Novel tumor suppressor microRNA at frequently deleted chromosomal region 8p21 regulates epidermal growth factor receptor in prostate cancer.
Genomic loss of chromosome (chr) 8p21 region, containing prostate-specific NKX3.1 gene, is a frequent alteration of the prostate cancer (PCa) oncogenome. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is also associated with a cluster of microRNA genes- miR-3622a/b- that are lost in PCa and play an important mechanistic role in progression and metastasis. In this study, we demonstrate the role of miR-3622b in prostate cancer. Expression analyses in a cohort of PCa clinical specimens and cell lines show that miR-3622b expression is frequently lost in prostate cancer. Low miR-3622b expression was found to be associated with tumor progression and poor biochemical recurrence-free survival. Further, our analyses suggest that miR-3622b expression is a promising prostate cancer diagnostic biomarker that exhibits 100% specificity and 66% sensitivity. Restoration of miR-3622b expression in PCa cell lines led to reduced cellular viability, proliferation, invasiveness, migration and increased apoptosis. miR-3622b overexpression in vivo induced regression of established prostate tumor xenografts pointing to its therapeutic potential. Further, we found that miR-3622b directly represses Epidermal Growth Factor Receptor (EGFR). In conclusion, our study suggests that miR-3622b plays a tumor suppressive role and is frequently downregulated in prostate cancer, leading to EGFR upregulation. Importantly, miR-3622b has associated diagnostic, prognostic and therapeutic potential. Considering the association of chr8p21 loss with poor prognosis, our findings are highly significant and support a novel concept that associates a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer.
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Nathan
N
Bucay
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Kirandeep
K
Sekhon
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Shahana
S
Majid
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Soichiro
S
Yamamura
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Varahram
V
Shahryari
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Z Laura
ZL
Tabatabai
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Kirsten
K
Greene
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Yuichiro
Y
Tanaka
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Rajvir
R
Dahiya
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Guoren
G
Deng
Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA.
Sharanjot
S
Saini
D000368:Aged; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8; D066246:ErbB Receptors / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*
D035683:MicroRNAs; C512478:EGFR protein, human; D066246:ErbB Receptors; D017430:Prostate-Specific Antigen
EGFR; chr8p21; miR-3622b; prostate cancer; tumor suppressor