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 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.

• Authors: Marco Chi-Chung Lau, Kai Yu Ng, Tin Lok Wong, Man Tong, Terence K Lee, Xiao-Yan Ming, Simon Law, Nikki P Lee, Annie L Cheung, Yan-Ru Qin, Kwok Wah Chan, Wen Ning, Xin-Yuan Guan, Stephanie Ma
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 21 Pg. 5886-5899 (11 01 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28883005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Bone Morphogenetic Proteins
• Follistatin-Related Proteins
• NF-kappa B
• FSTL1 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Blotting, Western
• Bone Morphogenetic Proteins (metabolism)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Esophageal Neoplasms (genetics, metabolism, pathology)
• Female
• Follistatin-Related Proteins (genetics, metabolism)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• NF-kappa B (metabolism)
• Neoplasm Metastasis
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)
• Transplantation, Heterologous
• Young Adult