Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.
OBJECTIVE
High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising therapeutic target in treating PC.


METHODS
In this study, we examined the functional relation between miR-296 and HMGA1 expression in several PC cell lines and a large PC cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296.


RESULTS
Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation. Repression of HMGA1 by miR-296 is direct and sequence specific. Importantly, ectopic miR-296 expression significantly reduced PC cell proliferation and invasion, in part through the downregulation of HMGA1. Examining PC patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage.


CONCLUSIONS
Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion.
Department of Pathology, Northwestern University, Feinberg Medical School, Chicago, Illinois, USA.
Jian-Jun
JJ
Wei
Xinyu
X
Wu
Yi
Y
Peng
Guizhi
G
Shi
Olca
O
Basturk
Basturk
B
Olca
Ximing
X
Yang
Garrett
G
Daniels
Iman
I
Osman
Jiangyong
J
Ouyang
Eva
E
Hernando
Angel
A
Pellicer
Johng S
JS
Rhim
Jonathan
J
Melamed
Peng
P
Lee
D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D015331:Cohort Studies; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D007797:Laminin / Q000737:chemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D004338:Drug Combinations; D007797:Laminin; C549871:MIRN296 microRNA, human; D035683:MicroRNAs; D011509:Proteoglycans; C059485:matrigel; D025741:HMGA1a Protein; D003094:Collagen