Estrogen Receptor β Promotes Renal Cell Carcinoma Progression via Regulating LncRNA HOTAIR-miR-138/200c/204/217 Associated CeRNA Network
INTRODUCTION
The estrogen receptor beta (ERβ), first discovered in 1996, has been recognized as a protective nuclear receptor in many hormone-sensitive tumors, including breast and prostate cancers. Yet in contrast, ERβ can also promote progression of bladder cancer. The roles of ERβ in RCC, however, remain to be further elucidated. Here we found ERβ could promote the RCC progression, and clinical sample investigation revealed that a higher ERβ expression is correlated with a worse overall survival rate/a shorter disease-free survival in RCC patients. The identification of the ERβ-HOTAIR-ceRNA axis may provide us new biomarkers and/or therapeutic targets to better suppress RCC progression in the future.
METHODS
RNAseq Data (TCGA, provisional of 537 RCC patients) were retrieved from the TCGA database. The role of ERβ, and the relationship between ERβ and HOTAIR were investigated thoroughly through in vitro and in vivo experiments. We established the orthotopic RCC model by implanting luciferase-labeled 786-O/Scr or 786-O/shERβ cells, also transduced into 6-week-old female nude mice (n = 8 mice per group). The non-invasive in vivo imaging system (IVIS) was used every 2 weeks to monitor tumor progression.
RESULTS
Here, we provide clinical evidence that ERβ expression is correlated in a negative manner with the overall survival/disease-free survival in RCC patients. Mechanism dissection revealed that targeting ERβ with ERβ-shRNA and stimulating the transactivation of ERβ with 17β-estradiol or environmental endocrine disrupting chemicals, all resulted in altering the lncRNA HOTAIR expression. The ERβ-modulated HOTAIR is able to function via antagonizing several microRNAs, including miR-138, -200c, -204, or -217 to impact various oncogenes, including ADAM9, CCND2, EZH2, VEGFA, VIM, ZEB1, and ZEB2, to promote RCC proliferation and invasion.
CONCLUSION
Our new finding from multiple RCC cell lines and the preclinical mouse RCC model as well as TCGA database analysis all conclude that ERβ could play a key role to promote ccRCC progression. This study focused on mechanisms how ERβ could promote RCC progression though transcriptionally up-regulating lncRNA HOTAIR and shifting the entire associated ceRNA and oncogene network. If supporting evidence continues to emerge, ERβ may become a feasible therapy target for metastatic RCC treatment and emerge as one important biomarker for the prediction of overall survival and progression-free survival.
Funding: This work was partially supported by URMC Urology Department Research fund, and George Whipple Professorship Endowment.