Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway
Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway
复制标题
长非编码 RNA 00976 通过 OTUD7B 海绵 miR-137（涉及 EGFR/MAPK 通路）促进胰腺癌进展。
DOI：
10.1186/s13046-019-1388-4
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发表时间：
2019-11-20
影响因子：
11.3
通讯作者：
Jiang, Jianxin
中科院分区：
文献类型：
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作者：
Lei, Shan;He, Zhiwei;Jiang, Jianxin
背景越来越多的证据表明，长非编码RNA(Long Non-Coding RNAs，LncRNAs)在包括胰腺癌(PC)在内的恶性肿瘤的发生和发展中起着至关重要的作用。方法采用原位杂交和定量逆转录聚合酶链式反应的方法，研究linc00976在胰腺癌中的表达与临床病理特征和预后的关系。随后，将linc00976过表达载体和shRNAs导入PC细胞，以上调或下调linc00976的表达。通过功能丧失和功能获得分析，研究linc00976在体内外增殖和转移中的作用。结果linc00976在PC组织和细胞系中高表达，且与PC患者的预后呈正相关。功能研究表明，linc00976基因敲除显著抑制了体内和体外细胞的增殖、迁移和侵袭，而其过表达则逆转了这些作用。根据iTRAQ结果和在线数据库预测，卵巢肿瘤蛋白酶OTUD7B被发现是linc00976的下游基因，其去泛素化的EGFR介导了MAPK信号的激活。此外，生物信息学分析、荧光素酶分析和挽救实验表明，linc00976/MIR137/OTUD7B建立了调控PC细胞增殖和肿瘤生长的CerNA网络。结论linc00976通过上调OTUD7B的表达增强PC细胞的增殖和侵袭能力，OTUD7B是miR-137的靶点。最终，OTUD7B介导了EGFR和MAPK信号通路，提示linc00976/miR-137/OTUD7B/EGFR轴可能成为PC潜在的生物标志物和治疗靶点。
BackgroundAccumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer.MethodsIn situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway.Resultslinc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth.ConclusionThe present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.