Um novo estudo revela que o HMGA1 estimula as características estaminais e aumenta a sensibilidade à monensina em células de cancro gástrico

Investigadores do grupo “Diferenciação e Cancro” do i3S, em colaboração com António Pombinho, da plataforma “BioSciences Screening”, e Filipe Pereira, da Universidade de Lund, elucidaram o papel do fator de transcrição HMGA1 nas células estaminais de cancro gástrico. O estudo, intitulado “HMGA1 stimulates cancer stem-like features and sensitivity to monensin in gastric cancer”, foi recentemente publicado na revista “Experimental Cell Research”.

O cancro gástrico continua a ser um problema de saúde global, muitas vezes diagnosticado em fases avançadas e com mau prognóstico. As células estaminais do cancro (CSCs) impulsionam o crescimento tumoral, a formação de metástases e a resistência ao tratamento. Este estudo identifica o HMGA1 como um regulador chave de características estaminais em células de cancro gástrico, enriquecidas em SOX2, C-MYC e outros marcadores estaminais. Mostra ainda que a monensina tem como alvo as CSCs que expressam HMGA1, oferecendo uma potencial estratégia terapêutica.  

Autores e afiliações:

Diana Pádua^1,2,3, Paula Figueira^1,2, António Pombinho^1,4, Inês Monteiro^1,2, Carlos Filipe Pereira^5,6,7, Raquel Almeida^1,2 and Patrícia Mesquita^1,2*

¹ i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

² IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal.

³ ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal.

⁴ IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal.

⁵ CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

⁶ Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden.

⁷ Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden.

Abstract:

Gastric cancer represents a serious health problem worldwide, with insufficient molecular biomarkers and therapeutic options. Consequently, several efforts have been directed towards finding specific disease markers in order to develop new therapies capable of defeating gastric cancer. Attention has been pointed to cancer stem cells (CSCs) as they are primarily responsible for tumor initiation and recurrence, making them essential therapeutic targets. Using the SORE6-GFP reporter system, based on the expression of SOX2 and/or OCT4 to drive GFP expression, we isolated gastric cancer stem-like cells (SORE6+ cells) enriched in several molecules, including SOX2, C-MYC, KLF4, HIF-1α, NOTCH1 and HMGA1. Here, we explored the previously undisclosed link of HMGA1 with gastric CSCs. Our results indicated that HMGA1 can activate a transcriptional program that includes SOX2, C-MYC, and KLF4 and endows cells with CSC features. We further showed that chemical induction of gastric CSCs using ciclopirox (CPX) can be mediated by HMGA1. Finally, we showed that HMGA1 GFP+ cells were sensitive to monensin confirming the selective activity of this drug over CSCs. Thus, HMGA1 is a key player in the cellular reprogramming of gastric non-CSCs to cancer stem-like cells.

Revista: Experimental Cell Research

Link: https://www.sciencedirect.com/science/article/pii/S0014482724003483?via%3Dihub