The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways
The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways
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DOI：
10.1007/s13277-015-3566-0
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发表时间：
2015-11-01
期刊：
影响因子：
--
通讯作者：
Huang, Chang-zhi
中科院分区：
文献类型：
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作者：
Gu, Yu-yu;Yang, Mei;Huang, Chang-zhi
泛素 C 末端水解酶-L1 (UCHL1) 是一种去泛素化酶，其酶活性依赖于 C90 位点。 UCHL1在不同类型癌症中的功能存在争议，其在胃癌进展中的作用仍不清楚。本研究采用免疫组织化学染色方法检测UCHL1在原发性胃癌及胃癌肝转移灶中的表达情况。通过慢病毒感染建立了稳定表达去泛素酶活性 UCHL1 或失活 UCHL1 变体 C90S 的 MKN45 和 BGC823 细胞系。通过MTT和集落形成测定评估UCHL1对细胞增殖的影响。通过Transwell实验测定细胞迁移和侵袭的能力。通过蛋白质印迹测定蛋白质表达水平。结果表明，UCHL1在胃癌肝转移灶中的阳性表达率显着高于原发性胃癌。 MKN45 和 BGC823 细胞中 UCHL1 的过度表达根据其去泛素酶活性促进细胞增殖、迁移和侵袭。 UCHL1 激活 Akt 和 Erk1/2，该过程也需要酶活性，并且对于介导细胞迁移和侵袭是必需的。这些发现表明，UCHL1通过激活Akt和Erk1/2，依赖于其去泛素酶活性，促进细胞增殖、迁移和侵袭，这可能是其在胃癌肝转移中较高阳性表达率的原因。 UCHL1可能是胃癌转移的候选生物标志物和治疗靶点。
Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a de-ubiquitinating enzyme, which enzymatic activity relies on the C90 site. The function of UCHL1 is controversial in different types of cancer, and its role in gastric cancer progression remains unclear. In this study, immunohistochemistry staining was applied to detect the expression of UCHL1 in primary gastric cancer and liver metastases from gastric cancer. MKN45 and BGC823 cell lines with stable expression of de-ubiquitinase active UCHL1 or inactive UCHL1-variant C90S were established by lentiviral infection. The effect of UCHL1 on cell proliferation was evaluated by MTT and colony formation assays. The abilities of cell migration and invasion were determined by transwell assay. Protein expression levels were determined by Western blot. The results indicated that UCHL1 had a significantly higher positive expression rate in liver metastases from gastric cancer compared with primary gastric cancer. Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity. UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion. These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer. UCHL1 could be a candidate biomarker and a therapeutic target for gastric cancer metastasis.