Downregulation of THBS2 suppresses tumorigenicity and liver metastasis of gastric cancer and increases its sensitivity to trastuzumab

Objective: Liver metastasis is one of the major causes of cancer-related death in gastric cancer (GC) patients. This study was to investigate the roles of THBS2 in the tumorigenesis and liver metastasis of GC and the sensitivity of GC to trastuzumab.Methods: Sequencing was employed to identify the differentially expressed genes in the GC. The THBS2 expression was detected in GC tissues and GC cell lines, its relationships with clinicopathological characteristics were further assessed, and its roles in the malignant behaviors of GC were further investigated in vitro and in vivo, by up-regulating or down-regulating THBS2 expression. The PTEN and its downstream AKT and FAK signaling pathways were investigated in the GC aiming to explore the potential mechanism underlying the regulatory effects of THBS2.Results: THBS2 expression increased significantly in the GC as compared to the normal gastric tissues, which was related to the distal metastasis and poor prognosis of GC patients. THBS2 expression also increased in the primary GC cells and human gastric cell line NCI-N87. THBS2 downregulation induced mesenchymal-epithelial transition (MET) and PTEN nuclear translocation, which inhibited the metastasis of GC cells. Carmofur promoted PTEN nuclear translocation, inhibiting the metastases and THBS2 downregulation together with carmofur improved the sensitivity of GC to trastuzumab.Conclusions: THBS2 is overexpressed in GC tissues of patients with synchronous liver metastases and its overexpression is associated with poor prognosis. THBS2 downregulation inhibits the metastases of GC. THBS2 down-regulation and carmofur can be used as a new treatment for the advanced GC with metastases.