RESUMEN
There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state.
Asunto(s)
Envejecimiento/genética , Transformación Celular Neoplásica/genética , MicroARNs/biosíntesis , Células Madre Neoplásicas/patología , Microambiente Tumoral/genética , Envejecimiento/patología , Diferenciación Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Senescencia Celular/genética , Inestabilidad Cromosómica/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Telómero/genéticaRESUMEN
Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype.
Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , MicroARNs/genética , Telómero/genética , Línea Celular Tumoral , Inestabilidad Cromosómica/genética , Daño del ADN/genética , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Células HEK293 , Humanos , Transcripción Genética/genéticaRESUMEN
The increased uncertainty caused by a sudden epidemic disease has had an impact on the global financial market. We aimed to assess the primary healthcare system of universal health coverage (UHC) during the coronavirus disease (COVID-19) pandemic and its relationship with the financial market. To this end, we employed the abnormal returns of 68 countries from January 2, 2019, to December 31, 2020, to test the impact of the COVID-19 outbreak on abnormal returns in the stock market and determine how a country's UHC changes the impact of a sudden pandemic on abnormal returns. Our findings show that the sudden onset of an epidemic disease results in unevenly distributed medical system resources, consequently diminishing the impact of UHC on abnormal returns.