Journal Article

Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma

Zhang, Liyuan, Deng, Jieqiong, Li, Fang, Guo, Binbin, Li, Wei, Wang, Yirong, Zhou, Yifeng, Wu, Siqi, Lu, Jiachun

2019

Overview

Background Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. Methods We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1 , TLR7 and NFκB. Results We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. Conclusions Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Alcohol / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Breast cancer / c-Myc protein / Cancer Research / Cell cycle / Cell division / Cell Line, Tumor / Cell Proliferation / Chromosomes / CSC / DNA microarrays / Equilibrium / ESCC / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - diagnosis / Esophageal Neoplasms - genetics / Esophageal Neoplasms - mortality / Esophageal Neoplasms - pathology / Esophageal Squamous Cell Carcinoma - diagnosis / Esophageal Squamous Cell Carcinoma - genetics / Esophageal Squamous Cell Carcinoma - mortality / Esophageal Squamous Cell Carcinoma - pathology / Esophagus / Exosome / Exosomes / Exosomes - metabolism / Exosomes - pathology / Female / Females / FMR1 protein / Gene expression / Gene Expression Regulation, Neoplastic / Genetic factors / Humans / lncRNA / Medical prognosis / Metastasis / Mice, Nude / Myc protein / Neoplastic Stem Cells / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / NFκB / Oligoribonucleotides - genetics / Oligoribonucleotides - metabolism / Oncology / Ovarian cancer / Phenotypes / Prognosis / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Reporter gene / RNA, Long Noncoding - agonists / RNA, Long Noncoding - antagonists & inhibitors / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Serum levels / Sex differences / Signal Transduction / Stem cells / Survival Analysis / TLR7 / TLR7 protein / Tobacco / Toll-Like Receptor 7 - genetics / Toll-Like Receptor 7 - metabolism / Toll-like receptors / Tumor Microenvironment / Womens health / Xenograft Model Antitumor Assays / Xenografts