Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
Carcinogenesis. 2012 Dec;33(12):2529-37. doi: 10.1093/carcin/bgs271. Epub 2012 Aug 23.
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.
我们之前的报告表明，RSK2 在细胞增殖和转化中发挥重要作用，这种作用是由肿瘤促进剂如表皮生长因子通过 RSK2 的 N 端激酶结构域在体外的 JB6 Cl41 鼠皮肤表皮细胞中介导的。然而，目前还没有关于 RSK2 活性与人类皮肤癌之间关系的直接证据。为了阐明 RSK2 活性与人类皮肤癌之间的关系，我们研究了敲低 RSK2 表达对表皮生长因子诱导的恶性潜能未定的 HaCaT 人皮肤角质形成细胞系的无锚定依赖性转化以及 SK-MEL-28 恶性黑素瘤细胞在软琼脂中的集落生长的影响。我们发现，在人类皮肤癌组织芯片中，与正常组织相比，癌症组织中 RSK2 的磷酸化蛋白水平增强。我们发现，UVB 刺激不仅诱导 ERKs 和 RSK2 的总蛋白和磷酸化蛋白水平增加，还诱导 RSK2 的核定位和基因表达增加。RSK2 敲低抑制 HaCaT 细胞的增殖和无锚定依赖性转化以及恶性黑素瘤细胞在软琼脂中的集落生长。此外，与 RSK2(+/+) MEF 相比，RSK2(-/-) 小鼠胚胎成纤维细胞 (MEF) 经 UVB 刺激后，Sub-G1 期细胞积累增加，表明 RSK2 可能在与紫外线相关的应激耐受中发挥重要作用。重要的是，与匹配的正常皮肤组织相比，激活的 RSK2 蛋白水平在人类皮肤癌组织中高度丰富。综上所述，我们的研究结果表明，RSK2 在人类皮肤细胞的肿瘤转化和皮肤癌生长中发挥关键作用。
