ABSTRACT
BACKGROUND: Gastric Cancer (GC) presents poor outcome, which is consequence of the high incidence of recurrence and metastasis at early stages. GC patients presenting recurrent or metastatic disease display a median life expectancy of only 8 months. The mechanisms underlying GC progression remain poorly understood. METHODS: We took advantage of public available GC datasets from TCGA using GEPIA, and identified the matched genes among the 100 genes most significantly associated with overall survival (OS) and disease free survival (DFS). Results were confirmed in ACRG cohort and in over 2000 GC cases obtained from several cohorts integrated using our own analysis pipeline. The Kaplan-Meier method and multivariate Cox regression analyses were used for prognostic significance and linear modelling and correlation analyses for association with clinic-pathological parameters and biological hallmarks. In vitro and in vivo functional studies were performed in GC cells with candidate genes and the related molecular pathways were studied by RNA sequencing. RESULTS: High expression of ANKRD6, ITIH3, SORCS3, NPY1R and CCDC178 individually and as a signature was associated with poor prognosis and recurrent disease in GC. Moreover, the expression of ANKRD6 and ITIH3 was significantly higher in metastasis and their levels associated to Epithelial to Mesenchymal Transition (EMT) and stemness markers. In line with this, RNAseq analysis revealed genes involved in EMT differentially expressed in ANKRD6 silencing cells. Finally, ANKRD6 silencing in GC metastatic cells showed impairment in GC tumorigenic and metastatic traits in vitro and in vivo. CONCLUSIONS: Our study identified a novel signature involved in GC malignancy and prognosis, and revealed a novel pro-metastatic role of ANKRD6 in GC.
ABSTRACT
Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from patients with DM1 and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples, as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas the DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds Quercetin, Dasatinib, or Navitoclax reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identify the accumulation of senescence as part of DM1 pathophysiology and, therefore, demonstrate the efficacy of senolytic compounds in the preclinical setting.
