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Carcinogenesis Advance Access originally published online on May 2, 2008
Carcinogenesis 2008 29(8):1509-1518; doi:10.1093/carcin/bgn105
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

TWIST modulates prostate cancer cell-mediated bone cell activity and is upregulated by osteogenic induction

Hiu-Fung Yuen1,2, Wai-Kei Kwok2, Ka-Kui Chan1, Chee-Wai Chua2, Yuen-Piu Chan1, Ying-Ying Chu3, Yong-Chuan Wong2, Xianghong Wang2 and Kwok-Wah Chan1,*

1 Department of Pathology
2 Department of Anatomy
3 Department of Chemistry, The University of Hong Kong, Pokfulam, Hong Kong, China

* To whom correspondence should be addressed. Department of Pathology, Queen Mary Hospital, Hong Kong, China. Tel: +852 28554874; Fax: +852 28725197; Email: kwchan{at}pathology.hku.hk

Correspondence may also be addressed to Xianghong Wang, Department of Anatomy, The University of Hong Kong, 1/F, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, China. Tel: +852 28192868; Fax: +852 28170857; Email: xhwang{at}hkucc.hku.hk

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.

Abbreviations: ALP, alkaline phosphate; ChIP, chromatin immunoprecipitation; DKK-1, dickkopf homolog 1; EMT, epithelial–mesenchymal transition; FBS, fetal bovine serum; PCR, polymerase chain reaction; TRACP, tartrate-resistant acid phosphatase

Received December 20, 2007; revised March 26, 2008; accepted April 22, 2008.


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