Src/STAT3 Signaling Pathways Are Involved in KAI1-induced Downregulation of VEGF-C Expression in Pancreatic Cancer

A previous study by our group demonstrated that overexpression of KAI1 was associated with lymphatic metastasis in pancreatic cancer. The present study further investigated the signaling pathways involved in KAI1‑induced downregulation of vascular endothelial growth factor C (VEGF‑C) and lymphatic metastasis in pancreatic cancer. Immunohistochemistry was performed to examine KAI1 and VEGF‑C expression in 28 surgically resected pancreatic cancer tissues. MIA PaCa‑2 and PCAN1 pancreatic cancer cell lines were transfected with KAI1 overexpression vector. VEGF‑C expression as well as phosphorylation of Src and signal transducer and activator of transcription (STAT)3 were assessed by western blot analysis. Furthermore, the signal transduction inhibitors PP2 and AG490 were used to block the Src and STAT3 signaling pathways, respectively. KAI1 was negatively correlated with VEGF‑C expression in pancreatic tumor samples. In MIA PaCa‑2 cells, VEGF‑C expression was more significantly inhibited by restoration of KAI1 than that in PCAN1 cells. In addition, Src and STAT3 phosphorylation was decreased by KAI1 in MIA PaCa‑2 cells. Of note, pre‑treatment with PP2 efficiently reversed the KAI1-induced enhancement of Src and STAT3 phosphorylation as well as VEGF‑C expression. Pre‑treatment with AG490 efficiently reversed the KAI1-induced enhancement of STAT3 phosphorylation and VEGF‑C expression, but had no effect on the upregulation of Src phosphorylation. The present study identified the involvement of Src/STAT3 signaling pathways in KAI1‑induced downregulation of VEGF‑C expression and suggested the implication of these pathways in lymphatic metastasis of pancreatic cancer.