The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway

Abstract

ObjectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence.DesignPRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1.ResultsPRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling.ConclusionsWe identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence.

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

“…Dysregulated expression of PRC1, as a critical protein of cytokinesis, can cause disorders of cytokinesis. Previous studies (8,9,11) have implicated PRC1 as an oncogenic factor in tumorigenesis of bladder cancer, breast, and hepatocellular carcinoma. Here, we showed that PRC1protein expression was upregulated in lung SCC compared to paired normal lung tissues.…”

“…PRC1 has been shown to overexpress in various cancers including breast cancer (8), bladder cancer (9), hepatocellular carcinoma (10,11) and pancreatic cancer (12). The previous study (13) showed that PRC1 was up-regulated in primary gastric cancers and overexpression of PRC1 in gastric cancers was associated with poor disease-specific survival and OS.…”

“…Recently, Chen et al (11) found that PRC1 had an oncogenic function in promoting cancer proliferation, metastasis and tumorigenesis of hepatocellular carcinoma. Currently, the expression profile of PRC1 and the prognostic value of PRC1 in lung SCC have not been determined.…”

MAPping the Wnt pathway to hepatocellular carcinoma recurrence

“…In this issue of Gut, Chen and collaborators 4 identified the microtubule-associated Protein Regulator of Cytokinesis 1 (PRC1/…”

Immunobiology of hepatocarcinogenesis: Ways to go or almost there?

“…It is a direct Wnt signaling target and is necessary for Wnt signaling to mediate oncogenesis. PRC1 also potentiates Wnt signaling by promoting membrane sequestration of the destruction complex, thereby reducing APC stability and promoting stabilization of β-catenin [134] . Therefore, there is mounting evidence that β-catenin is essential for tumor cell proliferation and survival.…”