Department of General Surgery, Peking University First Hospital, Beijing, China.
Department of Endoscopy Center, Peking University First Hospital, Beijing, China.
Cancer Lett. 2019 May 1;449:215-225. doi: 10.1016/j.canlet.2019.02.031. Epub 2019 Feb 18.
Brahma (BRM) has recently been documented as a significant predictor of pancreatic cancer (PC) metastasis. This study aimed to further elucidate molecular mechanism by which BRM promotes PC metastasis. We found that silencing BRM reduced PC cell migration and invasion both in vivo and in vitro, accompanied by reduced level of miR-302a-3p. BRM positively regulated the transcription of miR-302a-3p, which acted as a metastasis-promoting miRNA in PC cells. miR-302a-3p directly targeted SOCS5 to boost STAT3 phosphorylation and induce the transcription of STAT3 target genes. Furthermore, miR-302a-3p level was higher in tissue and plasma samples derived from PC patients, and was significantly associated with worse clinical pathological features. In xenograft models, inhibiting miR-302a-3p was synergistically lethal in BRM-silenced PC cells. In conclusion, our results suggest that transcriptional regulation of miR-302a-3p by BRM potentiates PC metastasis by epigenetically suppressing SOCS5 expression and activating STAT3 signaling. These new findings provide potential therapeutic avenues for preventing PC-associated death.
Brahma (BRM) 最近被证明是胰腺癌 (PC) 转移的一个重要预测因子。本研究旨在进一步阐明 BRM 促进 PC 转移的分子机制。我们发现，沉默 BRM 可减少体内和体外 PC 细胞的迁移和侵袭，同时降低 miR-302a-3p 的水平。BRM 可正向调控 miR-302a-3p 的转录，miR-302a-3p 在 PC 细胞中作为一种促进转移的 miRNA 发挥作用。miR-302a-3p 可直接靶向 SOCS5 以促进 STAT3 磷酸化，并诱导 STAT3 靶基因的转录。此外，PC 患者的组织和血浆样本中 miR-302a-3p 的水平较高，且与更差的临床病理特征显著相关。在异种移植模型中，抑制 miR-302a-3p 与沉默 BRM 的 PC 细胞协同致死。总之，我们的研究结果表明，BRM 通过表观遗传抑制 SOCS5 表达和激活 STAT3 信号转导来转录调控 miR-302a-3p，从而增强 PC 转移。这些新发现为预防与 PC 相关的死亡提供了潜在的治疗途径。
