Lnc-FAM84B-4 acts as an oncogenic lncRNA by interacting with protein hnRNPK to restrain MAPK phosphatases-DUSP1 expression
Lnc-FAM84B-4 acts as an oncogenic lncRNA by interacting with protein hnRNPK to restrain MAPK phosphatases-DUSP1 expression
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DOI：
10.1016/j.canlet.2020.08.036
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发表时间：
2020-12-01
期刊：
影响因子：
9.7
通讯作者：
Sun, Yueming
中科院分区：
文献类型：
--
作者：
Peng, Wen;Zhang, Chuan;Sun, Yueming
有报道称，丝裂原活化蛋白激酶(MAPK)通路参与了许多肿瘤的发生发展。正常情况下，MAPK活性在快速磷酸化和去磷酸化之间是自限的。然而，在异常情况下，这种动态平衡被打破，触发了抑制或促进肿瘤的作用。尽管双特异性MAPK磷酸酶(MKP/DUSPs)在MAPK通路的级联调控中起重要作用，但它们在结直肠癌(CRC)中的作用仍不清楚。在这里，我们研究了lnc-FAM84B-4和DUSP1，以系统地阐明它们在MAPK信号通路和功能中在结直肠癌中的潜在作用。再挖掘CRC微阵列鉴定上调表达的LNC-FAM84B-4。进行体外和体内功能测定。采用RNA-Seq、RNA下拉、RIP等方法研究LNC-FAM84B-4对DUSP1表达的调控机制。结果表明，LNC-FAM84B-4通过抑制DUSP1的表达来调节MAPK通路。从机制上讲，RNA下拉和质谱确定了hnRNPK在介导DUSP1表达中作为lnc-FAM84B-4的结合伙伴的作用。我们的发现证明了lnc-FAM84B-4-hnRNPK-DUSP1轴在结直肠癌发生发展中的重要作用，并为结直肠癌的治疗提供了一个靶点。
The mitogen activated protein kinase (MAPK) pathway has been reported to be involved in many cancer developments. Normally, MAPK activity is self-limited between rapid phosphorylation and dephosphorylation. In abnormal conditions, however, this dynamic equilibrium is broken, trigging tumor-suppressing or -promoting roles. While dual-specificity MAPK phosphatases (MKP/DUSPs) are important for cascade control in MAPK pathway, their role in colorectal cancer (CRC) remains largely unknown. Here, we investigated lnc-FAM84B-4 and DUSP1 to systematically elucidate their underlying roles in MAPK singling pathway and functions in CRC. Upregulated lnc-FAM84B-4 was identified by re-mining CRC microarray. Functional assays were performed in vitro and in vivo. RNA-Seq, RNA pull-down, and RIP assays were used to investigate the mechanisms of Lnc-FAM84B-4 in regulating expression of DUSP1. The results indicated that Lnc-FAM84B-4 regulates MAPK pathway by restraining DUSP1 expression. Mechanistically, RNA pull-down followed by mass spectrum determined hnRNPK functions as a binding partner of lnc-FAM84B-4 in mediating DUSP1 expression. Our findings demonstrate the important role of lnc-FAM84B-4-hnRNPK-DUSP1 axis in CRC development, and suggest a therapeutic target for CRC treatment.