Growth Differentiation Factor 15 Promotes Progression of Esophageal Squamous Cell Carcinoma via TGF-β Type II Receptor Activation
Growth Differentiation Factor 15 Promotes Progression of Esophageal Squamous Cell Carcinoma via TGF-β Type II Receptor Activation
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DOI：
10.1159/000504394
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发表时间：
2020-05-01
期刊：
影响因子：
5
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
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作者：
Okamoto, Maiko;Koma, Yu-ichiro;Yokozaki, Hiroshi
目的：生长分化因子15（GDF 15），来源于肿瘤相关巨噬细胞（TAM）和癌细胞，促进食管鳞状细胞癌（ESCC）的进展。然而，其在ESCC微环境中的作用仍不清楚。在这里，我们研究了GDF 15对ESCC细胞系和组织的影响。研究方法：Western印迹、MTS和Transwell迁移/侵袭测定分别用于评价用重组人GDF 15（rhGDF 15）处理的ESCC细胞系中的细胞信号传导、增殖和迁移/侵袭。向ESCC细胞系施用TGF-β RI/II抑制剂（LY 2109761）、针对TGF-β II型受体的小干扰RNA（TGF-β RII）或针对TGF-β RII的中和抗体，以研究TGF-β RII在介导rhGDF 15的作用中的作用。通过免疫荧光观察GDF 15和TGF-β RII在ESCC细胞系中的定位。采用免疫组化方法检测TGF-β RII在食管鳞癌组织中的表达，并分析其与临床病理因素及预后的关系。结果：rhGDF 15增加ESCC细胞系中磷酸化Akt、Erk 1/2和TGF-β RII的水平。TGF-β RII的抑制/敲低抑制了rhGDF 15诱导的Akt和Erk 1/2活化以及细胞增殖、迁移和侵袭的增强。免疫荧光显示TGF-β RII和GDF 15共定位于ESCC细胞系中。通过免疫组化测定，食管鳞癌组织中TGF-β RII的高表达与浸润深度和浸润性TAM数量增加相关。TGF-β RII高表达的ESCC患者预后差。结论：GDF 15通过TGF-β RII信号途径增加细胞增殖、迁移和侵袭，从而促进ESCC进展。
Objectives: Growth differentiation factor 15 (GDF15), which is derived from tumor-associated macrophages (TAM) and cancer cells, promotes progression of esophageal squamous cell carcinomas (ESCC). However, its role in the ESCC microenvironment remains unclear. Here, we examined the effects of GDF15 on ESCC cell lines and tissues. Methods: Western blotting, MTS, and Transwell migration/invasion assays were used to evaluate cell signaling, proliferation, and migration/invasion, respectively, in ESCC cell lines treated with recombinant human GDF15 (rhGDF15). ESCC cell lines were administered a TGF-beta RI/II inhibitor (LY2109761), small interfering RNA against TGF-beta type II receptor (TGF-beta RII), or neutralizing antibody against TGF-beta RII to study the role of TGF-beta RII in mediating the effects of rhGDF15. The localization of GDF15 and TGF-beta RII in ESCC cell lines was observed by immunofluorescence. TGF-beta RII expression in ESCC tissues was analyzed by immunohistochemistry, and the relationship between clinicopathological factors and prognosis in ESCC patients was evaluated. Results: rhGDF15 increased levels of phosphorylated Akt, Erk1/2, and TGF-beta RII in ESCC cell lines. Inhibition/knockdown of TGF-beta RII suppressed rhGDF15-induced activation of Akt and Erk1/2 and enhancement of cellular proliferation, migration, and invasion. Immunofluorescence revealed that TGF-beta RII and GDF15 were colocalized in ESCC cell lines. High TGF-beta RII expression in ESCC tissues, as determined by immunohistochemistry, correlated with depth of invasion and increased number of infiltrating TAMs. ESCC patients with high TGF-beta RII expression showed a tendency toward poor prognosis. Conclusions: GDF15 promotes ESCC progression by increasing cellular proliferation, migration, and invasion via TGF-beta RII signaling.