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2 results on '"DNAJB5"'

1. DNAJB5 (hsc40) gene as a novel biomarker for cervical cancer.

Author

Hu Yu, Ying Chen, Guoxin Zhang, Huijuan Wu, and Ke Wang

Subjects
*CERVICAL cancer, *BIOMARKERS, *CANCER-related mortality, *HEAT shock proteins, *POLYMERASE chain reaction
Abstract

Cervical cancer is among the most common malignant tumor and leading cause of cancer-related mortality in women worldwide. Heat shock proteins (HSPs) are reported increasingly as potential biomarkers and drug targets for cancers. DNAJB5 has been shown to be involved in HSP binding and response to unfolded proteins, but its role in cervical cancer remains currently unclear. In this study, DNAJB5 was knocked down in SiHa cells by short hairpin RNA (shRNA) and verified by quantitative real-time polymerase chain reaction (qRT-PCR) as well as Western blotting. Its effects on cell proliferation, apoptosis, viability, and cell cycle were investigated by Celigo assay, Annexin V-Allophycocyanin (Annexin V-APC) assay, tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye (MTT) assay and propidium iodide (PI) staining assay, respectively. shRNA experiments successfully knocked down DNAJB5 expression, which decreased the proliferation of SiHa cells, reduced the number of viable cells, affected the cell cycle of SiHa cells and increased their apoptosis. The knockdown of DNAJB5 acted as a tumor suppressor in cervical cancer cells, suggesting DNAJB5 as a new biomarker candidate and potential target for cervical cancer treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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2. MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

Author

Lampis, Andrea, Carotenuto, Pietro, Vlachogiannis, Georgios, Cascione, Luciano, Hedayat, Somaieh, Burke, Rosemary, Clarke, Paul, Bosma, Else, Simbolo, Michele, Scarpa, Aldo, Yu, Sijia, Cole, Rebecca, Smyth, Elizabeth, Mateos, Javier Fernández, Begum, Ruwaida, Hezelova, Blanka, Eltahir, Zakaria, Wotherspoon, Andrew, Fotiadis, Nicos, Bali, Maria Antonietta, Nepal, Chirag, Khan, Khurum, Stubbs, Mark, Hahne, Jens C., Gasparini, Pierluigi, Guzzardo, Vincenza, Croce, Carlo M., Eccles, Suzanne, Fassan, Matteo, Cunningham, David, Andersen, Jesper B., Workman, Paul, Valeri, Nicola, Braconi, Chiara, Lampis, A., Carotenuto, P., Vlachogiannis, G., Cascione, L., Hedayat, S., Burke, R., Clarke, P., Bosma, E., Simbolo, M., Scarpa, A., Yu, S., Cole, R., Smyth, E., Mateos, J. F., Begum, R., Hezelova, B., Eltahir, Z., Wotherspoon, A., Fotiadis, N., Bali, M. A., Nepal, C., Khan, K., Stubbs, M., Hahne, J. C., Gasparini, P., Guzzardo, V., Croce, C. M., Eccles, S., Fassan, M., Cunningham, D., Andersen, J. B., Workman, P., Valeri, N., and Braconi, C.

Subjects
WT, wild type, Time Factors, Transcription Factor, Mice, SCID, DMSO, dimethyl sulfoxide, Antineoplastic Agent, Cholangiocarcinoma, Mice, Inbred NOD, AUY922, DNAJB5, bile duct cancer, organoid, miRNA, microRNA, PDO, patient-derived organoid, Tumor Cells, Cultured, Nuclear Protein, Nuclear Proteins, MicroRNA, HTS, high-throughput screen, Isocitrate Dehydrogenase, DNA-Binding Proteins, Organoids, FFPE, formalin-fixed paraffin-embedded, Gene Expression Regulation, Neoplastic, GI, growth inhibition, HSP, heat shock protein, Human, Signal Transduction, CCA, cholangiocarcinoma, FGFR, fibroblast growth factor receptor, Xenograft Model Antitumor Assay, Time Factor, Cell Survival, DNA-Binding Protein, Antineoplastic Agents, Transfection, Article, Cell Line, Tumor, Journal Article, Animals, Humans, HSP90 Heat-Shock Proteins, Bile Duct Neoplasm, Dose-Response Relationship, Drug, iCCA, intrahepatic cholantiocarcinoma, Animal, HSP40 Heat-Shock Proteins, Xenograft Model Antitumor Assays, MicroRNAs, HSP90 Heat-Shock Protein, Bile Duct Neoplasms, Drug Resistance, Neoplasm, Mutation, HSP40 Heat-Shock Protein, Transcription Factors
Abstract

Background & Aims: \ud Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors.\ud \ud Methods: \ud We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice.\ud \ud Results: \ud Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21.\ud \ud Conclusions: \ud miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.

Published
2018
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