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VHL mutation-mediated SALL4 overexpression promotes tumorigenesis and vascularization of clear cell renal cell carcinoma via Akt/GSK-3β signaling
- Source :
- Journal of Experimental & Clinical Cancer Research : CR, Journal of Experimental & Clinical Cancer Research, Vol 39, Iss 1, Pp 1-17 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Background Although ongoing development of therapeutic strategies contributes to the improvements in clinical management, clear cell renal cell carcinoma (ccRCC) deaths originate mainly from radiochemoresistant and metastatic disease. Transcription factor SALL4 has been implicated in tumorigenesis and metastasis of multiple cancers. However, it is not known whether SALL4 is involved in the pathogenesis of ccRCC. Methods Analyses of clinical specimen and publicly available datasets were performed to determine the expression level and clinical significance of SALL4 in ccRCC. The influence of SALL4 expression on ccRCC tumor growth, metastasis and vascularity was evaluated through a series of in vitro and in vivo experiments. Western blotting, immunofluorescence staining and integrative database analysis were carried out to investigate the underlying mechanism for SALL4-mediated oncogenic activities in ccRCC. Results SALL4 expression was increased in ccRCC and positively correlated with tumor progression and poor prognosis. SALL4 could promote ccRCC cell proliferation, colony formation, cell cycle progression, migration, invasion and tumorigenicity and inhibit cell senescence. Further investigation revealed a widespread association of SALL4 with individual gene transcription and the involvement of SALL4 in endothelium development and vasculogenesis. In the context of ccRCC, SALL4 promoted tumor vascularization by recruiting endothelial cells. In addition, we found that SALL4 could exert its tumor-promoting effect via modulating Akt/GSK-3β axis and VEGFA expression. VHL mutation and DNA hypomethylation may be involved in the upregulation of SALL4 in ccRCC. Conclusions Overall, our results provide evidence that upregulated SALL4 can function as a crucial regulator of tumor pathogenesis and progression in ccRCC, thus offering potential therapeutic strategies for future treatment.
- Subjects :
- Clear cell renal cell carcinoma
Male
0301 basic medicine
Cancer Research
Angiogenesis
Cell
Apoptosis
medicine.disease_cause
Mice
0302 clinical medicine
Tumor Cells, Cultured
SALL4
Neovascularization, Pathologic
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Prognosis
Kidney Neoplasms
Gene Expression Regulation, Neoplastic
Survival Rate
Vascular endothelial growth factor A
medicine.anatomical_structure
Oncology
Von Hippel-Lindau Tumor Suppressor Protein
030220 oncology & carcinogenesis
Disease Progression
Female
Signal Transduction
Mice, Nude
Biology
lcsh:RC254-282
03 medical and health sciences
Biomarkers, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Carcinoma, Renal Cell
Protein kinase B
Cell Proliferation
Glycogen Synthase Kinase 3 beta
Cell growth
Research
medicine.disease
Xenograft Model Antitumor Assays
eye diseases
030104 developmental biology
Tumor progression
Tumorigenesis
Mutation
Cancer research
Carcinogenesis
Proto-Oncogene Proteins c-akt
VHL mutation
Transcription Factors
Subjects
Details
- ISSN :
- 17569966
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental & Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....3130e28da9a5ed237dd93a3da0934e7a