Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines.
Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines.
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氧甾醇结合蛋白相关蛋白 4L 通过维持宫颈癌细胞系的细胞内 Ca2 稳态来促进细胞增殖。
DOI：
10.18632/oncotarget.11671
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Yan DG
中科院分区：
文献类型：
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作者：
Li JW;Xiao YL;Lai CF;Lou N;Ma HL;Zhu BY;Zhong WB;Yan DG
Oxsterol binding protein related protein 4 （ORP4）在细胞增殖中起重要作用，但其作用机制尚不清楚。ORP4表达为ORP4L、ORP4M和ORP4S三个变体。在这里，我们报道了用特异性小干扰RNA （siRNA）沉默ORP4L抑制人宫颈癌细胞系C33A、HeLa和CaSki的增殖，在ORP4L过表达的细胞中观察到相反的效果。从分子角度来看，我们发现ORP4L维持细胞内Ca2+稳态。通过这一机制，ORP4L激活了活化T细胞的核因子（NFAT）活性，从而促进了一个支持细胞增殖的基因簇的表达。值得注意的是，ORP4L通过Ca2+依赖性NFAT3激活在mRNA和蛋白水平上持续表达肌醇-1,4,5-三磷酸受体1 (IP3R1)，这为ORP4L细胞内Ca2+稳态的作用提供了机制解释。此外，ORP4L敲低可显著抑制C33A细胞异种移植小鼠模型中的肿瘤生长。总之，我们的研究结果表明ORP4L通过维持细胞内Ca2+稳态来促进细胞增殖。
Oxsterol binding protein-related protein 4 (ORP4) is essential for cell proliferation, but the underlying mechanism is unclear. ORP4 is expressed as three variants, ORP4L, ORP4M and ORP4S. Here, we reported that silencing of ORP4L with specific small interfering RNA (siRNA) inhibited the proliferation of human cervical cancer cell lines C33A, HeLa and CaSki, the reverse effect being observed in ORP4L overexpressing cells. For molecular insight, we found that ORP4L maintained intracellular Ca2+ homeostasis. Through this mechanism, ORP4L activated nuclear factor of activated T cells (NFAT) activity and thus promoted expression of a gene cluster which supported cell proliferation. Of note, ORP4L sustained inositol-1,4,5-trisphosphate receptor 1 (IP3R1) expression at both mRNA and protein levels via Ca2+-dependent NFAT3 activation, which offered a mechanic explanation for the role of ORP4L intracellular Ca2+ homeostasis. Furthermore, ORP4L knockdown markedly inhibited tumor growth in a C33A cell xenograft mouse model. To conclude, our results reveal that ORP4L promotes cell proliferation through maintaining intracellular Ca2+ homeostasis.