HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

Autor: Moura DS; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain. dmoura@atbsarc.org.; Department of Oncology in University Hospital Fundación Jiménez Díaz,, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain. dmoura@atbsarc.org., Mondaza-Hernandez JL; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain., Sanchez-Bustos P; Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013, Seville, Spain., Peña-Chilet M; Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013, Seville, Spain.; Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, 41013, Seville, Spain.; Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, 41013, Seville, Spain., Cordero-Varela JA; Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013, Seville, Spain., Lopez-Alvarez M; Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013, Seville, Spain., Carrillo-Garcia J; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain., Martin-Ruiz M; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain., Romero-Gonzalez P; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain., Renshaw-Calderon M; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain., Ramos R; Pathology Department, Son Espases University Hospital, 07120, Mallorca, Spain., Marcilla D; Pathology Department, University Hospital Virgen del Rocio, 41013, Seville, Spain., Alvarez-Alegret R; Pathology Department, Miguel Servet University Hospital, 50009, Saragossa, Spain., Agra-Pujol C; Pathology Department, Gregorio Marañon Universitary Hospital, 28007, Madrid, Spain., Izquierdo F; Pathological Anatomy Service, Complejo Asistencial Universitario de León, 24071, Leon, Spain., Ortega-Medina L; Pathology Department, Hospital Clinico San Carlos, 28040, Madrid, Spain., Martin-Davila F; Pathology Department, Ciudad Real General Hospital, 13005, Ciudad Real, Spain., Hernandez-Leon CN; Pathology department, Canarias University Hospital, 38320, Santa Cruz de Tenerife, Spain., Romagosa C; Pathology department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain., Salgado MAV; Medical Oncology Department, Ramon y Cajal University Hospital, 28034, Madrid, Spain., Lavernia J; Medical Oncology Department, Instituto Valenciano de Oncologia, 46009, Valencia, Spain., Bagué S; Pathology Department, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain., Mayodormo-Aranda E; Pathology Department, Hospital Universitari i Politècnic la Fe, 46026, Valencia, Spain., Alvarez R; Medical Oncology Department, Gregorio Marañon Universitary Hospital, 28007, Madrid, Spain., Valverde C; Medical Oncology Department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain., Martinez-Trufero J; Medical Oncology Department, Miguel Servet University Hospital, 50009, Saragossa, Spain., Castilla-Ramirez C; Pathology Department, University Hospital Virgen del Rocio, 41013, Seville, Spain., Gutierrez A; Hematology Department, Son Espases University Hospital, 07120, Mallorca, Spain., Dopazo J; Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013, Seville, Spain.; Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, 41013, Seville, Spain.; Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, 41013, Seville, Spain.; INB-ELIXIR-es, FPS, Hospital Virgen del Rocío, 41013, Seville, Spain., Hindi N; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain.; Medical Oncology Department, Fundación Jimenez Diaz University Hospital, 28040, Madrid, Spain.; General de Villalba University Hospital, 28400, Madrid, Spain., Garcia-Foncillas J; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain.; Medical Oncology Department, Fundación Jimenez Diaz University Hospital, 28040, Madrid, Spain.; General de Villalba University Hospital, 28400, Madrid, Spain., Martin-Broto J; Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain. jmartin@atbsarc.org.; Medical Oncology Department, Fundación Jimenez Diaz University Hospital, 28040, Madrid, Spain. jmartin@atbsarc.org.; General de Villalba University Hospital, 28400, Madrid, Spain. jmartin@atbsarc.org.; Department of Oncology in University Hospital Fundación Jiménez Díaz,, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain. jmartin@atbsarc.org.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 May 17; Vol. 81 (1), pp. 219. Date of Electronic Publication: 2024 May 17.
DOI: 10.1007/s00018-024-05250-y
Abstrakt: HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.
(© 2024. The Author(s).)
Databáze: MEDLINE
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