Co-targeting FAK and Gli1 inhibits the tumor-associated macrophages-released CCL22-mediated esophageal squamous cell carcinoma malignancy.
Co-targeting FAK and Gli1 inhibits the tumor-associated macrophages-released CCL22-mediated esophageal squamous cell carcinoma malignancy.
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作者：
Chen, Jie;Zhu, Yanmeng;Zhao, Di;Zhang, Lingyuan;Zhang, Jing;Xiao, Yuanfan;Wu, Qingnan;Wang, Yan;Zhan, Qimin
食管鳞状细胞癌（ESCC）是中国常见的食道肿瘤类型。部分探讨了ESCC中信号蛋白的激活及其相关分子机制，影响了靶向治疗在ESCC治疗中的抗肿瘤效果。肿瘤相关巨噬细胞（Tumor - associated macrophages, tam）释放的C - C基序趋化因子22 （CCL22）可以激活瘤内局灶黏附激酶（focal adhesion kinase， FAK），从而促进ESCC的进展。在这里，我们证明了tam （CCL22阳性tam）高分泌的CCL22通过促进肿瘤内胶质瘤相关癌基因1 （Gli1）的转录活性诱导ESCC细胞的干细胞性和侵袭，Gli1是Hedgehog （HH）通路的下游效应物。在机制上，FAK激活的蛋白激酶B （AKT）介导Gli1在其Ser112/Thr115/Ser116位点的磷酸化，并从融合同源物的抑制因子（Gli1的内源性抑制剂）中释放Gli1，以激活下游干性相关因子，如SRY - box转录因子2 (SOX2)， Nanog同源盒（Nanog）或POU 5类同源盒（OCT4）。此外，在异种移植模型和体外实验中，FAK抑制剂VS‐4718对FAK活性的抑制，增强了HH抑制剂GDC‐0449的抗肿瘤作用。临床上，CCL22/Gli1轴用于评估ESCC的预后。总的来说，我们的研究建立了FAK与HH通路的通信，并提供了与Gli1激活无关的Smoothened的新机制，以及抗ESCC联合治疗的基本原理。tam‐释放的CCL22激活肿瘤内CCR4/FAK/AKT轴，诱导Gli1 Ser112/Thr115/Ser116位点磷酸化，刺激Gli1活性，诱导肿瘤细胞的干性和转移。FAK抑制剂‐VS‐4718增强了HH抑制剂‐GDC‐0449的抗肿瘤作用。我们的研究提供了独立于SMO的Gli1激活的新机制，以及抗ESCC联合治疗的基本原理。
Esophageal squamous cell carcinoma (ESCC) is a frequently seen esophageal tumor type in China. Activation of signaling proteins and relevant molecular mechanisms in ESCC are partially explored, impairing the antitumor efficiency of targeted therapy in ESCC treatment. Tumor‐associated macrophages (TAMs)‐released C‐C motif chemokine 22 (CCL22) can activate intratumoral focal adhesion kinase (FAK), thus promoting the progression of ESCC. Here, we demonstrated that highly secreted CCL22 by TAMs (CCL22‐positive TAMs) induced ESCC cell stemness and invasion through facilitating transcriptional activity of intratumoral glioma‐associated oncogene 1 (Gli1), a downstream effector for Hedgehog (HH) pathway. Mechanistically, FAK‐activated protein kinase B (AKT) mediated Gli1 phosphorylation at its Ser112/Thr115/Ser116 sites and released Gli1 from suppressor of fused homolog, the endogenous inhibitor of Gli1 to activate downstream stemness‐associated factors, such as SRY‐box transcription factor 2 (SOX2), Nanog homeobox (Nanog), or POU class 5 homeobox (OCT4). Furthermore, inhibition of FAK activity by VS‐4718, the FAK inhibitor, enhanced antitumor effect of GDC‐0449, the HH inhibitor, both in xenografted models and in vitro assays. Clinically, CCL22/Gli1 axis is used to evaluate ESCC prognosis. Overall, our study establishes the communication of FAK with HH pathway and offers the novel mechanism related to Gli1 activation independent of Smoothened as well as the rationale for the anti‐ESCC combination treatment. TAMs‐released CCL22 activates intratumoral CCR4/FAK/AKT axis, which induces the phosphorylation of Gli1 Ser112/Thr115/Ser116 sites, and stimulates Gli1 activity to induce the stemness and metastasis of tumor cells. FAK inhibitor‐VS‐4718 enhanced the antitumor effect of HH inhibitor‐GDC‐0449. Our study offers the novel mechanism related to Gli1 activation independent of SMO as well as the rationale for the anti‐ESCC combination treatment.
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影响因子：
12.4
作者：
Jin, Hongyue;He, Yang;Huang, Yongzhuo
通讯作者：
Huang, Yongzhuo
影响因子：
6.2
作者：
Belani CP;Dahlberg SE;Rudin CM;Fleisher M;Chen HX;Takebe N;Velasco MR Jr;Tester WJ;Sturtz K;Hann CL;Shanks JC;Monga M;Ramalingam SS;Schiller JH
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Schiller JH
影响因子：
51.1
作者：
Kato, Ken;Cho, Byoung Chul;Kitagawa, Yuko
通讯作者：
Kitagawa, Yuko
DOI：
10.1073/pnas.1421628112
发表时间：
2015-05-19
影响因子：
11.1
作者：
Han, Yuhong;Shi, Qing;Jiang, Jin
通讯作者：
Jiang, Jin
影响因子：
44.1
作者：
Cui Y;Chen H;Xi R;Cui H;Zhao Y;Xu E;Yan T;Lu X;Huang F;Kong P;Li Y;Zhu X;Wang J;Zhu W;Wang J;Ma Y;Zhou Y;Guo S;Zhang L;Liu Y;Wang B;Xi Y;Sun R;Yu X;Zhai Y;Wang F;Yang J;Yang B;Cheng C;Liu J;Song B;Li H;Wang Y;Zhang Y;Cheng X;Zhan Q;Li Y;Liu Z
通讯作者：
Liu Z