USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein.

Yue Ma,Jian Ni,Jie Song,Hua-Lin Fu,Hai Huang,Ying Xia,Wei-Lin Jin,Da-Xiang Cui,Zhen Wang

doi:10.18632/oncotarget.16445

Abstract

Increased ubiquitin-specific protease 22 (USP22) has been associated with poor prognosis in several cancers including gastric cancer. However, the role of USP22 in gastric tumorigenesis is still unclear. Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis. In this study, we found that silencing of USP22 inhibited proliferation of gastric cancer cells and suppressed the cancer stem cell spheroid formation in serum-free culture. Furthermore, cancer stem cell markers, such as CD133, SOX2, OCT4 and NANOG were down-regulated. Additionally, knockdown of USP22 inhibited gastric cancer xenografts growth. Our analysis of TCGA database indicated that BMI1 overexpression may predict gastric cancer patient survival, and TAT-BMI1 proteins reversed the USP22 knockdown-mediated decreased in cancer stem cell properties, and elevated the expression of stemness-associated genes. Furthermore, we found that overexpression of USP22 stabilized the BMI1 protein in gastric cancer cells. Taken together, our study demonstrates that USP22 is indispensable for gastric cancer stem cell self-renewal through stabilization of BMI1. These results may provide novel approaches to the theranostics of gastric cancer in the near future.

Highlights

Gastric cancer (GC) is a common malignancy worldwide with high death mortality and low cure rates
The results showed that cell proliferation was significantly inhibited in ubiquitin-specific protease 22 (USP22)-silenced cells
Because USP22 was identified as a cancer stem cells (CSC) marker and regulates the progression and prognosis of multiple cancers [10, 14], and CSCs are responsible for cancer initiation and metastasis, we explored the effect of USP22 on GC stemlike cell (SC) formation and GC progression

Summary

Introduction

Gastric cancer (GC) is a common malignancy worldwide with high death mortality and low cure rates. Elucidation of the mechanisms underlying GC and development of new treatment strategies are urgently needed. Cancer stem cells (CSCs) are a subpopulation of cells capable of self-renewal and unlimited replication to initiate tumors and have been well-characterized in multiple malignancies [3, 4]. CSC theory proposes that CSCs are the major cause of tumor recurrence due to their resistance to traditional radiotherapy and chemotherapy [5]. The knowledge of the generation and regulation of gastric CSCs is still unclear, and elucidation of the mechanisms www.impactjournals.com/oncotarget underlying gastric CSC induction is vital for GC diagnosis and treatment

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Results

Conclusion