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.

Ubiquitin‐specific protease 3 overexpression promotes gastric carcinogenesis and is predictive of poor patient prognosis

“…In addition, Weng et al found that the expression of OTUB1 in GC tissues was higher than that in nontumor tissues. Furthermore, Gu et al examined UCHL1 expression, which was higher in primary GC tissues and liver metastases from GC than in nontumor tissues. The expression of USP3 in human cancers is still unknown, and the present study is the first to investigate the expression of USP3 in gastric tissues and cells.…”

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

“…Additional mechanisms mediating self-renewal and invasion in our model system such as activation of Akt and Erk1/2 pathways [30, 36], or stabilization of the oxidase NOX4 and of membrane receptors like the cell adhesion protein NCAM among other yet to uncover targets [37, 38] should not be ruled out. For instance aberrant expression of the brain aquaporin 1 (AQ1) and 4 (AQ4), which regulate water flow in and out of the cells, have been found in glioblastoma sphere cultures and their role in this tumor has just started to be elucidated [39, 40].…”

Deubiquitylating enzymes and drug discovery: emerging opportunities

“…Indeed, in a transgenic mouse model with constitutively activated UCHL1, sporadic tumours developed in many tissues 116 . Moreover, in vitro tumorigenesis studies showed that UCHL1 expression stimulated oncogenesis and an invasive phenotype [117][118][119] , whereas UCHL1 depletion had antitumour effects and blocked cell migration in a lung cancer cell line 117 . The precise mechanism by which UCHL1 contributes to tumorigenesis remains unclear, although reports suggest that it contributes to cell survival signalling, cell cycle Regulatory T cells (T reg cells).…”