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 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 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. Cancer Res; 77(21); 5886-99. ©2017 AACR.
Highlights
Esophageal squamous cell carcinoma (ESCC) is the most common histologic subtype of esophageal cancer
Through data mining of our transcriptome sequencing data, we found the transmembrane glycoprotein follistatin-like 1 (FSTL1), belonging to the BM-40/SPARC/osteonectin family [6], to be commonly overexpressed in all three ESCC samples compared with its corresponding nontumor counterparts (P < 0.005)
FSTL1 was a candidate gene of interest due to increased expression in all three ESCC samples compared with its corresponding nontumor counterparts (Fig. 1A, left; P < 0.005) and that the chromosomal location (3q) on which FSTL1 is localized, has previously been reported to be frequently amplified in ESCC [7,8,9]. qRT-PCR was performed to validate our RNA-Seq finding, and the results were concordant with the transcriptomic results (Fig. 1A, right)
Summary
Esophageal squamous cell carcinoma (ESCC) is the most common histologic subtype of esophageal cancer. The disease is ranked as the eighth most common cancer and the sixth leading cause of cancer mortalities worldwide, with a dismal prognosis [1]. The overall prognosis for ESCC is poor due to late presentation, high incidences of tumor recurrence and metastasis, as well as the ability of the tumor to acquire chemoresistance. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). M. Chi-Chung Lau and K.Y. Ng contributed to this article
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