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

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.

SUBMITTER: Ma Y

PROVIDER: S-EPMC5464871 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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

Ma Yue Y Fu Hua-Lin HL Wang Zhen Z Huang Hai H Ni Jian J Song Jie J Xia Ying Y Jin Wei-Lin WL Cui Da-Xiang DX

Oncotarget 20170501 20

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. Furth ...[more]

PMID: 28415621

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Project description:Accumulating evidence supports the hypothesis that cancer stem cells (CSCs) are essential for cancer initiation, metastasis and drug resistance. However, the functional association of gastric CSC markers with stemness and epithelial-mesenchymal transition (EMT) signature genes is unclear.qPCR was performed to measure the expression profiles of stemness and EMT signature genes and their association with putative CSC markers in gastric cancer tissues, cancer cell lines and sphere cells. Western blot analysis was used to confirm the results of the transcript analysis. Cell proliferation, cell migration, drug resistance and sphere cell growth assays were conducted to measure the expansion and invasion abilities of the cells. Tumor xenograft experiments were performed in NOD/SCID mice to test cell stemness in vivo. Flow cytometry and immunofluorescence staining were used to analyze cell subpopulations.The expression of LGR5 was strikingly up-regulated in sphere cells but not in cancer tissues or parental adherent cells. The up-regulation of LGR5 was also positively associated with stemness regulators (NANOG, OCT4, SOX2, and AICDA) and EMT inducers (PRRX1, TWIST1, and BMI1). In addition, sphere cells exhibited up-regulated vimentin and down-regulated E-cadherin expression. Using gene-specific primers, we found that the NANOG expression primarily originates from the retrogene NANOGP8. Western blot analysis showed that the expression of both LGR5 and NANOG is significantly higher in sphere cells. LGR5 over-expression significantly enhanced sphere cell growth, cell proliferation, cell migration and drug resistance in MGC803 cells. Tumor xenografts in nude mice showed that sphere cells are at least 10 times more efficient at tumor initiation than adherent cells. Flow cytometry analysis showed that ~20% of sphere cells are LGR5+/CD54+, but only ~3% of adherent cells are Lgr5+/CD54+. Immunofluorescence staining supports the above results.The LGR5-expressing fraction of CD54+ cells represents gastric cancer CSCs, in which LGR5 is closely associated with stemness and EMT core genes, and NANOG expression is mainly contributed by the retrogene NANOGP8. Sphere cells are the best starting materials for the characterization of CSCs.

Project description:BackgroundRing finger protein 43 (RNF43) is a member of the transmembrane E3 ubiquitin ligase family that was originally found in stem cells and plays important roles in tumor formation and progression. Our previous study indicated that RNF43 might be a tumor suppressor protein in gastric cancer. Given its antagonistic relationship with leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), one of the gastric cancer stem cell markers, investigation of the potential role of RNF43 in gastric stem cancer cells is necessary.MethodsImmunohistochemistry staining, western blot analysis, and quantitative reverse transcription polymerase chain reaction were used to determine the mRNA and protein expression level of RNF43 and other Wnt pathway factors. Gastric cancer stem-like cells were obtained from gastric cancer tumor and cell lines by tumorsphere culture. The adeno-associated virus system was used to upregulate RNF43 expression in cancer cells. Functional experiments including tumorsphere formation, chemotherapy resistance, surface marker detection, and tumor xenograft assay were performed to measure stem-like properties in gastric cancer stem-like cells after RNF43 overexpression.ResultsRNF43 loss was significantly associated with TNM stage, distant metastasis, and Lauren classification, and predicted worse prognosis in gastric cancer patients. RNF43 expression was even lower in tumorspheres derived from tumor tissues or cell lines compared with adherent cancer cells and normal gastric cells. Overexpression of RNF43 in gastric cancer cells impaired their stem-like properties, including sphere formation ability, chemoresistance in vitro, and tumorigenicity in vivo. Moreover, Wnt pathway-related proteins were decreased in RNF43-overexpressing cells, while Wnt pathway activators could reverse the trend to some extent.ConclusionsOur findings indicated that RNF43 might not only participate in gastric cancer progression, but also attenuate the stemness of gastric cancer stem-like cells through the Wnt/β-catenin pathway.

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

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

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