MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence.
MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence.
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MCM6通过MEK/ERK途径促进肝细胞癌的转移，并作为早期复发的新型血清生物标志物。
DOI：
10.1186/s13046-017-0669-z
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发表时间：
2018-01-22
期刊：
影响因子：
--
通讯作者：
Luo R
中科院分区：
文献类型：
--
作者：
Liu M;Hu Q;Tu M;Wang X;Yang Z;Yang G;Luo R
肝细胞癌（HCC）的高复发率和高转移率迫切需要寻找新的预测侵袭和预后的生物标志物。微小染色体维持复合物组分6（MCM 6）在多种恶性肿瘤中表达上调，被认为是一种新的肝癌诊断标志物。然而，其功能贡献和预后价值仍不清楚。采用免疫组化和实时荧光定量RT-PCR方法检测70例肝癌组织和5株肝癌细胞系中MCM 6的表达。分别采用CCK 8、Wound愈合和Transwell实验研究MCM 6在肝癌细胞增殖、迁移和侵袭中的作用。采用Western blotting和免疫荧光染色检测ERK信号通路蛋白和EMT相关标志物的表达。为了在体内验证上述发现，我们建立了裸鼠皮下移植瘤和原位移植瘤模型。最后采用酶联免疫吸附法检测血清MCM 6水平。MCM 6在肝癌组织中表达显著上调。在HCC患者中，MCM 6表达增加与侵袭性临床病理特征和较差的预后相关。这些结果与我们对癌症基因组图谱数据库（TCGA）的分析一致。此外，MCM 6的敲低显著降低了体外HCC细胞的增殖和迁移/侵袭能力，以及体内肿瘤体积、重量和肺转移数目的减少。机制分析表明，MCM 6促进EMT和激活MEK/ERK信号转导。更重要的是，HCC患者的血清MCM 6水平显著高于肝硬化和健康对照（P < 0.0001），并且允许以高准确度区分早期复发（AUC = 0.773）。我们的研究结果表明，MCM 6预测预后不良，并促进肝癌转移。术后血清MCM 6水平可能对检测临床前早期复发有价值，表明需要更仔细的监测和积极的治疗干预。本文的在线版本（10.1186/s13046-017-0669-z）包含补充材料，可供授权用户使用。
The high incidence of recurrence and metastasis of hepatocellular carcinoma (HCC) necessitate the discovery of new predictive biomarkers of invasion and prognosis. Minichromosome maintenance complex component 6 (MCM6), which has been reported to up-regulate in multiple malignancies, was considered to be a novel diagnoses biomarker in HCC. However, its functional contributions and prognostic value remain unclear. The expression of MCM6 was analyzed in 70 HCC tissues and 5 HCC cell lines by immunohistochemistry and real-time RT-PCR. The roles of MCM6 in HCC cell proliferation, migration and invasion were explored by CCK8, Wound healing and Transwell assays, respectively. Western blotting and Immunofluorescence staining were conducted to detect the protein expressions of ERK signaling pathway and EMT-related markers. To verify the above findings in vivo, we established subcutaneous xenograft tumor and orthotopic xenograft tumor models in nude mice. Finally, Enzyme-linked immunosorbent assay was used to evaluate the serum MCM6 level. MCM6 was significantly up-regulated in HCC tissues. Increased MCM6 expression was associated with aggressive clinicopathological features and worse prognosis in HCC patients. These results were consistent with our analyses of The Cancer Genome Atlas database (TCGA). Furthermore, knockdown of MCM6 significantly decreased proliferative and migratory/invasive capability of HCC cells in vitro, as well as decreased tumor volume, weight and the number of pulmonary metastases in vivo. Mechanistic analyses indicated that MCM6 promoted EMT and activated MEK/ERK signaling. More importantly, serum MCM6 levels in HCC patients were significantly higher than those in cirrhosis and healthy controls (P < 0.0001), and allowed distinguishing early recurrence with high accuracy (AUC = 0.773). Our findings indicate that MCM6 predicts poor prognosis and promotes metastasis in HCC. Postoperative serum MCM6 level could be valuable to detect preclinical early recurrence, indicative of a need for more careful surveillance and aggressive therapeutic intervention. The online version of this article (10.1186/s13046-017-0669-z) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Tan DF;Huberman JA;Hyland A;Loewen GM;Brooks JS;Beck AF;Todorov IT;Bepler G
通讯作者：
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影响因子：
4.8
作者：
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DOI：
10.1016/j.bpg.2014.08.007
发表时间：
2014-10-01
影响因子：
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作者：
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作者：
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