Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma.
High-mobility group A2 (HMGA2) is commonly overexpressed in large leiomyomas. HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation. As a predicted target of Let-7 microRNAs (Let-7s), HMGA2 can be repressed by Let-7s in vitro. MicroRNA profiling analysis revealed that Let-7s were significantly dysregulated in uterine leiomyomas: high in small leiomyomas and lower in large leiomyomas. To evaluate whether Let-7 repression of HMGA2 plays a major role in leiomyomas, we analyzed the molecular relationship of HMGA2 and Let-7s, both in vitro and in vivo. We first characterized that exogenous Let-7 microRNAs could directly repress the dominant transcript of HMGA2, HMGA2a. This repression was also identified for two cryptic HMGA2 transcripts in primary leiomyoma cultures. Second, we found that the endogenous Let-7s were biologically active and played a major role in the regulation of HMGA2. Then, we illustrated that Let-7 repression of HMGA2 inhibited cellular proliferation. Finally, we examined the expression levels of Let-7c and HMGA2 in a large cohort of leiomyomas (n = 120), and we found high levels of Let-7 and low levels of HMGA2 in small leiomyomas, and low levels of Let-7 and high levels of HMGA2 in large leiomyomas. Our findings suggest that the Let-7-mediated repression of HMGA2 mechanism can be an important molecular event in leiomyoma growth.
Peng
Yi
Y
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Laser
Jordan
J
Shi
Guizhi
G
Mittal
Khush
K
Melamed
Jonathan
J
Lee
Peng
P
Wei
Jian-Jun
JJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology*
D025743:HMGA2 Protein; D019394:Ki-67 Antigen; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D008156:Luciferases