Yuen Hiu-Fung, Kwok Wai-Kei, Chan Ka-Kui, Chua Chee-Wai, Chan Yuen-Piu, Chu Ying-Ying, Wong Yong-Chuan, Wang Xianghong, Chan Kwok-Wah
Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Carcinogenesis. 2008 Aug;29(8):1509-18. doi: 10.1093/carcin/bgn105. Epub 2008 May 2.
TWIST, a helix-loop-helix transcription factor, is highly expressed in many types of human cancer. We have previously found that TWIST confers prostate cancer cells with an enhanced metastatic potential through promoting epithelial-mesenchymal transition (EMT) and a high TWIST expression in human prostate cancer is associated with an increased metastatic potential. The predilection of prostate cancer cells to metastasize to bone may be due to two interplaying mechanisms (i) by increasing the rate of bone remodeling and (ii) by undergoing osteomimicry. We further studied the role of TWIST in promoting prostate cancer to bone metastasis. TWIST expression in PC3, a metastatic prostate cancer cell line, was silenced by small interfering RNA and we found that conditioned medium from PC3 with lower TWIST expression had a lower activity on stimulating osteoclast differentiation and higher activity on stimulating osteoblast mineralization. In addition, we found that these effects were, at least partly, associated with TWIST-induced expression of dickkopf homolog 1 (DKK-1), a factor that promotes osteolytic metastasis. We also examined TWIST and RUNX2 expressions during osteogenic induction of an organ-confined prostate cancer cell, 22Rv1. We observed increased TWIST and RUNX2 expressions upon osteogenic induction and downregulation of TWIST through short hairpin RNA reduced the induction level of RUNX2. In summary, our results suggest that, in addition to EMT, TWIST may also promote prostate cancer to bone metastasis by modulating prostate cancer cell-mediated bone remodeling via regulating the expression of a secretory factor, DKK-1, and enhancing osteomimicry of prostate cancer cells, probably, via RUNX2.
TWIST是一种螺旋-环-螺旋转录因子，在多种人类癌症中高表达。我们之前发现，TWIST通过促进上皮-间质转化（EMT）赋予前列腺癌细胞更强的转移潜能，并且人类前列腺癌中TWIST的高表达与转移潜能增加相关。前列腺癌细胞倾向于转移至骨可能归因于两种相互作用的机制：（i）通过提高骨重塑速率；（ii）通过进行骨模拟。我们进一步研究了TWIST在促进前列腺癌骨转移中的作用。用小干扰RNA使转移性前列腺癌细胞系PC3中的TWIST表达沉默，我们发现TWIST表达较低的PC3条件培养基对刺激破骨细胞分化的活性较低，而对刺激成骨细胞矿化的活性较高。此外，我们发现这些效应至少部分与TWIST诱导的Dickkopf同源物1（DKK-1）的表达有关，DKK-1是一种促进溶骨性转移的因子。我们还检测了器官局限性前列腺癌细胞22Rv1在成骨诱导过程中TWIST和RUNX2的表达。我们观察到成骨诱导后TWIST和RUNX2表达增加，通过短发夹RNA下调TWIST可降低RUNX2的诱导水平。总之，我们的结果表明，除了EMT外，TWIST还可能通过调节分泌因子DKK-1的表达来调节前列腺癌细胞介导的骨重塑，并可能通过RUNX2增强前列腺癌细胞的骨模拟，从而促进前列腺癌骨转移。
