Long non-coding RNA ZFHX4-AS1 Upregulates the Neural Differentiation-related Gene ZFHX4 and thereby Promotes SOX2 Expression to Accelerate Glioma Progression

Abstract

Abstract Background ZFHX4-AS1 is a recently discovered long noncoding RNA, and whether it is involved in glioma progression is unclear. Results We found that ZFHX4-AS1 and its nearby gene ZFHX4 were highly expressed in gliomas through analysis of online databases combined with experimental validation of collected glioma tissues and cells. In functional experiments, we found that high expression levels of ZFHX4-AS1 or ZFHX4 stimulated the proliferation, invasion and migration of glioma cells. Furthermore, overexpression and silencing of ZFHX4-AS1 resulted in the same changes in ZFHX4 expression levels. Combined with rescue experiments, we concluded that ZFHX4-AS1 can affect glioma progression by regulating ZFHX4. Based on the differentially expressed genes and related gene analysis of ZFHX4, we hypothesized that SOX2 was highly correlated with ZFHX4. Subsequently, we confirmed that SOX2 was highly expressed in glioma tissues and cells and was able to bind to ZFHX4. In functional experiments, we demonstrated that highly expressed SOX2 promotes glioma cells invasion and migration. By analyzing the differentially expressed genes of SOX2, we found that the functional node enriched for this differential gene is roughly the same as that of ZFHX4. It appears that these two genes synergize with one another to promote glioma cells progression.Afterwards, SOX2 activates the JAK1/STAT3 pathway and ZFHX4-AS1 reverses the SOX2-induced changes. Conclusions In conclusion, ZFHX4-AS1 upregulates the neighboring gene ZFHX4, which in turn increases the expression of SOX2 and stimulates glioma cells proliferation, invasion and migration.