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The effect of miRNA-135b overexpression on the gene expression profile of LNCaP cells

ABSTRACT: MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor α (ERα). Here we show that miR-135b expression inversely correlates with ER protein in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples) and with AR protein in 47 PCa patient samples. We identify ERα as a novel miR-135b target by demonstrating miR-135b binding to the 3’UTR of the ERα and decreased ERα protein and mRNA level in breast cancer cells upon miR-135b overexpression. miR-135b inhibits proliferation of hormone receptor positive cancer cell lines as shown by overexpression in ERα-positive BCa cells (MCF-7) and AR-positive PCa cells (LNCaP, 22Rv1) when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a potential link to the hypoxia-inducible factor-1α (HIF1α) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia-inducible factor-1 (HIF1AN), which also demonstrated an inverse correlation with miR-135b in a cohort of breast tumor samples. Taken together, our study demonstrates that miR-135b regulates ERα, AR and HIF1AN protein levels and proliferation in ERα -positive breast and AR-positive-prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57820 | GEO | 2015/04/21

SECONDARY ACCESSION(S): PRJNA248178

REPOSITORIES: GEO

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Project description:Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Estrogen receptor alpha (ERa) is overexpressed in 70% of diagnosed BCa patients and androgen receptor (AR) is overexpressed in 80-90% of diagnosed PCa patients. Thus, BCa and PCa patients are given therapy that reduces hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. 15-30% of BCa patients and ≥ 30% of PCa patients that acquire treatment resistance develop tumors enriched in cancer cells with low or no HR accumulation. Furthermore, 15-20% of BCa patients and 10-20% of PCa patients are intrinsically HR-negative (HR-), and thus, have intrinsic resistance to therapy. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERa and AR mRNA in HR-positive (HR+) BCa and PCa cell lines. Additionally, we had identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells, to promote HR-independent survival and tumorigenicity. Methods: To identify changes in global gene expression we performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in BCa and PCa cell lines. We also compared our gene expression data with publicly available data sets from hormone receptor-independent sublines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encode by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in hormone receptor-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HR- cell line viability in response verteporfin, an FDA approved therapy for macular degeneration known to target p62, and we found that verteporfin is cytotoxic for HR- cells lines. Conclusions: Taken together, our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic hormone receptor-independent BCa and PCa.

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The effect of miRNA-135b overexpression on the gene expression profile of LNCaP cells

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