Transcription factor and microRNA regulation in androgen-dependent and -independent prostate cancer cells.
BACKGROUND
Prostate cancer is one of the leading causes of cancer death in men. Androgen ablation, the most commonly-used therapy for progressive prostate cancer, is ineffective once the cancer cells become androgen-independent. The regulatory mechanisms that cause this transition (from androgen-dependent to androgen-independent) remain unknown. In this study, based on the microarray data comparing global gene expression patterns in the prostate tissue between androgen-dependent and -independent prostate cancer patients, we identify a set of transcription factors and microRNAs that potentially cause such difference, using a model-based computational approach.


RESULTS
From 335 position weight matrices in the TRANSFAC database and 564 microRNAs in the microRNA registry, our model identify 5 transcription factors and 7 microRNAs to be potentially responsible for the level of androgen dependency. Of these transcription factors and microRNAs, the estimated function of all the 5 transcription factors are predicted to be inhibiting transcription in androgen-independent samples comparing with the dependent ones. Six out of 7 microRNAs, however, demonstrated stimulatory effects. We also find that the expression levels of three predicted transcription factors, including AP-1, STAT3 (signal transducers and activators of transcription 3), and DBP (albumin D-box) are significantly different between androgen-dependent and -independent patients. In addition, microRNA microarray data from other studies confirm that several predicted microRNAs, including miR-21, miR-135a, and miR-135b, demonstrate differential expression in prostate cancer cells, comparing with normal tissues.


CONCLUSIONS
We present a model-based computational approach to identify transcription factors and microRNAs influencing the progression of androgen-dependent prostate cancer to androgen-independent prostate cancer. This result suggests that the capability of transcription factors to initiate transcription and microRNAs to facilitate mRNA degradation are both decreased in androgen-independent prostate cancer. The proposed model-based approach indicates that considering combinatorial effects of transcription factors and microRNAs in a unified model provides additional transcriptional and post-transcriptional regulatory mechanisms on global gene expression in the prostate cancer with different hormone-dependency.
Wang
Guohua
G
School of Computer Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, PR China. ghwang@hit.edu.cn
Wang
Yadong
Y
Feng
Weixing
W
Wang
Xin
X
Yang
Jack Y
JY
Zhao
Yuming
Y
Wang
Yue
Y
Liu
Yunlong
Y
D020413:3' Untranslated Regions / Q000235:genetics; D000728:Androgens / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D000728:Androgens; D035683:MicroRNAs; D014157:Transcription Factors