FAM83A promotes the progression and metastasis of human pancreatic neuroendocrine tumors by inducing the epithelial-mesenchymal transition via the PI3K/AKT and ERK pathways

Abstract

Background: Family with sequence similarity 83, member A (FAM83A) has been reported to play an important role in cancer progression and metastasis. The purpose of this study was to clarify the role and mechanism of FAM83A in pancreatic neuroendocrine tumors (PanNETs). Methods: PanNET specimens and adjacent nontumor pancreatic tissues obtained from 68 patients who underwent curative surgery for PanNETs were assessed using immunochemical staining to identify FAM83A expression. The relationships between FAM83A expression, clinicopathological parameters and prognosis were statistically analyzed. PanNET cell lines were used to study the role of FAM83A in the progression and metastasis of PanNETs in vitro and in vivo. Results: FAM83A was overexpressed in PanNET specimens compared with adjacent nontumor tissues. Furthermore, FAM83A expression was closely associated with lymph node metastasis (P = 0.02), perineural invasion (P = 0.001), the WHO classification (P = 0.039), AJCC stage (P = 0.01) and shorter disease-free survival in patients with PanNETs (P < 0.001). Enforced expression of FAM83A effectively promoted PanNET cell proliferation, migration, invasion and growth both in vitro and in vivo, whereas FAM83A inhibition exerted the opposite effects. Subsequent mechanistic investigations revealed that FAM83A promoted the progression and metastasis of PanNETs by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK pathways. More importantly, specific inhibition of either the AKT or ERK pathways partially rescued the effect of FAM83A overexpression on promoting PanNET progression and metastasis. Conclusions: FAM83A plays an important role in the progression and metastasis of PanNET by inducing the EMT via the activation of the ERK and PI3K/AKT pathways and may serve as a valuable molecular target in PanNET treatment.