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TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling.
TGF-β 促进 Gli2-induced 甲状旁腺激素相关蛋白的表达,甲状旁腺激素相关蛋白是骨转移中重要的溶骨因子,独立于经典 Hedgehog 信号。

摘要

Breast cancer frequently metastasizes to bone, in which tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-β, which upregulates expression of the Hedgehog (Hh) signaling molecule, Gli2, which in turn increases secretion of important osteolytic factors such as parathyroid hormone-related protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 overexpression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-MB-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-repressor gene (Gli2-rep) reduced endogenous and TGF-β-stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep-expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-β propagation of a vicious osteolytic cycle in this MDA-MB-231 model of bone metastasis. Accordingly, in the absence of TGF-β signaling, Gli2 expression was downregulated in cells, whereas enforced overexpression of Gli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-β to stimulate PTHrP expression and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction.

译文

乳腺癌经常转移到骨骼,在骨骼中,肿瘤细胞接收来自骨髓微环境的信号。一个相关因素是 TGF-β,它上调 Hedgehog (Hh) 信号分子 Gli2 的表达, 这反过来增加重要溶骨因子的分泌,如甲状旁腺激素相关蛋白 (PTHrP)。PTHrP 抑制可阻止肿瘤诱导的骨破坏,而肿瘤细胞中 Gli2 过表达可促进骨溶解。在这项研究中,我们验证了骨转移性乳腺癌中 Hh 抑制会降低 PTHrP 表达,从而导致溶骨性骨破坏的假设。然而,当移植了人 MDA-MB-231 乳腺癌细胞的小鼠用 Hh 受体拮抗剂 cyclopamine 处理时,我们观察到对肿瘤负荷或骨破坏没有影响。体外分析显示溶骨性肿瘤细胞缺乏 Hh 受体的表达,平滑,表明 Gli2 调控的独立于 Hh 的机制。用 Gli2-repressor 基因 (Gli2-rep) 阻断转移性乳腺癌细胞中的 Gli 信号减少了内源性和 TGF-β 刺激的 PTHrP mRNA 表达,但没有改变肿瘤细胞增殖。此外,接种了 Gli2-Rep-expressing 细胞的小鼠表现出骨溶解减少,表明 Gli2 抑制可能会阻断该 MDA-MB-231 骨转移模型中恶性溶骨循环的 TGF-β 的传播。因此,在缺乏 TGF-β 信号传导的情况下,细胞中 Gli2 的表达下调,而 Gli2 的强制过表达恢复了 PTHrP 的活性。综上所述,我们的发现表明 Gli2 是 TGF-β 刺激 PTHrP 表达所必需的,阻断 Hh 非依赖性 Gli2 活性将抑制肿瘤诱导的骨破坏。

parathyroid hormone-related protein

肿瘤 PTHrP 临床研究术语
概述  :  

甲状腺旁素相关蛋白(PTHrP)可表达于皮肤、骨髓、脑、心血管、甲状腺、甲状旁腺和骨等多种组织,主要以自分泌或旁分泌的形式发挥作用。是由多种组织细胞分泌的一种活性分子,具有广泛的生物学功效,参与多种器官的生长发育,能促进乳腺癌、前列腺癌、非小细胞肺癌的浸润和转移,亦是骨溶解最重要的调节因子之一。最早发现于恶性肿瘤致体液性高钙血症(HHM)患者的血浆中,具有与甲状旁腺激素相似的生物活性,是引起HHM的体液因素之一。临床上高钙血症表现为无食欲、恶心、多尿、精神异常,甚至昏迷,一般多出现在癌症末期

Parathyroid   英 /pærə'θaɪrɒɪd/   美 /,pærə'θaɪrɔɪd/

释    义   adj. 副甲状腺的;n. 甲状旁腺

例句 Some tumours produce compounds characteristic or other tissues, e.g. parathyroid hormone by cells of tumour arising in the bronchus. 一些肿瘤产生具有其他组织特征的复合物,例如来源于支气管的瘤细胞产生甲状旁腺激素。

 

Hormone   英 /ˈhɔːməʊn/   美 /ˈhɔːrmoʊn/

释    义   n. [生理] 激素,荷尔蒙;复数 hormones

同根词   hormonal adj. 荷尔蒙的,激素的

例    句   Some people have higher levels of this hormone in their blood, others have lower levels . 一些人在他们的血液中有高含量的这种荷尔蒙,而另一些人低些。

 

Related   英 /rɪˈleɪtɪd/   美 /rɪˈleɪtɪd/

释    义   adj. 有关系的,有关联的;讲述的,叙述的;v. 叙述(relate过去式)

同根词   relative adj. 相对的;有关系的;成比例的

               relational adj相关的;亲属的

               relative n. 亲戚;相关物;[语] 关系词;亲缘植物

               relationship n. 关系;关联

               relation n. 关系;叙述;故事;亲属关系

               relativity n. 相对论;相关性;相对性

               relatedness n. 关联性;关系;亲缘

               relate vi. 涉及;认同;符合;与…有某种联系

               relate vt. 叙述;使…有联系

例    句   How are they related to me? 他们和我有什么关系?

 

Protein   英 /ˈprəʊtiːn/   美 /ˈproʊtiːn/

释    义   n. 蛋白质;朊;adj. 蛋白质的

同根词   proteolytic adj. [生化] 蛋白水解的;解蛋白的

               proteinaceous adj. 蛋白质的;朊的

               proteolytic n. 解朊作用

               proteolysis n. [生化] 蛋白质水解;蛋白水解作用

例    句   Where do you get your protein? 你从哪里获得蛋白质?

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