The TGF-[beta] signalling negative regulator PICK1 represses prostate cancer metastasis to bone
A partir d'échantillons tumoraux prélevés sur 198 patients atteints d'un cancer de la prostate, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation TGF-bêta, la protéine PICK1 réprime la formation de métastases osseuses
Backgroud: Constitutive activation of TGF-
β signalling is a well-recognised mechanism in bone metastasis of prostate cancer (PCa). Protein Interacting with PRKCA 1 (PICK1) is a critical negative regulator of the TGF-β pathway. However, the clinical significance and biological role of PICK1 in PCa bone metastasis remain obscure. Methods:
PICK1 expression is evaluated by immunohistochemistry (IHC) in 198 PCa patients. Statistical analysis is performed to explore correlation between PICK1 expression and clinicopathological features in PCa patients. The biological role of PICK1 is examined in PC-3 and C4-2B cells in vitro and a mouse intracardial model in vivo. Results:
PICK1 expression is decreased in PCa tissues with bone metastasis and bone-derived cells and downregulation of PICK1 positively correlates with serum PSA level, Gleason grade and bone metastasis status in PCa patients. Overexpression of PICK1 suppresses PCa cell invasion and migration in vitro and bone metastasis in vivo. Our results further indicate downregulation of PICK1 is caused by miR-210-3p overexpression in PCa tissues with bone metastasis. Clinical negative correlation of PICK1 with miR-210-3p is confirmed in PCa tissues. Conclusions:
Our findings uncover a novel functionally and clinically relevant epigenetic regulatory mechanism for constitutive activation of TGF-β signalling in bone metastasis of PCa.