PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing.
PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing.
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DOI：
10.1038/s41419-018-0608-8
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Liang X;Chen W;Shi H;Gu X;Li Y;Qi Y;Xu K;Zhao A;Liu J
多聚嘧啶片段结合蛋白3（PTBP 3）是一种重要的RNA结合蛋白，参与RNA的剪接、3′端加工和翻译。尽管越来越多的证据表明PTBP 3与多种癌症有关，但其在胃癌转移中的作用仍然很少探索。在这项研究中，我们发现PTBP 3在淋巴结转移患者的胃癌组织中上调。PTBP 3高表达患者的生存期明显短于PTBP 3低表达患者。PTBP 3表达的过表达/敲低对增殖没有影响，而它调节体外迁移和侵袭。此外，当建立MKN 45的小鼠异种移植模型时，MKN 45细胞中PTBP 3的敲低导致形成尺寸小于其对应物的肿瘤，并抑制肿瘤淋巴管生成和向区域淋巴结的转移。此外，我们确定了窖蛋白1（CAV 1）作为PTBP 3的下游靶标。RNA免疫沉淀（RIP）分析和双荧光素酶报告基因分析表明，PTBP 3与CAV 1基因的富含CU的区域相互作用，下调CAV 1 α的表达。敲低CAV 1 α可消除PTBP 3敲低诱导的FAK和Src的减少。总之，我们的研究结果提供了实验证据，PTBP 3可能作为一个转移基因在胃癌中通过调节CAV 1通过选择性剪接。
Polypyrimidine tract-binding protein 3 (PTBP3) is an essential RNA-binding protein with roles in RNA splicing, 3′ end processing and translation. Although increasing evidence implicates PTBP3 in several cancers, its role in gastric cancer metastasis remains poorly explored. In this study, we found that PTBP3 was upregulated in the gastric cancer tissues of patients with lymph node metastasis. Patients with high PTBP3 expression levels had significantly shorter survival than those with low PTBP3 expression. Overexpression/knockdown of PTBP3 expression had no effect on proliferation, whereas it regulated migration and invasion in vitro. In addition, when a mouse xenotransplant model of MKN45 was established, knockdown of PTBP3 in MKN45 cells caused the formation of tumours that were smaller in size than their counterparts, with suppression of tumour lymphangiogenesis and metastasis to regional lymph nodes. Furthermore, we identified caveolin 1 (CAV1) as a downstream target of PTBP3. RNA immunoprecipitation (RIP) assays and dual-luciferase reporter gene assays indicated that PTBP3 interacted with the CU-rich region of the CAV1 gene to downregulate CAV1α expression. Knockdown of CAV1α abrogated the reduction of FAK and Src induced by PTBP3 knockdown. In summary, our findings provide experimental evidence that PTBP3 may function as a metastatic gene in gastric cancer by regulating CAV1 through alternative splicing.
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DOI：
10.1093/jnci/94.11.819
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
He, YL;Kozaki, KI;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
4.8
作者：
Bailey, Kelly M.;Liu, Jun
通讯作者：
Liu, Jun
影响因子：
3.5
作者：
Kogo, H;Fujimoto, T
通讯作者：
Fujimoto, T
影响因子：
4.8
作者：
Liu, Wei;Lin, Yan-Ting;Lin, Xu
通讯作者：
Lin, Xu
影响因子：
--
作者：
Montenegro RC;Clark PG;Howarth A;Wan X;Ceroni A;Siejka P;Nunez-Alonso GA;Monteiro O;Rogers C;Gamble V;Burbano R;Brennan PE;Tallant C;Ebner D;Fedorov O;O'Neill E;Knapp S;Dixon D;Müller S
通讯作者：
Müller S