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MiR-106b-25 cluster targets caspase 7 and focal adhesion in human prostate cancer

ABSTRACT: We and others previously reported that the miR-106b-25 microRNA cluster is a candidate oncogene in human prostate cancer. Here, we made the novel observation that miR-106b-25 expression is further up-regulated in distant metastasis. Moreover, increased tumor miR-106b expression was associated with early disease recurrence. To identify yet unknown oncogenic functions of the prognostic miR-106b, we overexpressed it in LNCaP human prostate cancer cells to examine miR-106b-induced global expression changes among protein-coding genes. The approach revealed that caspase-7 is a candidate direct target of miR-106b, which was confirmed by Western blot analysis and a 3’UTR reporter assay. Other analyses showed that caspase-7 is down-regulated in primary human prostate tumors and metastatic lesions across multiple datasets and is by itself associated with disease recurrence. Using bioinformatics, we also discovered that miR-106b-25 may specifically influence focal adhesion-related pathways. This observation was experimentally confirmed using miR-106b-25-transduced 22Rv1 human prostate cancer cells. After infection with a miR-106b-25 lentiviral expression construct, 22Rv1 cells showed increased adhesion to basement membrane- and bone matrix-related filaments and enhanced soft agar growth. In summary, miR-106b-25 was found to be associated with prostate cancer progression and metastasis and may do so by altering apoptosis- and focal adhesion-related pathways. To elucidate the effects miR-106b, we up-regulated miR-106b in LNCaP cells and examined gene expression alterations on a global scale with Affymetrix arrays.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34893 | GEO | 2012/05/01

SECONDARY ACCESSION(S): PRJNA150187

REPOSITORIES: GEO

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Project description:miR-93/106b and their host gene minichromosome maintenance complex component 7 (MCM7) reside at chr7q22, a region frequently rearranged in leiomyomas. We explored the expression of miR-93/106b in leiomyoma and paired myometrium (N=62) from untreated and patients exposed to hormonal therapies (GnRHa, Depo-Provera and oral contraceptives) from African Americans and Caucasians, and their regulatory functions in isolated paired (N=15) leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) and leiomyosarcoma cell line (SKLM-S1). At tissue level leiomyomas expressed significantly lower levels of miR-93 and elevated MCM7 as compared to myometrium with limited racial influence or hormonal exposure on their expression. Assessing the regulatory function of miR-93/106b through doxycycline-inducible lentiviral transduction in microarray analysis, tissue factor (F3) and IL-8 were identified as their possible targets. At tissue level leiomyomas expressed a significantly lower level of F3 and an elevated IL-8 which exhibited an inverse relationship with miR-93, but with limited racial or hormonal influences. Gain-of-function of miR-93/106b in LSMC, MSMC and SKLM-S1 dose-dependently repressed F3 and IL-8 through direct interactions with their respective 3M-bM-^@M-^YUTRs and indirectly through F3 repression inhibited IL8, CTGF and PAI-1 expression, confirmed by using siRNA silencing or factor Vlla (FVIIa) activation of F3, as well as reducing the rate of proliferation, while increasing caspase 3/7 activity. We concluded that differential expression of miR-93/106b and their direct and/or indirect regulatory functions on F3, IL-8, CTGF and PAI-1 expression, with key roles in inflammation and tissue turnover may be of significance in the outcome of leiomyoma growth and associated symptoms. Total RNA isolated from TF324 cells transfected with DOX-inducible lentiviral construct carrying miR-106b~25 cluster with and without Dox treatments for 6 days was subjected to gene expression profiling using Sentirx Beadchip Array HumanHT-12_v4.

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MiR-106b-25 cluster targets caspase 7 and focal adhesion in human prostate cancer

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