title: The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis.
abstract: CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that 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. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. 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 two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance.
authors.affiliation: Cancer Research Unit, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri 64128, USA.
authors.forename: Inamul
authors.initials: I
authors.lastname: Haque
authors.forename: Archana
authors.initials: A
authors.lastname: De
authors.forename: Monami
authors.initials: M
authors.lastname: Majumder
authors.forename: Smita
authors.initials: S
authors.lastname: Mehta
authors.forename: Douglas
authors.initials: D
authors.lastname: McGregor
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
authors.forename: Peter
authors.initials: P
authors.lastname: Van Veldhuizen
authors.forename: Snigdha
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000737:chemistry / Q000502:physiology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055515:Cysteine-Rich Protein 61; D053823:Hedgehog Proteins; D016023:Integrins; D051880:Receptors, Notch; D046988:Proteasome Endopeptidase Complex