IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα− BCa and AR− PCa cells and promotes cell survival
Autor: | Vanessa Anunobi, Monica Bautista, Kelly Daescu, Nikki A. Delk, Rachel Meade, Haley Dahl, Chao Xing, Felix Bayerl, Ally Wong, Nisha Ghatwai, Ragini Mistry, Mohammed Kanchwala, Afshan Fathima Nawas, Shayna E. Thomas-Jardin |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment p62/SQSTM1 Estrogen receptor Biology lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Breast cancer Downregulation and upregulation Gene expression Genetics medicine Cytotoxic T cell skin and connective tissue diseases Gene 030304 developmental biology 0303 health sciences Prostate cancer lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens In vitro 3. Good health Androgen receptor 030104 developmental biology Cytokine Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Signal transduction Interleukin-1 |
Zdroj: | BMC Cancer, Vol 20, Iss 1, Pp 1-15 (2020) |
ISSN: | 1471-2407 |
Popis: | Background Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly block HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR+) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we 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 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 the BCa and PCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) and used the gene ontology web-based tool, GOrilla, to identify signaling pathways encoded 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 HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired hormone receptor independence and treatment resistance. We also assessed HR− cell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HR− cell lines. Conclusions 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 HR-independent BCa and PCa. |
Databáze: | OpenAIRE |
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