Integrin αv Expression Is Required for the Acquisition of a Metastatic Stem/Progenitor Cell Phenotype in Human Prostate Cancer

Hoogen, Christel van den; Horst, Geertje van der; Cheung, Hiu Wing; Buijs, Jeroen T.; Pelger, Rob C.M.; Pluijm, Gabri van der

doi:10.1016/j.ajpath.2011.07.011

Cited by 64 publications

(57 citation statements)

References 52 publications

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“…In line with the miR-25 data presented in this study, we previously found that a v -integrins play a pivotal role in the acquisition of a migratory stem/progenitor phenotype, tumorigenicity and the formation of distant bone metastasis in vivo (31,45). Moreover, a 6 b 4 integrin expression has already been associated with prostate cancer invasion, metastasis, and disease progression (46)(47)(48).…”

Section: Discussionsupporting

confidence: 62%

“…Previously, we have shown that ITGAV is required for the acquisition of a stem/progenitor phenotype (31). In addition, ITGAV and ITGA6 are highly expressed in prostate progenitor cells and ITGA6 has been established as maker for progenitor cells in prostate and breast cancer.…”

Section: Rac1 (Fig 2c-e Andmentioning

confidence: 99%

“…S1A) that are all involved in cell-matrix interactions and adhesion. Among the target genes involved in the regulation of the F-actin cytoskeleton, ITGAV and ITGA6 are members of the integrin family of transmembrane receptors that regulate cell adhesion, migration, and remodeling of the ECM (29)(30)(31). In addition, ITGAV and ITGA6 were also identified as miR-25-predicted targets using miRDB (15) and microTCDS (16).…”

Section: Mir-25 Expression Is Downregulated In Normal and Transformedmentioning

confidence: 99%

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miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression

et al. 2015

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Altered microRNA (miRNA; miR) expression is associated with tumor formation and progression of various solid cancers. A major challenge in miRNA expression profiling of bulk tumors is represented by the heterogeneity of the subpopulations of cells that constitute the organ, as well as the tumor tissue. Here, we analyzed the expression of miRNAs in a subpopulation of epithelial stem/progenitor-like cells in human prostate cancer [prostate cancer stem cell (PCSC)] and compared their expression profile to more differentiated cancer cells. In both cell lines and clinical prostate cancer specimens, we identified that miR-25 expression in PCSCs was low/absent and steadily increased during their differentiation into cells with a luminal epithelial phenotype. Functional studies revealed that overexpression of miR-25 in prostate cancer cell lines and selected subpopulation of highly metastatic and tumorigenic cells (ALDH high ) strongly affected the invasive cytoskeleton, causing reduced migration in vitro and metastasis via attenuation of extravasation in vivo. Here, we show, for the first time, that miR-25 can act as a tumor suppressor in highly metastatic PCSCs by direct functional interaction with the 3 0 -untranslated regions of proinvasive a vand a 6 -integrins. Taken together, our observations suggest that miR-25 is a key regulator of invasiveness in human prostate cancer through its direct interactions with a v -and a 6 -integrin expression. Cancer Res; 75(11); 2326-36. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 62%

Section: Rac1 (Fig 2c-e Andmentioning

confidence: 99%

Section: Mir-25 Expression Is Downregulated In Normal and Transformedmentioning

confidence: 99%

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miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression

et al. 2015

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“…Integrin ␣ V expression is required for the acquisition of a cancer metastatic stem or progenitor cell phenotype ( 31 ). Transcriptional silencing of ␣ V and ␤ 3 integrin subunits suppresses cancer metastasis ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

Dong

Shi

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org linked ␣ -and ␤ -subunit, with each subunit having a large extracellular domain, a single membrane-spanning domain, and a short, noncatalytic cytoplasmic tail. Integrins seem to be the major receptors by which cells attach to components of the extracellular matrix (ECM), such as vitronectin, etc. ( 4 ), and are involved in the metastasis signaling of hepatocellular carcinoma (HCC) ( 5 ).The integrin ␣ V subunit associates with one of fi ve integrin ␤ subunits, ␤ 1, ␤ 3, ␤ 5, ␤ 6, or ␤ 8, to form fi ve distinct ␣ V ␤ heterodimers ( 6 ). The integrin ␣ V ␤ heterodimers on the cell surface interact with cell adhesive proteins, such as collagen, fi brinogen, fi bronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. Integrins increase in invasive tumors and distant metastases, characterize the metastatic phenotype, and play a key role in tumor metastasis ( 7,8 ). Many studies have documented marked differences in the surface expression and distribution of integrins between malignant tumors and preneoplastic tissues. For example, the integrin ␣ V ␤ 3 complex is strongly expressed in the invasive front cells of malignant melanoma and angiogenic blood vessels, but it is weakly expressed on preneoplastic melanomas and quiescent blood vessels ( 9 ). Also, it has been demonstrated that ␣ V ␤ 3 integrin is specifi cally required to sustain neovascularization induced in vivo by fibroblast growth factor-2 ( 10 ). Integrin ␣ V ␤ 3 physically associates with phosphorylated and activated insulin-like growth factor receptor, and it may be involved in the HCC cell migration and progression ( 11 ). Furthermore, inducing the expression of the integrin ␣ V ( 7 ) or ␤ 3 ( 12 ) subunit in melanoma cells increases their metastatic potential. Integrins have been implicated as very important adhesion molecules that are involved in multiple physiological processes, such as cell adhesion, proliferation, and survival ( 1-3 ). Each integrin generally consists of a noncovalently Abstract Integrin is important in migration and

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“…ATTC characterized the cell lines using short tandem repeat profiling. PC3-derived PC3-M-Pro4luc cells (15) and LNCaP-derived cell lines C4-2 and C4-2 B were grown in DMEM and T-Medium, respectively. For FACS, primary antibodies included AIIB2 anti-human integrin b1, 4A10 anti-human integrin a2, and sc-18849 antihuman CD44 (Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

SYK Is a Candidate Kinase Target for the Treatment of Advanced Prostate Cancer

Ghotra

Horst

et al. 2015

Cancer Research

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Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin a2b1 and CD44 were diminished. RNAimediated silencing of a2b1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for a2b1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer. Cancer Res; 75(1); 230-40. Ó2014 AACR.

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Integrin αv Expression Is Required for the Acquisition of a Metastatic Stem/Progenitor Cell Phenotype in Human Prostate Cancer

Cited by 64 publications

References 52 publications

miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression

miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

SYK Is a Candidate Kinase Target for the Treatment of Advanced Prostate Cancer

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