SOST Inhibits Prostate Cancer Invasion

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.已有研究证实，Wnt信号通路（Wnt signaling）抑制剂可参与前列腺癌（prostate cancer, PC）的转移进程，但骨硬化蛋白（Sclerostin, Sost）的相关作用尚未被阐明。本研究发现，由Sost缺陷型成骨细胞介导的活化Wnt信号通路可促进前列腺癌细胞侵袭，而重组人骨硬化蛋白（rhSOST）则对此过程具有抑制作用。与之相反，重组人DKK1（rhDKK1）可促进前列腺癌细胞的形态伸长与丝状伪足（filopodia）形成——这是侵袭性表型的典型形态学特征。进一步研究发现，rhDKK1可激活PC3细胞内的经典Wnt信号通路（canonical Wnt signaling），提示在此研究背景下，SOST与DKK1对Wnt信号通路的调控作用截然相反。对与不同Wnt信号活性水平的成骨细胞（OBs）共培养的PC3细胞进行基因表达分析，结果鉴定出CRIM1为高侵袭条件下上调的转录本之一；实验还证实，CRIM1过表达同样可促进细胞侵袭。上述研究结果表明，骨源性Wnt信号通路可通过上调CRIM1的表达、促进癌细胞侵袭与骨黏附，增强前列腺癌的骨趋向性。综上，本研究证实SOST与DKK1对PC3细胞侵袭具有相反的调控作用，且骨源性Wnt信号通路可通过激活CRIM1表达、促进前列腺癌细胞与成骨细胞的物理相互作用，正向调控PC3细胞的侵袭表型。基于上述发现，我们进一步探究了高浓度SOST在体内的生物学效应。实验结果显示，将过表达SOST的PC3细胞经尾静脉注射至NSG小鼠体内后，肿瘤难以发生转移；而经股骨腔内注射的小鼠则出现了显著减轻的骨溶解（osteolysis）症状。这提示靶向骨骼微环境的分子干预策略，或可在临床场景中改善骨转移性前列腺癌的预后。