MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin-associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting -catenin and ATP-binding cassette, subfamily G, member 2
MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin-associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting -catenin and ATP-binding cassette, subfamily G, member 2
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DOI：
10.1002/path.4866
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发表时间：
2017-04-01
影响因子：
7.3
通讯作者：
Min, Do Sik
中科院分区：
文献类型：
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作者：
Kang, Dong Woo;Yang, Eun Sun;Min, Do Sik
幽门螺杆菌感染与胃癌风险增加密切相关。细胞毒素相关基因A（cytotoxinassociatedgene A，CagA）是H.幽门螺杆菌（pylori）是胃癌发生的一个致病因素，但CagA与胃癌起始细胞（CIC）样特性之间的分子联系仍不清楚。在这里，我们证明，CagA是需要通过下调microRNA（miR）-320a和miR-4496的β-catenin及其目标CIC标记物的表达增加。CagA促进胃循环免疫复合物的性质，并负责化疗耐药性。miR-320 a和miR-4496通过靶向β-连环蛋白减弱表达CagA的CIC的体外自我更新和肿瘤起始能力。此外，miR-320 a和miR-4496分别通过在转录和转录后水平靶向ATP结合盒亚家族G成员2（ABCG 2）来降低CagA诱导的化疗耐药性。5-氟尿嘧啶和miR-320a/miR-4496联合治疗抑制原位小鼠模型中的胃肿瘤发生和转移潜力，可能通过抑制CagA诱导的CIC特性和化疗耐药性。我们的研究结果提供了新的证据表明，CIC的性质，化疗耐药性和肿瘤发生与H。pylori感染与CagA诱导的β-catenin和ABCG 2上调有关。这些数据为CagA诱导的致癌作用的分子机制以及miR-320a和miR-4496的治疗潜力提供了新的见解。版权所有（c）2016大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Infection with Helicobacter pylori is closely linked to an increased risk of gastric cancer. Although cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer-initiating cell (CIC)-like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of -catenin and its target CIC markers via downregulation of microRNA (miR)-320a and miR-4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR-320a and miR-4496 attenuated the in vitro self-renewal and tumour-initiating capacity of CagA-expressing CICs by targeting -catenin. Moreover, miR-320a and miR-4496 decreased CagA-induced chemoresistance by targeting ATP-binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post-transcriptional levels, respectively. Combination therapy with 5-fluorouracil and miR-320a/miR-4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA-induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with H. pylori are linked to CagA-induced upregulation of -catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA-induced carcinogenisis and the therapeutic potential of of miR-320a and miR-4496. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.