CD133-AKT-Wnt signal axis drives GBM stem cells

Cell surface markers play an important role in identifying tumor types and drug screeningCD133 was originally used as a marker for identifying self-renewing hematopoietic and neural stem cell subgroupsLater used to identify brain tumors, including glioblastoma (GBM), the stem cells that initiate tumor occurrence, and CD133 is an important marker of GBM stem cellsHowever, its biological function in GBM and its mechanism of regulating downstream signaling pathways are still unclearBranavan Manoranjan of the Michael GDeGroote School of Medicine at McMaster University in Canada and others found CD133-AKT-Wnt signal transduction axis by identifying GBM tumor samples with high expression and CD133 low expressionThe results were published online in Oncogene in November 2019the study methodsthe researchers screened the GBM BTIC line to evaluate the variability of CD133 cell surface protein expression, and detected CD133 expression in 8 cases of GBM glioma stem cell lines, and found significant differences in CD133 expression between different samplesTo determine the degree of activation of the downstream extracellular factor Wnt, the activity level of the endogenous Wnt pathway was measured using TCF reporting assayWnt reported that gene activity was very similar to the observed trend of CD133 expressionThe researchers were higher in expressing CD133 and low expression CD133 glioma stem cell lines with TCF reported gene activity and Axin2 expressionCompared with the low-expression CD133 sample, both indicators were significantly enriched in GBM with high expression CD133The findings support the associated effects of GBM subgroup stem cells, in which both CD133 and Wnt pathways are enriched to maintain BTIC statusthen, CD133 was overexpressed on the glioma stem cell line to clarify its functionAfter over-expression of CD133, a significant increase in glioma stem cell proliferation and self-renewal was observedTo determine the effect of CD133 on endogenous Wnt activity, the tCF reporting gene levels in the control group and CD133 overexpression samples were compared, and the Wnt reporting gene activity in CD133 overexpression group was found to be significantly enhanced After CD133 was expressed, pAKT (Ser473), pGSK-3 (Ser9) and beta-catenin increased significantly The use of Wnt inhibitor XAV939 to treat BTIC can inhibit this trend, pAKT (Ser473) and CD133 expression decreased These results suggest that CD133 may be acting downstream by activating the AKT's Wnt path the results of the study the researchers applied small molecular inhibitors for CD133, monoclonal antibody RW03, after treating glioma stem cell lines, observed CD133 and AKT expression, as well as the downstream effect of the Wnt signal pathway, found that RW03 can lead to CD133 expression reduction in multiple independent glioma stem cell lines, the self-renewal potential of glioma stem cell lines and tCF reported a significant reduction in gene activity Finally, the validation of Wnt signal path activity in mouse models can promote tumor formation of gliomas and reveal the importance of wnt pathways in the course of GBM occurrence conclusions , the study found CD133-AKT-Wnt signal transduction shaft in the glioma stem cell line, where CD133 acts as a cell surface receptor for AKT dependence and activates the Wnt signal pathway The results of the study may have potential implications for further targeted PI3K/AKT or Wnt tumor trials, as these two information pathways, independent of their classic drivers, can be activated by CD133, leading to treatment resistance and disease recurrence.