BRM transcriptionally regulates miR-302a-3p to target SOCS5/STAT3 signaling axis to potentiate pancreatic cancer metastasis
BRM transcriptionally regulates miR-302a-3p to target SOCS5/STAT3 signaling axis to potentiate pancreatic cancer metastasis
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BRM转录调节miR-302a-3p以靶向SOCS5/STAT3信号轴以增强胰腺癌转移
DOI：
10.1016/j.canlet.2019.02.031
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发表时间：
2019
期刊：
影响因子：
9.7
通讯作者：
Yang Yinmo
中科院分区：
文献类型：
--
作者：
Zhang Zhengkui;Li Jisong;Guo Huahu;Wang Feng;Ma Ling;Du Chong;Wang Yazhou;Wang Qi;Kornmann Marko;Tian Xiaodong;Yang Yinmo
Brahma（BRM）最近被证明是胰腺癌（PC）转移的重要预测因子。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在体内和体外均降低PC细胞迁移和侵袭，伴随着miR-302 a-3 p水平的降低。BRM正调控miR-302 a-3 p的转录，miR-302 a-3 p在PC细胞中充当促进转移的miRNA。miR-302 a-3 p直接靶向SOCS 5以促进STAT 3磷酸化并诱导STAT 3靶基因的转录。此外，来自PC患者的组织和血浆样品中的miR-302 a-3 p水平更高，并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-302 a-3 p在BRM沉默的PC细胞中协同致死。总之，我们的研究结果表明，BRM对miR-302 a-3 p的转录调控通过表观遗传学抑制SOCS 5表达和激活STAT 3信号转导增强PC转移。这些新发现为预防PC相关死亡提供了潜在的治疗途径。
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.