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. 2023 Apr 5;42(20):1649–1660. doi: 10.1038/s41388-023-02683-w

Fig. 5. Low expression of RAF1 correlates with the downregulation of target genes involved in STAT3 activation and angiogenesis.

Fig. 5

A mRNA expression levels of BHLHE40, EMP1 and LDLR in human CRC spheroids RAF1 WT or KO. B Representative STAT3/pSTAT3 western blot of 3D spheroids derived from human CRC cell lines. Numbers represent the ratio between the total STAT3 and the phosphorylated protein, after individual normalization on Tubulin, used as a loading control, and compared to the parental cell line. C BHLHE40, EMP1 and LDLR expression is significantly downregulated in human primary CRC expressing low levels of RAF1. Comparison was done between RAF1 high expression group (34 patients) and RAF1 low expression group (34 patients). D FGF2, HGF, MCL1 and MMP2 expression is significantly downregulated in CRC expressing low levels of RAF1. Comparison was performed as in (C). E BHLHE40, EMP1 and LDLR expression is significantly downregulated in human primary LUAD expressing low levels of RAF1. Comparison was done between the RAF1 high expression group (150 patients) and the RAF1 low expression group (150 patients). F Expression of FGF2, HGF and MCL1 is significantly downregulated in LUAD expressing low levels of RAF1. Comparison was performed as in (E). G Working model of RAF1 impact on CRC through BHLHE40, LDLR and EMP1. 1. RAF1 impacts expression of BHLHE40, LDLR and EMP1 via undescribed but ERK-independent mechanisms. 2. BHLHE40, LDLR and EMP1 trigger STAT3 phosphorylation and activation through distinct pathways. 3. Activated STAT3 induces angiogenesis. A, C, D, *p < 0.05, **p < 0.01, ***p < 0.001.