| Autor: |
Rivas S; Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Calle Sergio Livingstone 943, Independencia, Santiago, Chile.; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile., Silva P; Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Calle Sergio Livingstone 943, Independencia, Santiago, Chile.; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile., Reyes M; Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile., Sepúlveda H; Institute of Biomedical Sciences and FONDAP Center for Genome Regulation, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile., Solano L; Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Calle Sergio Livingstone 943, Independencia, Santiago, Chile.; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile., Acuña J; Laboratory of Pathological Anatomy, Hospital San José, Santiago, Chile., Guerrero M; Laboratory of Pathological Anatomy, Hospital San José, Santiago, Chile., Varas-Godoy M; Center for Cell Biology and Biomedicine (CEBICEM), Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile., Quest AFG; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile.; Center for Studies on Exercise, Metabolism and Cancer (CEMC), Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile., Montecino M; Institute of Biomedical Sciences and FONDAP Center for Genome Regulation, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile., Torres VA; Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Calle Sergio Livingstone 943, Independencia, Santiago, Chile. vatorres@odontologia.uchile.cl.; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile. vatorres@odontologia.uchile.cl. |
| Abstrakt: |
Tumor hypoxia and the hypoxia inducible factor-1, HIF-1, play critical roles in cancer progression and metastasis. We previously showed that hypoxia activates the endosomal GTPase Rab5, leading to tumor cell migration and invasion, and that these events do not involve changes in Rab protein expression, suggesting the participation of intermediate activators. Here, we identified ALS2, a guanine nucleotide exchange factor that is upregulated in cancer, as responsible for increased Rab5-GTP loading, cell migration and metastasis in hypoxia. Specifically, hypoxia augmented ALS2 mRNA and protein levels, and these events involved HIF-1α-dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1α-binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1α stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1α. Strikingly, ALS2 upregulation in hypoxia was required for Rab5 activation, tumor cell migration and invasion, as well as experimental metastasis in C57BL/6 mice. Finally, immunohistochemical analyses in patient biopsies with renal cell carcinoma showed that elevated HIF-1α correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis. |
