FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB–BMP Signaling Cross-talk

Abstract

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 and tumorigenicity and distant metastasis 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 NFκB and BMP signaling figuring prominently. Cross-talk between the NFκB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NFκB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinating NFκB 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. .

Identification of lncRNA‐associated differential subnetworks in oesophageal squamous cell carcinoma by differential co‐expression analysis

“…Compared with the empty vector controls, 119 genes were up‐regulated and 53 down‐regulated in the samples overexpressing AL121899.1 (Table , Figure B). Overexpressing AL121899.1 did not affect the expression of genes in the core module, but instead regulated a set of genes enriched on hallmark epithelial‐mesenchymal transition and other 19 immunologic or oncogenic signatures in MSigDB v6.2 (Table ), and also many genes that have been reported to be associated with prognosis, metastasis, chemoresistance or radioresistance of ESCC, such as SPARC, FSTL1, MUC4, DHCR7, LOX and CXCL1 . In addition, the up‐regulated genes were enriched on biological processes associated with regulation of insulin‐like growth factor transport and uptake ( P = 1.43 × 10 −6 ), post‐translational protein phosphorylation ( P = 8.70 × 10 −6 ), steroid metabolic process ( P = 1.32 × 10 −5 ) and digestion ( P = 3.09 × 10 −3 ) (Figure C, Table ).…”

Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer

“…These proteins have been linked to cancer progression, resistance to chemo-and radiotherapy, poor prognosis and/or metastasis [4,[44][45][46][47][48][49][50][51]. Therefore, targeting these proteins with JQ1 could be of clinical interest in TNBC.…”

Follistatin‐like protein 1 (FSTL1) promotes chondrocyte expression of matrix metalloproteinase and inflammatory factors via the NF‐κB pathway

“…36 Previous studies showed that FSTL1 stimulates NF-κB signalling. 37,38 F I G U R E 3 Effects of FSTL1 on MMP-1, MMP-3, MMP-13, iNOS and COX-2 protein expression. Each column represents the mean ± SD.…”