Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma.
Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma.
复制标题
RIPK4 的缺失与皮肤鳞状细胞癌的更高恶性潜能相关
作者：
Xu J;Wu D;Zhang B;Pan C;Guo Y;Wei Q
RIPK4（受体相互作用蛋白激酶4）是RIPK家族的一员，在表皮分化、皮肤炎症和皮肤伤口修复中起着重要的调节作用。然而，到目前为止，RIPK4在肿瘤发生中的作用仍然难以捉摸。目前还没有关于RIPK4在皮肤鳞状细胞癌（SCC）信号通路中的作用的研究。影响表皮分化程度的RIPK4表达是否也会影响皮肤SCC的放射敏感性，目前尚不清楚。目前迫切需要全面阐明RIPK4促进皮肤鳞状细胞癌发生的生物学机制，并确定RIPK4表达水平是否预测皮肤鳞状细胞癌对放疗的敏感性。方法用靶向RIPK4的小干扰rna (siRNA) （siR-RIPK4）或阴性对照siRNA （siR-NC）转染人皮肤SCC细胞株A431。Western blotting检测RIPK4和Raf/MEK/ERK通路相关蛋白的表达。用不同剂量（0、2、6和10 Gy）的6 MV x射线照射器照射细胞。通过细胞增殖分析、集落形成实验、transwell细胞迁移和侵袭实验、细胞周期和凋亡分析，探讨RIPK4沉默对皮肤SCC恶性肿瘤及放射敏感性的影响。结果与转染siR-NC的A431细胞相比，转染siR-RIPK4的A431细胞中RIPK4蛋白的表达明显降低。RIPK4沉默促进了A431细胞系的增殖、集落形成、迁移和侵袭能力，而对细胞周期进程和细胞凋亡无明显影响。与之前的文献相反，在皮肤SCC中，Raf/MEK/ERK通路不受RIPK4敲低的影响。在体外实验中，RIPK4敲低不能逆转A431细胞对辐照的抗性。总的来说，尽管RIPK4的缺失不能在体外逆转A431细胞的辐射抗性，但它在皮肤SCC中具有更高的恶性潜能。据我们所知，这是首次报道RIPK4表达对皮肤SCC中Raf/MEK/ERK信号通路和放射敏感性的影响。更好地了解RIPK4在皮肤鳞状细胞癌中的分子机制可能为皮肤鳞状细胞癌的预后和治疗提供一个有希望的生物标志物。
Background The RIPK4 (receptor-interacting protein kinase 4), a member of the RIPK family, acts as an important regulator of epidermal differentiation, cutaneous inflammation, and cutaneous wound repair. However, Until now, the role of RIPK4 in tumorigenesis remains elusive. There have been no studies exploring the effects of RIPK4 on the signaling pathway in cutaneous squamous cell carcinoma (SCC). It remains unknown whether RIPK4 expression, which can affect the degree of epidermal differentiation can also influence the radiosensitivity of skin SCC. It is urgent to fully elucidate the biological mechanism by which RIPK4 promotes carcinogenesis in skin SCC and determine whether RIPK4 expression levels predicts the sensitivity to radiotherapy in skin SCC. Methods Human skin SCC cell line, A431, was transfected with either small interfering RNAs (siRNAs) targeting RIPK4 (siR-RIPK4) or negative control siRNA (siR-NC). Western blotting was used to detect the expression of RIPK4 and Raf/MEK/ERK pathway-related proteins. The cells were irradiated using an X-ray irradiator at 6 MV with different radiation doses (0, 2, 6, and 10 Gy). Cell proliferation analysis, colony formation assay, transwell cell migration and invasion assay, cell cycle and apoptosis analysis were conducted to investigate the effect of RIPK4 silencing on skin SCC malignancy and radiosensitivity. Results RIPK4 protein expression was significantly decreased in the A431 cells transfected with siR-RIPK4, compared with the A431 cells transfected with siR-NC. RIPK4 silencing facilitated the proliferation, colony formation, migration, and invasion ability of A431 cell line, while cell cycle progression or cell apoptosis were not significantly influenced. In contrast with the previous literature, Raf/MEK/ERK pathway was not effected by RIPK4 knockdown in skin SCC. RIPK4 knockdown could not reverse the radiation resistance of A431 cells to irradiation in vitro. Conclusions In general, although depletion of RIPK4 cannot reverse the radiation resistance of A431 cells in vitro, it parallels higher malignancy potential in cutaneous SCC. To our knowledge, this is the first report of the effects of RIPK4 expression on the Raf/MEK/ERK signaling pathway and radiosensitivity in cutaneous SCC. The better understanding of the molecular mechanism of RIPK4 in cutaneous SCC may provide a promising biomarker for skin SCC prognosis and treatment.
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影响因子：
4.9
作者：
Cai L;Ye L;Hu X;He W;Zhuang D;Guo Q;Shu K;Jie Y
通讯作者：
Jie Y
DOI：
10.1158/1078-0432.ccr-14-1773
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li YY;Hanna GJ;Laga AC;Haddad RI;Lorch JH;Hammerman PS
通讯作者：
Hammerman PS
影响因子：
3.8
作者：
Anaya, Jordan
通讯作者：
Anaya, Jordan
影响因子：
9.8
作者：
Kalay, Ersan;Sezgin, Orhan;Akarsu, Nurten A.
通讯作者：
Akarsu, Nurten A.
影响因子：
7
作者：
Gillison, Maura L.;Akagi, Keiko;Symer, David E.
通讯作者：
Symer, David E.