Abstract
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.
Highlights
Uterine leiomyomas are a major public health problem, represented by a high incidence [1], a high rate of hysterectomies for symptomatic disease [2], and a high medical cost [3, 4]
We previously found that transfection of exogenous Let-7c in primary leiomyoma culture cells can repress high-mobility group A2 (HMGA2) translation [30] with minimal effect on HMGA2 mRNA levels (Fig. 1A)
Provided that the presence of Let-7 microRNAs (Let-7s) Let-7 complementary sites (LCS) at the 3¶ untranslation region (3¶-UTR) of HMGA2 is required for Let-7 activity, several potential mechanisms can explain the overexpression of HMGA2 in uterine leiomyomas: (a) loss or reduction of Let7 expression; (b) the truncated transcripts of HMGA2 with a partial or complete loss of Let-7 LCS, secondary to chromosomal 12q13-15 changes [7, 31]; and (c) expression of cryptic HMGA2 isoforms (HMGA2b-HMGA2g; refs. 17, 32) that may lack Let-7 LCS
Summary
Uterine leiomyomas are a major public health problem, represented by a high incidence [1], a high rate of hysterectomies for symptomatic disease [2], and a high medical cost [3, 4]. Overexpression of high-mobility group A2 (HMGA2) is very common in uterine leiomyomas and it is induced by chromosomal changes involving 12q13-15 [5, 6]. Leiomyomas with and without HMGA2 expression have distinctly different gene expression profiles [11, 12], indicative of the unique molecular role of HMGA2 in the tumorigenesis of uterine leiomyomas. HMGA2, a high-mobility-group AT-hook (HMGA) protein, is a non-histone DNA binding factor. It has three AT-hook DNA binding domains through which HMGA2 binds to ATrich sequences in the minor groove of the DNA helix. As an important regulator of cell growth, differentiation, apoptosis, and transformation [15], HMGA2 interacts with many different transcription factors and influences numerous gene expression patterns [15]
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