GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway.
GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway.
复制标题
DOI：
10.18632/oncotarget.13649
复制
发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Cheng AJ
中科院分区：
文献类型：
--
作者：
Li YL;Chang JT;Lee LY;Fan KH;Lu YC;Li YC;Chiang CH;You GR;Chen HY;Cheng AJ
放射治疗是头颈癌治疗中不可或缺的一部分，而放射抵抗是导致治疗失败的主要原因。GDF15是转化生长因子-β超家族的成员之一，被认为参与多种类型的动态平衡。然而，该分子在调节放射敏感性方面的潜在作用仍不清楚。在这项研究中，我们证明了GDF15有助于HNC的辐射抗性，这是通过功能增益和功能丧失实验确定的。这些结果是通过诱导线粒体膜电位和抑制细胞内活性氧自由基(ROS)实现的。我们进一步表明，GDF15促进了癌症干细胞的转化，这是通过促进CD44+和ALDH1+细胞群和球形细胞的形成来评估的。在分子水平上，GDF15通过磷酸化的Smad1蛋白向下游信号分子精英传递这些细胞功能。这些细胞学结果在肿瘤异种移植小鼠研究中得到了进一步证实。综上所述，我们的结果表明，GDF15通过SMAD相关的信号通路调节细胞ROS水平，从而参与辐射抗性和癌症的干性。GDF15可作为放射抵抗的预测指标和放射增敏剂治疗难治性鼻咽癌的靶点。
Radiotherapy is an integral part for the treatment of head and neck cancer (HNC), while radioresistance is a major cause leads to treatment failure. GDF15, a member of the TGF-β superfamily, is hypothesized to participate in various types of homeostasis. However, the potential role of this molecule in regulation of radiosensitivity remains unclear. In this study, we demonstrated that GDF15 contributed to radioresistance of HNC, as determined by both gain- and lost-of-functional experiments. These results were achieved by the induction of mitochondrial membrane potential and suppression of intracellular reactive oxygen species (ROS). We further showed that GDF15 facilitated the conversion of cancer stemness, as assessed by the promotion of CD44+ and ALDH1+ cell populations and spheroid cell formation. At molecular level, GDF15 conferred to these cellular functions was through phosphorylated SMAD1 proteins to elite downstream signaling molecules. These cellular results were further confirmed in a tumor xenograft mouse study. Taken together, our results demonstrated that GDF15 contributed to radioresistance and cancer stemness by regulating cellular ROS levels via a SMAD-associated signaling pathway. GDF15 may serve as a prediction marker of radioresistance and a therapeutic target for the development of radio-sensitizing agents for the treatment of refractory HNC.