Overexpression of MAPK15 in gastric cancer is associated with copy number gain and contributes to the stability of c-Jun.
Overexpression of MAPK15 in gastric cancer is associated with copy number gain and contributes to the stability of c-Jun.
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DOI：
10.18632/oncotarget.4171
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发表时间：
2015-08-21
期刊：
影响因子：
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通讯作者：
Park J
中科院分区：
文献类型：
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作者：
Jin DH;Lee J;Kim KM;Kim S;Kim DH;Park J
本研究旨在了解胃癌中MAPK15基因改变的功能和临床病理意义。使用Agilent aCGH- 244k或aCGH- 400k首次在40例胃癌中研究了全基因组拷贝数改变（CNAs），并在另一组48例胃癌组织中验证了aCGH中发现的MAPK15拷贝数增加。应用免疫组织化学分析了MAPK15在另外45例胃癌患者的正常、腺瘤和癌并发病变中的表达。在胃癌细胞中分析MAPK15对细胞周期、c-Jun磷酸化和mRNA稳定性的影响。88个肿瘤组织中有15个（17%）发现MAPK15拷贝数增加。胃癌组织和胃癌细胞中MAPK15 mRNA水平相对较高，拷贝数增益高于未转染的胃癌细胞。在胃癌细胞中使用siRNA敲低MAPK15可显著抑制细胞增殖，导致细胞周期阻滞在G1-S期。在mapk15敲除的细胞中，c-Jun磷酸化降低，c-Jun半衰期缩短。此外，将MAPK15瞬时转染到低拷贝数的AGS胃癌细胞中，可导致c-Jun磷酸化和稳定性增加。与同期正常组织（2%）和腺瘤（21%）相比，MAPK15在癌组织中的过表达频率更高（37%）。综上所述，本研究提示MAPK15过表达可能通过延长c-Jun的稳定性参与胃黏膜的恶性转化。并且，在胃正常组织或癌前组织中，MAPK15拷贝数增加的患者可能有机会进展为侵袭性癌症。
This study was aimed at understanding the functional and clinicopathological significance of MAPK15 alteration in gastric cancer. Genome-wide copy number alterations (CNAs) were first investigated in 40 gastric cancers using Agilent aCGH-244K or aCGH-400K, and copy number gains of MAPK15 found in aCGH were validated in another set of 48 gastric cancer tissues. The expression of MAPK15 was analyzed using immunohistochemistry in concurrent lesions of normal, adenoma, and carcinoma from additional 45 gastric cancer patients. The effects of MAPK15 on cell cycle, c-Jun phosphorylation, and mRNA stability were analyzed in gastric cancer cells. Copy number gains of MAPK15 were found in 15 (17%) of 88 tumor tissues. The mRNA levels of MAPK15 were relatively high in the gastric cancer tissues and gastric cancer cells with higher copy number gains than those without. Knockdown of MAPK15 using siRNA in gastric cancer cells significantly suppressed cell proliferation and resulted in cell cycle arrest at G1-S phase. Reduced c-Jun phosphorylation and c-Jun half-life were observed in MAPK15-knockdowned cells. In addition, transient transfection of MAPK15 into AGS gastric cancer cells with low copy number resulted in an increase of c-Jun phosphorylation and stability. The overexpression of MAPK15 occurred at a high frequency in carcinomas (37%) compared to concurrent normal tissues (2%) and adenomas (21%). In conclusion, the present study suggests that MAPK15 overexpression may contribute to the malignant transformation of gastric mucosa by prolonging the stability of c-Jun. And, patients with copy number gain of MAPK15 in normal or premalignant tissues of stomach may have a chance to progress to invasive cancer.