Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, China.
FASEB J. 2022 Feb;36(2):e22163. doi: 10.1096/fj.202101645R.
Early clinical studies indicated that estrogen receptor beta (ERβ) might play key roles to impact the progression of clear cell renal cell carcinoma (ccRCC). The detailed molecular mechanisms, however, remain unclear. Here, we found ERβ could increase the cancer stem cell (CSC) population via altering the circPHACTR4/miR-34b-5p/c-Myc signaling. Mechanism dissection revealed that ERβ could suppress circular RNA PHACTR4 (circPHACTR4) expression via direct binding to the estrogen response elements (EREs) on the 5' promoter region of its host gene, phosphatase and actin regulator 4 (PHACTR4) to decrease miR-34b-5p expression. The decreased miRNA-34b-5p could then increase c-Myc mRNA translation via targeting its 3' untranslated region (3' UTR). The in vivo mouse model with subcutaneous xenografts of ccRCC cells also validated the in vitro data. Importantly, analysis results from ccRCC TCGA database and our clinical data further confirmed the above in vitro/in vivo data. Together, these results suggest that ERβ may increase CSC population in ccRCC via altering ERβ/circPHACTR4/miR-34b-5p/c-Myc signaling and that targeting this newly identified signal pathway may help physicians to better suppress ccRCC progression.
早期临床研究表明，雌激素受体β（ERβ）可能在影响透明细胞肾细胞癌（ccRCC）的进展中发挥关键作用。然而，其详细的分子机制仍不清楚。在这里，我们发现 ERβ 可以通过改变 circPHACTR4/miR-34b-5p/c-Myc 信号来增加癌症干细胞（CSC）群体。机制分析表明，ERβ 可以通过直接结合其宿主基因磷酸酶和肌动蛋白调节因子 4（PHACTR4）5'启动子区域上的雌激素反应元件（EREs）来抑制环状 RNA PHACTR4（circPHACTR4）的表达，从而降低 miR-34b-5p 的表达。减少的 miRNA-34b-5p 可以通过靶向其 3'非翻译区（3'UTR）来增加 c-Myc mRNA 的翻译。ccRCC 细胞皮下异种移植的体内小鼠模型也验证了体外数据。重要的是，ccRCC TCGA 数据库和我们的临床数据的分析结果进一步证实了上述体外/体内数据。总之，这些结果表明，ERβ 通过改变 ERβ/circPHACTR4/miR-34b-5p/c-Myc 信号可以增加 ccRCC 中的 CSC 群体，靶向这个新确定的信号通路可能有助于医生更好地抑制 ccRCC 的进展。
