VHL mutation-mediated SALL4 overexpression promotes tumorigenesis and vascularization of clear cell renal cell carcinoma via Akt/GSK-3β signaling.

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.

• Authors: Jinbo Sun, Qisheng Tang, Yongheng Gao, Wei Zhang, Zhining Zhao, Fan Yang, Xiangnan Hu, Dan Zhang, Yong Wang, Huizhong Zhang, Bin Song, Bo Zhang, He Wang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 39 Issue 1 Pg. 104 (Jun 08 2020) ISSN: 1756-9966 [Electronic] England
• PMID: 32513235 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• SALL4 protein, human
• Transcription Factors
• Von Hippel-Lindau Tumor Suppressor Protein
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• VHL protein, human

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Renal Cell (blood supply, genetics, metabolism, pathology)
• Cell Proliferation
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 beta (genetics, metabolism)
• Humans
• Kidney Neoplasms (blood supply, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Mutation
• Neoplasm Invasiveness
• Neovascularization, Pathologic
• Prognosis
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Survival Rate
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)
• Xenograft Model Antitumor Assays