Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer

Autor: Ying-qun Yang, Peng Wang, Liwen Zhang, Chang Hongyuan, Shaowei Du, Haiyue Liu, Yuwei Liu, Mengzhu Xue
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Science
Gene regulatory network
General Physics and Astronomy
Biology
Bioinformatics
medicine.disease_cause
urologic and male genital diseases
General Biochemistry
Genetics and Molecular Biology
Article
Metastasis
Cell Line
03 medical and health sciences
Prostate cancer
Cell Line
Tumor
microRNA
medicine
Humans
Neoplasm Metastasis
Transcription factor
Regulation of gene expression
Homeodomain Proteins
Multidisciplinary
Gene Expression Profiling
Computational Biology
Nuclear Proteins
Prostatic Neoplasms
General Chemistry
Zebrafish Proteins
medicine.disease
Gene expression profiling
Gene Expression Regulation
Neoplastic
MicroRNAs
030104 developmental biology
Homeobox Protein Nkx-2.2
Receptors
Androgen
Cancer research
Carcinogenesis
human activities
Transcription Factors
Zdroj: Nature Communications, Vol 8, Iss 1, Pp 1-9 (2017)
Nature Communications
ISSN: 2041-1723
Popis: Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance. Hence, a systematic identification of additional drivers may provide useful insights into the development of effective therapies. Numerous microRNAs that are critical for metastasis are dysregulated in metastatic prostate cancer, but the underlying molecular mechanism is poorly understood. We perform an integrative analysis of transcription factor (TF) and microRNA expression profiles and computationally identify three master TFs, AR, HOXC6 and NKX2-2, which induce the aberrant metastatic microRNA expression in a mutually exclusive fashion. Experimental validations confirm that the three TFs co-dysregulate a large number of metastasis-associated microRNAs. Moreover, their overexpression substantially enhances cell motility and is consistently associated with a poor clinical outcome. Finally, the mutually exclusive overexpression between AR, HOXC6 and NKX2-2 is preserved across various tissues and cancers, suggesting that mutual exclusivity may represent an intrinsic characteristic of driver TFs during tumorigenesis.
Dysregulation of microRNAs is thought to be important for metastasis in castration-resistant prostate cancer (CRPC), but its drivers are unknown. Here, the authors use computational analysis to identify HOXC6 and NKX2-2 in addition to AR as alternative drivers of dysregulated miRNA expression in CRPC.
Databáze: OpenAIRE
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