title: The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways.
abstract: 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.
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Yu-yu
authors.initials: YY
authors.lastname: Gu
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Affiliated Hospital of Zunyi Medical College, Zunyi, 563003, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
authors.forename: Sheng-kai
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Department of Abdomen Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China. zzx-2003@126.com.
authors.forename: Zhao-xu
authors.initials: ZX
authors.lastname: Zheng
authors.affiliation: Department of Abdomen Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China. Haroldyuan@sohu.com.
authors.forename: Xing-hua
authors.initials: XH
authors.lastname: Yuan
authors.affiliation: The Institute of Clinical Pharmacology of Chinese PLA General Hospital, Beijing, People's Republic of China. liuping301@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China. huangpumc@163.com.
authors.forename: Chang-zhi
authors.initials: CZ
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D020935:MAP Kinase Signaling System; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C482860:UCHL1 protein, human; D051058:Oncogene Protein v-akt; D043222:Ubiquitin Thiolesterase
keywords: Akt; Erk1/2; Gastric cancer; Metastasis; UCHL1