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 2,000 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. Among the 5 genes, ANKRD6, ITIH3 and NPY1R represented independent prognostic factors determined through multivariate Cox regression analyses. Moreover, the expression of ANKRD6 and ITIH3 was significantly higher in metastasis and its levels associated to EMT and stemness markers. Moreover, ANKRD6 silencing in GC metastatic cells showed impairment in GC tumorigenic activity and EMT in functional studies in vivo and in molecular pathways in transcriptomic studies.
Conclusions: Our study identified a novel signature involved in GC malignancy and prognosis, and revealed a novel pro-metastatic role of ANKRD6 in GC.