科研之友
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Purpose: To explore the targeted therapy of estrogen-related receptor a (ERR alpha) in endometrial cancer (EC) cells and its potential mechanisms. @@@ Methods: The mRNA and protein expression levels of ERRa and estrogen receptor a (ERa) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERR alpha-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERRa (siRNA-ERR alpha), cell proliferation and apoptosis were evaluated by MTS assay and flow cytometry. After treatment with siRNA-ERR alpha, the expression profiles of transcription factors (Us) were analyzed by protein/DNA arrays in EC cells. @@@ Results: The relative m RNA levels of ERR alpha in RL-952 (1 +/- 0.0831) and AN3-CA (1.162 +/- 0.0325) were significantly higher than those in HEC-1 A (0.3081 +/- 0.0339) and HEC-1B (0.1119 +/- 0.0091) (P<0.05), and similar results were observed for ERRa protein levels. A higher ratio of ER alpha/ ERR alpha was observed in ER alpha-positive RL-952 (10-fold) and ANC-3A (8.5-fold) cells, whereas a lower ratio was observed in ER alpha-negative HEC-1A (3.75-fold) and HEC-1B cells (0-fold). Both - exogenous XCT790 and endogenous siRNA-ERR alpha - can decrease the expression of ERRa, thereby inhibiting proliferation but promoting apoptosis in both ER alpha-positive and -negative EC cells. The XCT790 presented higher proliferation-inhibition and apoptosis rates in the ER alpha-positive than ER alpha-negative cells, whereas the siRNA-ERR alpha exhibited higher proliferation-inhibition and apoptosis rates in the ER alpha-negative than in ER alpha-positive cells. In total, 3 upregulated and 17 downregulated TFs were screened out by knocked-down expression of ERR alpha in all EC cells. Among them, the upregulated TFs organic cation transporter 3/4(Oct3/4), hepatic nuclear factor 4 (HNF4), HNF4 and chicken ovalbumin upstream TF (COUP-TF) as well as downregulated transcription factor EB (TFEB) were found to be statistically significant (P<0.05). @@@ Conclusion: Targeting ERR alpha provides a promising novel endocrine therapeutic strategy.
