Circular RNAs (circRNAs) play critical roles in tumorigenesis and the progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown. In this study, we confirmed that circBCBM1 was a stable and cytoplasmic circRNA. Functionally, circBCBM1 promoted the proliferation and migration of 231-BR cells in vitro and growth and brain metastasis in vivo. Mechanistically, circBCBM1 acted as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 (bromodomain containing 4) and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, circBCBM1 overexpression in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients. These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis. CircBCBM1 may serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

中文翻译：

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环状RNA circBCBM1通过调节miR-125a/BRD4轴促进乳腺癌脑转移

环状 RNA (circRNA) 在肿瘤发生和各种癌症的进展中起关键作用。我们之前在乳腺癌脑转移的背景下发现了一种新的上调 circRNA，circBCBM1 (hsa_circ_0001944)。然而，circBCBM1在乳腺癌脑转移中的潜在生物学功能和分子机制仍然很大程度上未知。在这项研究中，我们证实了 circBCBM1 是一种稳定的细胞质 circRNA。功能上，circBCBM1在体外促进231-BR细胞的增殖和迁移，在体内促进生长和脑转移. 从机制上讲，circBCBM1 作为内源性 miR-125a 海绵抑制 miR-125a 活性，导致 BRD4（含溴结构域 4）上调，随后通过 Sonic Hedgehog (SHH) 信号通路上调 MMP9（基质金属肽酶 9）。重要的是，circBCBM1 在乳腺癌脑转移细胞和临床组织和血浆样本中显着上调；此外，circBCBM1 在原发性癌组织中的过表达与乳腺癌患者的脑转移生存期 (BMFS) 较短有关。这些发现表明circBCBM1通过circBCBM1/miR-125a/BRD4轴参与乳腺癌脑转移。CircBCBM1可作为乳腺癌脑转移的新型诊断和预后生物标志物和潜在治疗靶点。