Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer.
Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer.
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DOI：
10.1007/s10585-014-9682-1
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发表时间：
2014-12
影响因子：
4
通讯作者：
Sterling JA
中科院分区：
文献类型：
--
作者：
Johnson RW;Merkel AR;Page JM;Ruppender NS;Guelcher SA;Sterling JA
甲状旁腺相关蛋白（PTHrP）是骨转移瘤中骨破坏的重要调节因子。转化生长因子-β（TGF-β）部分通过转录因子Gli 2刺激PTHrP产生，Gli 2在溶骨性癌细胞中独立于Hedgehog信号传导途径进行调节。然而，体内抑制TGF-β并不能完全抑制骨中的肿瘤生长或肿瘤诱导的骨破坏，这表明还涉及其他途径。虽然Wnt信号在发育中调节Gli 2，但Wnt信号在骨转移中的作用尚不清楚。因此，我们研究了Wnt信号传导是否调节诱导骨破坏的肿瘤细胞中Gli 2的表达。我们在此报道了通过β-连环蛋白/T细胞因子4（TCF 4）过表达或氯化锂（LiCl）处理的Wnt激活增加溶骨性癌细胞中Gli 2和PTHrP的表达。这是通过启动子突变研究确定的Gli 2启动子内的TCF和Smad结合位点介导的，表明TGF-β和Wnt信号传导之间存在串扰。在具有骨样硬度的基质上培养肿瘤细胞增加了Gli 2和PTHrP的产生，增强了自分泌Wnt活性，并导致TCF/Wnt信号报告基因（TOPFlash）的增加，富集了β-连环蛋白核积聚，并通过PCR阵列提高了Wnt相关基因。基质细胞作为Wnt配体的额外旁分泌来源，在体外MDA-MB-231和RWGT 2细胞中增强Gli 2和PTHrP mRNA水平，并在β-连环蛋白/Wnt 3a依赖性机制中促进体内肿瘤诱导的骨破坏。这些数据表明，基质刚性和基质分泌因子的组合通过溶骨性乳腺癌细胞中的Wnt信号传导刺激Gli 2和PTHrP，并且在Wnt和TGF-β信号传导途径之间存在显著的串扰。这表明Wnt信号通路可能是抑制肿瘤细胞对骨微环境反应的潜在治疗靶点，至少应在靶向TGF-β信号传导的临床方案中予以考虑。
Parathyroid hormone-related protein (PTHrP) is an important regulator of bone destruction in bone metastatic tumors. Transforming growth factor-beta (TGF-β) stimulates PTHrP production in part through the transcription factor Gli2, which is regulated independent of the Hedgehog signaling pathway in osteolytic cancer cells. However, inhibition of TGF-β in vivo does not fully inhibit tumor growth in bone or tumor-induced bone destruction, suggesting other pathways are involved. While Wnt signaling regulates Gli2 in development, the role of Wnt signaling in bone metastasis is unknown. Therefore, we investigated whether Wnt signaling regulates Gli2 expression in tumor cells that induce bone destruction. We report here that Wnt activation by β-catenin/T-cell factor 4 (TCF4) over-expression or lithium chloride (LiCl) treatment increased Gli2 and PTHrP expression in osteolytic cancer cells. This was mediated through the TCF and Smad binding sites within the Gli2 promoter as determined by promoter mutation studies, suggesting cross-talk between TGF-β and Wnt signaling. Culture of tumor cells on substrates with bone-like rigidity increased Gli2 and PTHrP production, enhanced autocrine Wnt activity and led to an increase in the TCF/Wnt signaling reporter (TOPFlash), enriched β-catenin nuclear accumulation, and elevated Wnt-related genes by PCR-array. Stromal cells serve as an additional paracrine source of Wnt ligands and enhanced Gli2 and PTHrP mRNA levels in MDA-MB-231 and RWGT2 cells in vitro and promoted tumor-induced bone destruction in vivo in a β-catenin/Wnt3a-dependent mechanism. These data indicate that a combination of matrix rigidity and stromal-secreted factors stimulate Gli2 and PTHrP through Wnt signaling in osteolytic breast cancer cells, and there is significant cross-talk between the Wnt and TGF-β signaling pathways. This suggests that the Wnt signaling pathway may be a potential therapeutic target for inhibiting tumor cell response to the bone microenvironment and at the very least should be considered in clinical regimens targeting TGF-β signaling.
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影响因子：
5.6
作者：
Atance, J;Yost, MJ;Carver, W
通讯作者：
Carver, W
影响因子：
4.5
作者：
Jamieson, Cara;Sharma, Manisha;Henderson, Beric R.
通讯作者：
Henderson, Beric R.
影响因子：
4.8
作者：
Lim, Shen Kiat;Orhant-Prioux, Magali;Lim, Yoon Pin
通讯作者：
Lim, Yoon Pin
影响因子：
15.9
作者：
Gallwitz, WE;Guise, TA;Mundy, GR
通讯作者：
Mundy, GR
DOI：
10.1158/1078-0432.ccr-12-3654
发表时间：
2013-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jimeno A;Weiss GJ;Miller WH Jr;Gettinger S;Eigl BJ;Chang AL;Dunbar J;Devens S;Faia K;Skliris G;Kutok J;Lewis KD;Tibes R;Sharfman WH;Ross RW;Rudin CM
通讯作者：
Rudin CM