MAPK and JAK/STAT pathways targeted by miR-23a and miR-23b in prostate cancer: computational and in vitro approaches
- 626 Downloads
The long-lasting inadequacy of existing treatments for prostate cancer has led to increasing efforts for developing novel therapies for this disease. MicroRNAs (miRNAs) are believed to have considerable therapeutic potential due to their role in regulating gene expression and cellular pathways. Identifying miRNAs that efficiently target genes and pathways is a key step in using these molecules for therapeutic purposes. Moreover, computational methods have been devised to help identify candidate miRNAs for each gene/pathway. MAPK and JAK/STAT pathways are known to have essential roles in cell proliferation and neoplastic transformation in different cancers including prostate cancer. Herein, we tried to identify miRNAs that target these pathways in the context of prostate cancer as therapeutic molecules. Genes involved in these pathways were analyzed with various algorithms to identify potentially targeting miRNAs. miR-23a and miR-23b were then selected as the best potential candidates that target a higher number of genes in these pathways with greater predictive scores. We then analyzed the expression of candidate miRNAs in LNCAP and PC3 cell lines as well as prostate cancer clinical samples. miR-23a and miR-23b showed a significant downregulation in cell line and tissue samples, a finding which is consistent with overactivation of these pathways in prostate cancer. In addition, we overexpressed miR-23a and miR-23b in LNCAP and PC3 cell lines, and these two miRNAs decreased IL-6R expression which has a critical role in these pathways. These results suggest the probability of utilizing miR-23a and miR-23b as therapeutic targets for the treatment of prostate cancer.
KeywordsmiR-23a miR-23b Prostate cancer MAPK pathway JAK/STAT pathway
The authors appreciate the Pasteur Institute of Iran, Tehran, Iran for providing technical support. The authors are thankful to Vahid Haghpanah and Mohsen Khorashadizadeh for reading the manuscript and critical discussions. The authors are grateful to Zahra Masoumi and Fatemeh Kohram for editing the manuscript.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
This study was funded by the Stem Cell Technology Research Center, Tehran, Iran.
Seyed Hamid Aghaee-Bakhtiari carried out the practical tests and drafted the manuscript. Ehsan Arefian carried out the study design and drafting. Mahmood Naderi participated in the design of the study and drafting. Farshid Noorbakhsh participated in study design, data analysis, and draft preparation. Vahideh Nodouzi helped in clinical sample gathering and assisted in data analysis. Mojgan Asgari aided sample gathering and analyzed the stage of tumor samples. Pezhman Fard-Esfahani participated in data analysis and assisted in drafting the manuscript. Reza Mahdian helped in study design and aided in manuscript editing. Masoud Soleimani assisted in study design, data analysis, and draft preparation. All authors read and approved the final manuscript.
Conflicts of interest
- 1.Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. Globocan 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase no. 11; in Cancer IAfRo (ed), 2013.Google Scholar
- 19.Harrison DA. The jak/stat pathway. Cold Spring Harbor perspectives in biology 2012;4Google Scholar
- 22.Aalinkeel R, Hu Z, Nair BB, Sykes DE, Reynolds JL, Mahajan SD, et al. Genomic analysis highlights the role of the JAK-STAT signaling in the anti-proliferative effects of dietary flavonoid-‘ashwagandha’ in prostate cancer cells. Evid Based Complement Alternat Med: eCAM. 2010;7:177–87.CrossRefPubMedGoogle Scholar
- 27.Aghaee-Bakhtiari SH, Arefian E, Soleimani M, Noorbakhsh F, Samiee SM, Fard-Esfahani P, Mahdian R. Reproducible and reliable real-time pcr assay to measure mature form of mir-141. Appl Immunohistochem Mol Morphol 2015;Epub Ahead of PrintGoogle Scholar
- 30.Pulukuri SM, Gondi CS, Lakka SS, Jutla A, Estes N, Gujrati M, et al. RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo. J Biol Chem. 2005;280:36529–40.CrossRefPubMedGoogle Scholar
- 32.Coppola V, De Maria R, Bonci D. Micrornas and prostate cancer. Endocrine-related cancer 2010;17:F1-17Google Scholar