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HMGA2-mediated tumorigenesis through angiogenesis in leiomyoma

      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.
      Tumorogénesis mediada por HMGA2 a través de la angiogénesis en miomas.

      Objetivo

      Estudiar el papel de HMGA2 en promover la angiogénesis en miomas uterinos (LM).

      Diseño

      Este estudio implica la evaluación de la densidad vascular y de factores angiogénicos en miomas con sobreexpresión de HMGA2; examinando la expresión de factores angiogénicos y la señalización AKT en células de miometrio (MM) y de mioma mediante la sobreexpresión in vitro de HMGA2; y explorando la formación de vasos inducida por la sobreexpresión de HMGA2 in vitro e in vivo.

      Lugar

      Laboratorio universitario de investigación

      Pacientes

      Ninguna.

      Intervenciones

      Ninguna

      Principales medidas de resultados

      Las principales medidas de los resultados incluyen la densidad vascular en miomas con alteraciones en HMGA2 (HMGA-LM) o MED12 (MED12-LM); la expresión de factores angiogénicos en miomas primario y modelos in vitro de líneas celulares; y formación de vasos en células de mioma sobreexpresión de HMGA2 in vitro e in vivo.

      Resultados

      Los factores y receptores angiogénicos fueron significativamente regulados al alza a nivel de ARNm y proteína en HMGA2-LM. Específicamente, HMGA2-LM exhibieron una aumentada expresión de VEGFA, EGF, ΒFGF, TGFα, VEGFR1, y VEGFR2 comparada con MED12-LM y miometrio. La sobreexpresión de HMGA2 en líneas celulares de MM y LM resultó en un aumento de la secreción de factores asociados con angiogénesis. Los factores secretados promovieron la migración de las células endoteliales de cordón umbilical (HUVEC: Human umbilical vein endotelial cell), la formación de tubos y la cicatrización. La sobreexpresión de HMGA2 reguló al alza IGF2BP2 y pAKT, y silenciando el gen IGF2BP2 se redujo los niveles de pAKT y la migración de las células HUVEC. Las células de miometrio con sobreexpresión estable de HMGA2 exhibieron una mayor formación de colonias y crecimiento celular in vitro y formaron xenoinjertos con vasos sanguíneos aumentados.

      Conclusión

      HMGA2-LM tiene una alta densidad vascular, la cual puede contribuir al crecimiento del tumor y la carga de morbilidad en este subtipo de miomas. HMGA2 juega un importante papel en la angiogénesis y la implicación de la actividad de pAKT en angiogénesis mediada por IGF2BP2, la cual proporciona una nueva diana para la terapia de este subtipo de LM.

      Key Words

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