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Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7.

ABSTRACT: MiRNAs regulate cancer cells, but their potential effects on cancer stem/progenitor cells are still being explored. In this study, we used quantitative real-time-PCR to define miRNA expression patterns in various stem/progenitor cell populations in prostate cancer, including CD44+, CD133+, integrin ?2?1+, and side population cells. We identified distinct and common patterns in these different tumorigenic cell subsets. Multiple tumor-suppressive miRNAs were downregulated coordinately in several prostate cancer stem/progenitor cell populations, namely, miR-34a, let-7b, miR-106a, and miR-141, whereas miR-301 and miR-452 were commonly overexpressed. The let-7 overexpression inhibited prostate cancer cell proliferation and clonal expansion in vitro and tumor regeneration in vivo. In addition, let-7 and miR-34a exerted differential inhibitory effects in prostate cancer cells, with miR-34a inducing G1 phase cell-cycle arrest accompanied by cell senescence and let-7 inducing G2-M phase cell-cycle arrest without senescence. Taken together, our findings define distinct miRNA expression patterns that coordinately regulate the tumorigenicity of prostate cancer cells.

SUBMITTER: Liu C

PROVIDER: S-EPMC3872033 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7.

Liu Can C Kelnar Kevin K Vlassov Alexander V AV Brown David D Wang Junchen J Tang Dean G DG

Cancer research 20120619 13

MiRNAs regulate cancer cells, but their potential effects on cancer stem/progenitor cells are still being explored. In this study, we used quantitative real-time-PCR to define miRNA expression patterns in various stem/progenitor cell populations in prostate cancer, including CD44+, CD133+, integrin α2β1+, and side population cells. We identified distinct and common patterns in these different tumorigenic cell subsets. Multiple tumor-suppressive miRNAs were downregulated coordinately in several p ...[more]

PMID: 22719071

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Project description:BACKGROUND:Kindlin-1, -?2, and?-?3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described. METHODS:To better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n?=?58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n?=?438) and protein (n?=?129) levels and we evaluated their correlation with the clinical outcome. RESULTS:We determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients' outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients. CONCLUSION:This study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors. These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression.

Dataset Information

Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7.

Publications

Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7.

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