RSK2 as a key regulator in human skin cancer
RSK2 as a key regulator in human skin cancer
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DOI：
10.1093/carcin/bgs271
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发表时间：
2012-12-01
期刊：
影响因子：
4.7
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Cho, Yong-Yeon;Lee, Mee-Hyun;Dong, Zigang
我们之前的报告表明，在体外 JB6 Cl41 小鼠皮肤表皮细胞中，RSK2 在肿瘤促进剂（如表皮生长因子）通过 RSK2 N 端激酶结构域介导诱导的细胞增殖和转化中发挥重要作用。然而，尚未报道 RSK2 活性与人类皮肤癌之间关系的直接证据。为了阐明 RSK2 活性与人类皮肤癌的关系，我们研究了敲除 RSK2 表达对癌前 HaCaT 人类皮肤角质形成细胞系中表皮生长因子诱导的贴壁独立转化以及 SK-MEL-28 恶性黑色素瘤细胞软琼脂集落生长的影响。我们发现，在人类皮肤癌组织阵列中，与正常组织相比，癌症组织中 RSK2 的磷酸化蛋白水平有所增强。我们发现 UVB 刺激不仅诱导 ERK 和 RSK2 的总蛋白和磷酸化蛋白水平增加，而且还诱导 RSK2 的核定位和基因表达增加。 RSK2 敲除抑制 HaCaT 细胞的增殖和不依赖贴壁的转化以及恶性黑色素瘤细胞的软琼脂集落生长。此外，与RSK2(/)小鼠胚胎成纤维细胞(MEF)相比，RSK2(/)小鼠胚胎成纤维细胞(MEF)显示出UVB刺激诱导的亚G(1)积累增强，表明RSK2可能在抵抗紫外线相关应激方面发挥重要作用。重要的是，与匹配的皮肤正常组织相比，人类皮肤癌组织中激活的 RSK2 蛋白水平非常丰富。总而言之，我们的结果表明 RSK2 在人类皮肤细胞的肿瘤转化和皮肤癌生长中发挥着关键作用。
Our previous report demonstrated that RSK2 plays an important role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor mediated through the N-terminal kinase domain of RSK2 in JB6 Cl41 mouse skin epidermal cells in vitro. However, no direct evidence has been reported regarding the relationship of RSK2 activity and human skin cancer. To elucidate the relationship of RSK2 activity and human skin cancer, we examined the effect of knocking down RSK2 expression on epidermal growth factor-induced anchorage-independent transformation in the premalignant HaCaT human skin keratinocyte cell line and on soft agar colony growth of SK-MEL-28 malignant melanoma cells. We found that the phosphorylated protein levels of RSK2 were enhanced in cancer tissues compared with normal tissues in a human skin cancer tissue array. We found that UVB stimulation induced increased in not only the total and phosphorylated protein levels of ERKs and RSK2 but also the nuclear localization and gene expression of RSK2. RSK2 knockdown inhibited proliferation and anchorage-independent transformation of HaCaT cells and soft agar colony growth of malignant melanoma cells. Moreover, RSK2(/) mouse embryonic fibroblast (MEF) showed enhanced sub-G(1) accumulation induced by UVB stimulation compared with RSK2(/) MEFs, indicating that RSK2 might play an important role in tolerance against stress associated with ultraviolet. Importantly, activated RSK2 protein levels were highly abundant in human skin cancer tissues compared with matched skin normal tissues. Taken together, our results demonstrated that RSK2 plays a key role in neoplastic transformation of human skin cells and in skin cancer growth.