Kinase D-interacting substrate of 220kDa (Kidins220) in pancreatic cancer, molecular and cellular mechanism for its association with disease progression

Abstract

Kidins220 (Kinase D-Interacting Substrate, 220kDa) is a transmembrane scaffold protein and has been implicated in several malignancies. However, its role in pancreatic cancer remains unknown. The present study aims to investigate the role of Kidins220 in pancreatic cancer. A QPCR analysis showed that Kidins220 mRNA expression was reduced in pancreatic tumour tissues compared with adjacent normal pancreatic tissues. Reduced expression was also observed in the advanced tumours compared with tumours of an early stage. Furthermore, immunohistochemistry (IHC) staining presented reduced protein expression of Kidins220 in pancreatic tumour tissues compared with adjacent normal tissues and normal pancreatic tissues. Its reduced expression was also seen in invasive cancer originating in intraductal papillary mucinous neoplasm (IPMN) compared with normal pancreatic tissue. Moreover, primary tumours with distance metastasis exhibited a decreased level of Kidins220 protein expression compared to those without metastasis. Knockdown of Kidins220 promoted proliferation, migration and invasion of pancreatic cancer cells. Panc-1 cells with Kidins220 knockdown also exhibited an enhanced metastatic capability in vivo in peritoneal metastatic mouse model. An enhanced epithelial–mesenchymal transition (EMT) was observed in the pancreatic cancer cell lines with the knockdown of Kidins220 following an elevated expression and activation of EGFR and consequent activation of its downstream signalling pathways including extracellular signal-regulated kinase (ERK) and Protein kinase B (AKT) pathways. Taken together, a reduced expression of Kidins220 is observed in pancreatic cancer which is associated with disease progression, distant metastases and poor prognosis. The loss of Kidins220 in pancreatic cancer may contribute to the disease progression through an upregulation of EGFR signalling. It suggests that Kidins220 is a putative negative regulator for development and progression of pancreatic cancer. Further study will shed light on the interaction between Kidins220 and EGFR, and potential of this molecule in targeted therapy, for example EGFR or other HER family members for pancreatic cancer