang

et al. 2016

Laboratory Investigation

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miR-186 has been demonstrated to have a significant role as a tumor suppressor in many types of cancers. Nevertheless, its biological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we found that the expression level of miR-186 was downregulated in ESCC in comparison with the adjacent normal tissues and was significantly associated with differentiation level, TNM stage, and lymph node metastasis of ESCC. Functional experiments revealed that enforced overexpression of miR-186 in ESCC cells suppressed the proliferation, invasion, and induced the apoptosis of cells. Luciferase reporter assay and western blotting analysis were performed to verify the target gene regulated by miR-186, SKP2. Our findings established that the miR-186 has a suppressive role in ESCC progression via SKP2-mediated pathway, and this implies that miR-186 could be a potential therapeutic target for ESCC.

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“…Apart from inducing cell-cycle entry, emerging evidence implies that SKP2 overexpression may play a role in promoting metastatic propensity in common carcinomas, such as prostatic and esophageal cancers (26,27). As SKP2 amplification was an adverse harbinger of metastasis in primary myxofibrosarcomas, this prompted us to further examine whether SKP2 silencing can lead to attenuated cell migration and/or invasion.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gene Amplification–Driven SKP2 Overexpression in Myxofibrosarcoma: Potential Implications in Tumor Progression and Therapeutics

Wang

Kang

et al. 2012

Clinical Cancer Research

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Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification.Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib.Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2-expressing OH931 cells and 14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.

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Suppression of Anoikis by SKP2 Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma

Cited by 48 publications

References 31 publications

Skp2 Overexpression Is Associated with Loss of BRCA2 Protein in Human Prostate Cancer

Skp2 Overexpression Is Associated with Loss of BRCA2 Protein in Human Prostate Cancer

microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2

Characterization of Gene Amplification–Driven SKP2 Overexpression in Myxofibrosarcoma: Potential Implications in Tumor Progression and Therapeutics

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