Silencing IGFBP-2 decreases pancreatic cancer metastasis and enhances chemotherapeutic sensitivity

Abstract

Pancreatic cancer has remained one of the most devastating and lethal malignancies characterized by local invasion, distant metastasis and a high degree of chemoresistance. Insulin-like growth factor binding protein 2 (IGFBP-2) is a member of the IGFBP family of proteins, and it is highly expressed in pancreatic cancer patients’ serum and tumor tissues. IGFBP-2 also mediates tumor cell growth, invasion and resistance, while the mechanisms remain unclear. In this study, we sought to determine the impact of IGFBP-2 expression on pancreatic cancer tumorigenesis and metastasis in vitro and in vivo. Wound healing, migration and invasion assays revealed that knockdown of IGFBP-2 inhibits cancer cell migration and invasion. Downregulation of IGFBP-2 attenuates EMT via increasing the E-cadherin and reducing the vimentin and N-cadherin. PTCH-1 is found contribute to the function of IGFBP-2 in suppressing metastasis and EMT of pancreatic cancer. Silencing IGFBP-2 inhibited invasion and metastatic properties, partially through inhibiting PTCH1 in pancreatic cancer. Additionally, inhibition of IGFBP-2 enhanced the sensitivity of pancreatic cancer cells to gemcitabine, suppressed tumor growth and potentiated the anti-tumor effect of gemcitabine in the orthotopic tumor model. Our results provide novel insight of IGFBP-2 as a promising target to inhibit the metastasis and overcome the chemoresistance in pancreatic cancer.