Abstract
Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20–30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor β (ERβ) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERβ, but not ERα, increases with tumor stage and grade, and also observed that modification of ERβ signals using estrogens/anti‐estrogens, shRNA knockdown of ERβ and overexpression of ERβ using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ERβ can promote RCC cell invasion via an increase in transforming growth factor β1 (TGF‐β1)/SMAD3 signals, and interrupting TGF‐β1/SMAD3 signals with a TGFβR1 inhibitor can reverse/block ERβ‐increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERβ/TGF‐β1/SMAD3 pathway with either the FDA‐approved anti‐estrogen ICI182,780 (Faslodex) or a selective ERβ antagonist 4‐[2‐phenyl‐5,7 bis(trifluoromethyl)pyrazolo[1,5‐a]pyrimidin‐3‐yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC.
Highlights
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and is the third leading cause of death among urological tumors (Comperat and Camparo, 2012)
A similar conclusion was made when we compared estrogen receptor b (ERb) staining in different pathological grades; the results showed that 21% Fuhrman’s grade 1 (G1) RCC tumors vs. 49% (23 of 47) grade G2-3 RCC tumors have higher and stronger ERb immunohistochemical staining (IHC) staining signals (P = 0.0184) (Fig. 1B)
In addition to detecting the expression of epithelial–mesenchymal transition (EMT) markers, we further examined a group of EMT/metastasis-related miRNAs using a quantitative PCR assay and the results revealed that microRNAs such as miR126, miR145 and miR155 were upregulated in RCC cells, with higher ERb expression in both cell lines (Fig. 4D)
Summary
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and is the third leading cause of death among urological tumors (Comperat and Camparo, 2012). It is estimated that approximately 25–30% of RCC patients have metastases at the time of diagnosis. Even after resection of the primary tumor by radical or partial nephrectomy, relapse occurs in 20–30% of Abbreviations ccRCC, clear cell renal cell carcinoma; E2, 17 b-estradiol; EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; ER, estrogen receptor; ESR2, estrogen receptor b; ICI, ICI182, 780; IF, immunofluorescence; IGF-1, insulin-like growth factor-1; IHC, immunohistochemical staining; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; PHTPP, 4-[2-phenyl-5,7 bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol; RCC, renal cell carcinoma; TCGA, The Cancer Genome Atlas; TGF-b1, transforming growth factor b1; TGFbR-1, transforming growth factor b receptor-1.
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