Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of -radiation in an ERK-1/2-independent manner
Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of -radiation in an ERK-1/2-independent manner
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DOI：
10.1093/carcin/bgt303
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发表时间：
2014-02-01
期刊：
影响因子：
4.7
通讯作者：
Chandna, Sudhir
中科院分区：
文献类型：
--
作者：
Ghosh, Soma;Kumar, Ashish;Chandna, Sudhir
放射治疗使实体肿瘤的某些区域暴露于可能引起继发性恶性肿瘤的低亚致死剂量的辐射下。因此，评估低剂量辐射诱导的致瘤潜能改变并了解其机制有助于改善放疗效果。有限的研究表明连接蛋白（Cx）在低剂量下上调，而Cxs被独立证明可以改变未辐照细胞的细胞迁移。我们研究了低剂量辐射诱导的各种肿瘤细胞系中Cx43表达和细胞增殖/迁移/侵袭的改变，以及p38和细胞外信号调节激酶-1/2 （ERK-1/2）丝裂原活化蛋白激酶（MAPKs）等可能的分子途径。有趣的是，低剂量（1020 cGy）可增强Cx43的表达，并选择性地诱导胶质瘤细胞迁移，但不改变细胞增殖，同时伴有p38的持续激活和p21（waf1/cip1）的上调，而最低剂量（5 cGy）可诱导细胞增殖，同时增强p-ERK1/2、增殖细胞核抗原和p-H3水平，但不诱导细胞迁移。最重要的是，低剂量辐射诱导的细胞迁移和p38激活被强烈抑制，通过敲低Cx43的表达，从而证明后者的上游作用，而敲低对ERK-1/2或细胞增殖没有影响。在所有肿瘤细胞系（U87、BMG-1、A549和HeLa）中，沉默Cx43几乎完全抑制了辐射诱导的细胞迁移/侵袭，而在未辐照的原代VH10或转化的AA8成纤维细胞中没有诱导细胞迁移/侵袭。我们的研究首次证明了低剂量辐射诱导p38-MAPK介导的肿瘤细胞选择性迁移。此外，这种作用是由Cx43调节的，因此它可能是辐射诱导的继发性恶性肿瘤和/或转移的重要介质。
Radiotherapy exposes certain regions of solid tumours to low sublethal doses of -radiation that may cause secondary malignancies. Therefore, evaluating low-dose--radiation-induced alterations in tumorigenic potential and understanding their mechanisms could help in improving radiotherapy outcome. Limited studies have indicated connexin (Cx) up-regulation by low doses, whereas Cxs are independently shown to alter cell migration in unirradiated cells. We investigated low-dose--radiation-induced alterations in Cx43 expression and cell proliferation/migration/invasion in various tumour cell lines, along with the putative molecular pathways such as p38 and extracellular signal-regulated kinase-1/2 (ERK-1/2)mitogen-activated protein kinases (MAPKs). Interestingly, a narrow range of low doses (1020 cGy) enhanced Cx43 expression and also selectively induced glioma cell migration without altering cell proliferation, accompanied by sustained activation of p38 and up-regulation of p21(waf1/cip1), whereas the lowest (5 cGy) dose induced cell proliferation coupled with enhanced p-ERK1/2, proliferating cell nuclear antigen and p-H3 levels without inducing cell migration. Most importantly, low-dose--radiation-induced cell migration and p38 activation was strongly inhibited by knocking down Cx43 expression, thereby demonstrating latters upstream role, whereas the knock-down had no effect on ERK-1/2 or cell proliferation. Silencing Cx43 caused near-complete inhibition of radiation-induced cell migration/invasion in all tumour cell lines (U87, BMG-1, A549 and HeLa), whereas no cell migration/invasiveness was induced in the -irradiated primary VH10 or transformed AA8 fibroblasts. Our study demonstrates for the first time that low-dose -radiation induces p38-MAPK mediated cell migration selectively in tumour cells. Further, this effect is regulated by Cx43, which could thus be an important mediator in radiation-induced secondary malignancies and/or metastasis.