Polycystin‐1 and polycystin‐2 are involved in the acquisition of aggressive phenotypes in colorectal cancer

Abstract

The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR 5 1.016, p 5 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p 5 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.Invasion and metastasis are responsible for 90% of cancerassociated mortality. While the role of biochemical signals in invasion and metastasis is well established, growing evidence reveals that mechanical signals also regulate cancer-cell

Deciphering signaling networks in osteosarcoma pathobiology

“…81 Polycystins have been also associated with cancer and have recently emerged as novel prognostic tools in colorectal tumors. 82,83 Unpublished data from our laboratory indicate that modulation of PC1 activity affects cell migration and proliferation in MG-63 cells. In addition, Adamopoulos et al Signal transduction in osteosarcoma 1301 stable downregulation of Polycystic Kidney Disease 1 gene in MG-63 cells enhances cell proliferation and affects proper cell differentiation, alterations mediated through impaired intracellular calcium-cAMP regulation, and activation of PKA.…”

Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

“…This is believed to play a major role in the invasion and metastasis of tumor cells[49,57]. Gargalionis et al[58] report that overexpression of the epithelial polycystins PC1 and PC2 in a human colon carcinoma cell line, HCT116, is able to induce EMT-related alteration in E-cadherin, N-cadherin, Snail and Twist (EMT trigger) mRNA expression. PC2 exogenous expression was also found to increase cell migration[58].…”

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

“…A particularly unexpected finding was that the rate of non-kidney cancer was also lower in patients with ADPKD than in those without (adjusted IRR 0.83–0.84, P <0.0001). Similarly, a 2011 study suggested that a loss-of-function mutation in the ARPKD-associated gene PKHD1 (which encodes fibrocystin) provides protection against colorectal cancer [213], whereas a 2014 study indicated that overexpression of intact polycystin 1 or polycystin 2 promotes colorectal cancer aggressiveness [214]. …”