Abstract
In this study, we investigated the role of ubiquitin-specific protease 22 (USP22) in the growth and progression of gastric cancer (GC). USP22 mRNA and protein levels were significantly higher in GC tissue samples and GC cell lines than in adjacent noncancerous tissue samples and a normal gastric mucosal epithelial cell line (GES1), respectively. USP22 knockdown significantly decreased in vitro survival, proliferation, migration, and invasiveness of GC cells compared with the controls. Western blot analysis of control and USP22-silenced GC cells showed that USP22 modulates the c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling pathways. Subcutanenous injection of USP22-silenced GC cells into SCID mice generated significantly smaller xenograft tumors than did control cells. Moreover, USP22-silenced GC cells showed less lung metastasis than the controls following tail vein injection in SCID mice. In addition, high USP22 expression correlated positively with tumor size, advanced stage and metastasis, and correlated negatively with tumor differentiation and prognosis in GC patients. These results show that USP22 regulates growth and progression of GC via the c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling pathways.
Highlights
Gastric cancer (GC) is the second most common malignancy and the third leading cause of cancer-related deaths in China [1]
Quantitative RT-PCR (n=40 samples each) and western blot (n=8 samples each) analyses showed that the levels of Ubiquitin-specific protease 22 (USP22) mRNA and protein expression were significantly higher in the GC tissues compared with the corresponding adjacent noncancerous tissues (Figure 1A, 1B)
These data suggest that USP22 is overexpressed in GC tissues and cell lines compared with the corresponding controls
Summary
Gastric cancer (GC) is the second most common malignancy and the third leading cause of cancer-related deaths in China [1]. USP22 is highly expressed in several www.aging-us.com cancers [6,7,8], which considerably contributes to tumor recurrence, distant metastasis, therapeutic failure, and poor prognosis [9]. Downregulation of USP22 reduces in vitro cancer cell proliferation, survival, migration, and invasion, and decreases in vivo tumor growth and metastasis [6, 10,11,12,13]. He et al reported increased co-expression of USP22 and c-Myc in GC tissues [7]. YAP increases GC cell motility by increasing the expression of matrix metalloproteinases, MMP-2 and MMP-9 [24]
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