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Trop-2 promotes prostate cancer metastasis by modulating ?(1) integrin functions.

ABSTRACT: The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that ?(1) integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on ?(1) integrins. Mechanistically, we demonstrate that Trop-2 and the ?(5)?(1) integrin associate through their extracellular domains, causing relocalization of ?(5)?(1) and the ?(1)-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, ?(v)?(3) integrin, and does not affect localization of ?(v)?(3) integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that ?(1) integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2.

SUBMITTER: Trerotola M

PROVIDER: S-EPMC3655712 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Trop-2 promotes prostate cancer metastasis by modulating β(1) integrin functions.

Trerotola Marco M Jernigan Danielle L DL Liu Qin Q Siddiqui Javed J Fatatis Alessandro A Languino Lucia R LR

Cancer research 20130327 10

The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β(1) integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes p ...[more]

PMID: 23536555

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Project description:BACKGROUND: Metastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells. METHODS: A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143. RESULTS: The expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo. CONCLUSIONS: These data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer.

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Trop-2 promotes prostate cancer metastasis by modulating ?(1) integrin functions.

Publications

Trop-2 promotes prostate cancer metastasis by modulating β(1) integrin functions.

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