FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB-BMP Signaling Cross-talk
FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB-BMP Signaling Cross-talk
复制标题
DOI：
10.1158/0008-5472.can-17-1411
复制
发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Ma, Stephanie
中科院分区：
文献类型：
--
作者：
Lau, Marco Chi-Chung;Ng, Kai Yu;Ma, Stephanie
食管鳞状细胞癌（ESCC）的预后普遍较差，非常需要分子标记来改善早期检测和预测结果。在此，我们报告 BMP 结合卵泡抑素样蛋白 FSTL1 在食管鳞癌中过度表达，与较差的总生存率相关。 FSTL1 或其所在染色体 3q 的基因扩增在 ESCC 中频繁发生，其中 FSTL1 拷贝数与较高的 FSTL1 蛋白表达呈正相关。通过各种方式提高FSTL1水平足以驱动ESCC细胞增殖、克隆形成、迁移、侵袭、自我更新和体外顺铂耐药性以及体内致瘤性和远处转移。相反，shRNA 或中和抗体减弱 FSTL1 在 ESCC 细胞中引起相反的效果。 mRNA 分析表明，FSTL1 通过多种途径驱动 ESCC 肿瘤发生和转移，其中 NFkB 和 BMP 信号传导的失调尤为突出。使用 NFkB 和 TLR4 抑制剂进行的功能拯救实验证明了 NFkB 和 BMP 通路之间的串扰。我们的结果确立了 FSTL1 通过协调 NFkB 和 BMP 通路控制来驱动 ESCC 肿瘤发生和转移的重要性，这对其作为诊断或预后生物标志物以及作为该疾病背景下的候选治疗靶点的潜在用途具有影响。 (C) 2017 年 AACR。
Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, and molecular markers to improve early detection and predict outcomes are greatly needed. Here, we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs, where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q, where it is located, occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal, and cisplatin resistance in vitro and tumorigenicity and distant metastasis in vivo. Conversely, FSTL1 attenuation by shRNA or neutralizing antibody elicited the opposite effects in ESCC cells. mRNA profiling analyses suggested that FSTL1 drives ESCC oncogenesis and metastasis through various pathways, with deregulation of NFkB and BMP signaling figuring prominently. Cross-talk between the NFkB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NFkB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinating NFkB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in this disease setting. (C) 2017 AACR.