CCN1/Cyr61 regulates Sonic Hedgehog Signaling through Activation of Notch‐1 in Pancreatic Carcinogenesis: A Novel Targeting Pathway for Pancreatic Cancer Therapy

Abstract

CCN1 is a member of the CCN family of growth factors. It is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Previously we found CCN1 as an important factor in determining PDAC aggressiveness as it promotes epithelial to mesenchymal transition, tumor stemness, in vitro migration and tumorigenicity in xenograft model, possibly through the regulation of multiple miRNAs that are known to link with the progression of cancers and survival and the maintenance of cancer stem cells. CCN1 mRNA and protein expression was intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Our objective was to see whether CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch‐1. Notably, active Notch‐1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. Moreover, the functional role of CCN1 could be mediated through the interaction with the αvβ3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks Notch1 and SHh signaling pathways.This work was supported by VA Merit Review Grants (Sushanta K. Banerjee and Snigdha Banerjee)