HMGA2-mediated tumorigenesis through angiogenesis in leiomyoma

Leiomyomas with HMGA2 overexpression tend to be large with high vasculature. Introducing HMGA2 overexpression in myometrial cells enhances angiogenesis through IFG2BP2/AKT pathway in vitro and in vivo.

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VOLUME 114, ISSUE 5, P1085-1096

Authors:

Yinuo Li, M.D., Wenan Qiang, M.D., Ph.D., Brannan Brooks Griffin, M.D., Tingting Gao, M.D., Debabrata Chakravarti, Ph.D., Serdar Bulun, M.D., J. Julie Kim, Ph.D., Jian-Jun Wei, M.D.

Abstract:

Objective

To study the role of HMGA2 in promoting angiogenesis in uterine leiomyoma (LM).


Design

This study involved evaluation of vessel density and angiogenic factors in leiomyomas with HMGA2 overexpression; examining angiogenic factor expression and AKT signaling in myometrial (MM) and leiomyoma cells by introducing HMGA2 overexpression in vitro; and exploring vessel formation induced by HMGA2 overexpression both in vitro and in vivo.


Setting

University research laboratory.


Patients

None.


Interventions

None.


Main Outcome Measures

The main outcome measures include vessel density in leiomyomas with HMGA2 (HMGA2-LM) or MED12 (MED12-LM) alteration; angiogenic factor expression in primary leiomyoma and in vitro cell line model; and vessel formation in leiomyoma cells with HMGA2 overexpression in vitro and in vivo.


Results

Angiogenic factors and receptors were significantly upregulated at mRNA and protein levels in HMGA2-LM. Specifically, HMGA2-LM exhibited increased expression of VEGFA, EGF, bFGF, TGFα, VEGFR1, and VEGFR2 compared to MED12-LM and myometrium. Overexpression of HMGA2 in MM and LM cell lines resulted in increased secretion of angiogenesis-associated factors. Secreted factors promoted human umbilical vein endothelial cell (HUVEC) migration, tube formation, and wound healing. HMGA2 overexpression upregulated IGF2BP2 and pAKT, and silencing the IGF2BP2 gene reduced pAKT levels and reduced HUVEC migration. Myometrial cells with stable HMGA2 overexpression exhibited increased colony formation and cell growth in vitro and formed xenografts with increased blood vessels.


Conclusions

HMGA2-LM have a high vasculature density, which likely contributes to tumor growth and disease burden of this leiomyoma subtype. HMGA2 plays an important role in angiogenesis and the involvement of IGF2BP2-mediated pAKT activity in angiogenesis, which provides a potential novel target for therapy for this subtype of LM.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.