Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis

Abstract

BackgroundDespite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood.ResultsWe show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP) cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1.ConclusionsIn conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

“…Bioinformatic analysis of a microarray dataset demonstrated that CYR61 expression was increased in PDAC samples compared with matched normal adjacent tissue ( Figure 3A and B), supporting increased CYR61 expression in PDAC, consistent with a prior report (32). Further analysis demonstrated that patients with familial PanIN precursor lesions (27) have an intermediate level of CYR61 ( Figure 3C).…”

CCN1: a novel target for pancreatic cancer

“…In a report recently published (Haque et al 2011), CCN1 was shown to have elevated mRNA and protein expression in~85% of pancreatic cancer specimens compared to adjacent normal samples where expression was essentially absent. In cell lines, the highest expression of RNA and protein was detected in Panc-1 cells followed by AsPC-1, Capan-1 and BxPC-3.…”

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

“…Its binding to cell-surface integrins promotes cancer cell proliferation and metastasis. Notably, overexpression of CYR61 in breast, prostate or ovarian cancer cells enhances tumour growth 21,22,40 , whereas CYR61 silencing in pancreatic and prostate cancer cells decreases tumour growth 22,23 . Finally, recombinant CYR61 treatment accelerates repair of epithelium in vitro in a model of inflammatory lung epithelium injury 41 .…”

“…Depending on the cell type and context, CYR61 can promote the proliferation, survival, migration or senescence of cells 14,[17][18][19][20] . CYR61 is overexpressed in various cancer cells, including cancers of epithelial origin, and can promote their proliferation [21][22][23] . Furthermore, specific expression of CYR61 in thymic stroma was evidenced in a study aimed at mapping thymic stromal gene expression 24 .…”