Abstract
Epithelial-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining metastatic behavior during cancer progression. NOV/CCN3 is a matrix-associated protein involved in many cellular functions. Previous studies have shown that CCN3 expression is upregulated in prostate cancer (PCa) cells and in PCa patients. In this study, we have provided evidence of tumor promoting effects of CCN3, which includes induction of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We used an orthotopic in vivo model to demonstrate the prometastatic effects of CCN3. Overexpression or knockdown of CCN3 changed the EMT phenotype in PCa cells. Moreover, treatment with recombinant CCN3 promoted EMT in PCa cells. We also found that CCN3 may promote EMT by activating the FAK/Akt/HIF-1α pathway and this activation is responsible for Twist expression. IHC staining confirmed a positive correlation between the expression of CCN3, Twist, and tumor stage in PCa tissue. Our findings provide insight into the involvement of CCN3 in the EMT regulation of prostate cancer. CCN3 is a promising molecular target that may contribute to a novel therapeutic strategy against metastatic PCa.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries [1]
We found that E-cadherin and Twist expression correlated with CCN3 expression in tumor specimens (Figure 1H)
These results show that CCN3 serves as a critical regulator of prostate cancer (PCa) metastasis in vivo and correlates with the Epithelial-mesenchymal transition (EMT) status
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries [1]. Epithelial-to-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm that may explain invasive and metastatic behavior during cancer progression [3]. EMT-activating transcription factors such as Twist, Snail, Slug, ZEB1 and ZEB2 orchestrate the EMT process and promote the early steps of metastasis, which consist mainly of local invasion and subsequent dissemination of tumor cells to distant sites [5]. These transcription factors repress E-cadherin expression through binding to the E-box in the E-cadherin gene promoter, which in turn promotes EMT [6,7,8,9,10]. Substantial evidence shows that PCa progression exhibits EMT-like states, characterized by changes in the expression of various markers such as E-cadherin and vimentin, which are associated with invasive behavior [11]
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