All-trans retinoic acid inhibits tumor growth of human osteosarcoma by activating Smad signaling-induced osteogenic differentiation.
All-trans retinoic acid inhibits tumor growth of human osteosarcoma by activating Smad signaling-induced osteogenic differentiation.
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DOI：
10.3892/ijo.2012.1426
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发表时间：
2012-07
影响因子：
5.2
通讯作者：
Qiu-Jun Yang;Long-Yang Zhou;Y. Mu;Qi-Xin Zhou;Jin-yong Luo;Lanqing Cheng;Z. Deng;T. He;R. H
中科院分区：
文献类型：
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作者：
Qiu-Jun Yang;Long-Yang Zhou;Y. Mu;Qi-Xin Zhou;Jin-yong Luo;Lanqing Cheng;Z. Deng;T. He;R. H
骨肉瘤（OS）是最常见的恶性骨肿瘤之一。尽管OS的诊断和治疗取得了进步，但预后仍然较差。我们研究了全反式视黄酸 (ATRA) 对人 OS 的增殖抑制作用以及这种作用的可能机制。我们检测了 ATRA 在 143B OS 细胞中的增殖抑制和凋亡诱导作用。我们通过在 143B OS 细胞中外源表达视黄酸受体 α (RARα) 并将细胞注射到裸鼠体内来验证这种效应。我们通过检测成骨标志物探讨了ATRA对OS细胞和多能祖细胞增殖抑制作用的可能机制。我们证明，内源性视黄酸受体和类视黄醇 X 受体在市售 OS 细胞系和原代骨肉瘤细胞中均可检测到。 ATRA 以浓度依赖性方式抑制 OS 细胞的增殖，并诱导 143B OS 细胞凋亡。 RARα的外源表达抑制体内肿瘤生长和细胞增殖。在 OS 细胞和小鼠胚胎成纤维细胞 (MEF) 中，ATRA 至少通过激活 Smad 信号通路来促进碱性磷酸酶活性、骨桥蛋白 (OPN) 和骨钙素 (OCN) 的蛋白质水平。总的来说，我们的结果强烈表明，ATRA 可以通过促进 OS 细胞的成骨分化来抑制 OS 肿瘤的生长，这部分是通过激活 Smad 信号传导介导的。因此，ATRA与其他现有化疗药物的联合可能是治疗OS的一种有前途的治疗策略。
Osteosarcoma (OS) is one of the most common malignant bone tumors. Despite the advancement of diagnosis and treatment for OS, the prognosis remains poor. We investigated the proliferation inhibitory effect of all-trans retinoic acid (ATRA) for human OS and the possible mechanism underlying this effect. We examined the proliferation inhibition and apoptosis-inducing effects of ATRA in 143B OS cells. We validated this effect by exogenously expressing the retinoic acid receptor alpha (RARα) in 143B OS cells and injecting the cells into nude mice. We explored the possible mechanism for the proliferation inhibitory effect of ATRA on OS cells and multipotential progenitor cells by detecting osteogenic markers. We demonstrated that the endogenous retinoic acid receptor and retinoid X receptor are all detectable in the commercially available OS cell lines and in primary osteosarcoma cells. ATRA inhibits the proliferation of OS cells in a concentration-dependent manner, as well as induces apoptosis in 143B OS cells. The exogenous expression of RARα inhibits the tumor growth and cell proliferation in vivo. The alkaline phosphatase activity, protein levels of osteopontin (OPN) and osteocalcin (OCN) are all promoted by ATRA in OS cells and mouse embryonic fibroblasts (MEFs), at least by activating the Smad signaling pathway. Collectively, our results strongly indicate that ATRA can inhibit the tumor growth of OS by promoting osteogenic differentiation in OS cells, which is mediated in part by activating Smad signaling. Therefore, combination of ATRA with other current chemotherapy agents may be a promising therapy strategy for OS treatment.