Abstract
BackgroundThough 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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
Our results revealed the function of exosomal FMR1-AS1 in maintaining Esophageal squamous cell carcinoma (ESCC) Cancer stem cells (CSCs) dynamic interconversion and the possible mechanism of its action, which shed light on the functional exosomal lncRNAs might be taken as attractive targets for ESCC precision therapeutics and improved the understanding how CSCs and non-CSCs cell states coexist, transmit and evolve within tumors that may futher facilitate the development of more effective therapies
FMR1-AS1 highly expressed in ESCC tissues and indicate a poor prognosis in female patients We first compared the lncRNA expression profiles of 179 pairs ESCC tissues and its adjacent normal tissues
Summary
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. Esophageal cancer is three to four times more common among men than among women, this type of cancer still ranks in the top-6 incidence among women, even more than the female specific cancer types. Current epidemiologic studies often focus on the extrinsic environmental factors that may play a role in the observed sex disparity in ESCC incidence, such as tobacco use and alcohol consumption. The intrinsic molecular and genetic factors underlaying the incidence of ESCC based on gender remain largely unknown, especially in female patients. The roles of X-associated lncRNAs in female specific ESCC are unexplored
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