Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway
Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway
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Linc01232通过抑制泛素介导的HNRNPA2B1降解并激活A-Raf诱导的MAPK/ERK信号通路促进胰腺癌转移
DOI：
10.1016/j.canlet.2020.08.001
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发表时间：
2020-12-01
期刊：
影响因子：
9.7
通讯作者：
Jiang, Kui-Rong
中科院分区：
文献类型：
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作者：
Meng, Ling-Dong;Shi, Guo-Dong;Jiang, Kui-Rong
胰腺癌是一种死亡率高、预后差的恶性肿瘤。在这项研究中，我们发现Linc 01232在PC组织和细胞中显著上调，并且较高的Linc 01232表达与较差的预后相关。Linc 01232过表达促进PC细胞的迁移和侵袭，而Linc 01232敲低抑制PC细胞的迁移和侵袭。RNA pull-down、RNA结合蛋白免疫沉淀（RIP）实验结果表明，Linc 01232与异源核核糖核蛋白A2/B1（HNRNPA 2B 1）（680-890 nt的RNA识别基序2结构域片段）发生物理相互作用，抑制其在PC细胞中的泛素介导的降解。通过RNA测序获得Linc 01232调控的转录谱，进一步证明Linc 01232通过稳定HNRNPA 2B 1参与A-Raf的选择性剪接，进而调控MAPK/ERK信号通路。综上所述，我们的研究表明Linc 01232/HNRNPA 2B 1/A-Raf/MAPK轴参与了PC的发病过程，为PC的治疗提供了一个潜在的靶点。
Pancreatic cancer (PC) is a malignant cancer with high mortality and poor prognosis. In this study, we found that Linc01232 was significantly upregulated in PC tissues and cells and higher Linc01232 expression was associated with poorer prognosis. Linc01232 overexpression promoted and Linc01232 knockdown inhibited the migration and invasion of PC cells. The results of RNA pull-down, RNA Binding Protein Immunoprecipitation (RIP) assays revealed that Linc01232 physically interacted with Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) (680-890 nt fragment with the RNA recognition motif 2 domain) to inhibit its ubiquitin-mediated degradation in PC cells. RNA sequencing was performed to obtain the transcriptional profiles regulated by Linc01232 and we further demonstrated that Linc01232 participated in the alternative splicing of A-Raf by stabilizing HNRNPA2B1 and subsequently regulated the MAPK/ERK signaling pathway. Collected, our study showed that Linc01232/HNRNPA2B1/A-Raf/MAPK axis participated in the progression of PC and provided a potential therapeutic target for PC.