FSTL1 promotes metastasis and chemoresistance in esophageal squamous cell carcinoma through NF{kappa}B-BMP signaling crosstalk

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 attenution 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 NF-κB and BMP signaling figuring prominently. Crosstalk between the NF-κB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NF-κB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinate NF-κB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and a candidate therapeutic target in this disease setting.

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