Fig. 6

Circ-FBXW7 did not function through Let-7 rescue, but formed negative feedback through Wnt/β-catenin signaling mediation. A The overexpression of circ-FBXW7 led to an upregulation of Let-7d expression. B In Osimertinib-resistant HCC827OR and H1975OR cells, inhibition of the Wnt signaling pathway resulted in increased Let-7d expression. Strong stimulation of Let-7d expression was observed upon β-catenin inhibition. C The effects of Wnt signaling on sphere-forming ability were assessed, and no significant differences were observed among groups treated with circ-FBXW7, si-β-catenin, or their combination, indicating their similar functions. However, the synthesized compound of Wnt signaling stimulator increased sphere-forming ability, which was partially relieved by circ-FBXW7. D Putative binding sites were identified between the m6A readers (YTHDF3) and Let-7 miRNAs. E Manipulation of Let-7b, Let-7d, or Let-7i did not significantly alter the mRNA levels of YTHDF3. F Among the Let-7 miRNAs tested, Let-7d showed the most effective decrease in YTHDF3 expression. G Let-7d inhibited the luciferase activity of wild-type YTHDF3 mRNA, but had no effect on mutant groups. H Let-7d inhibited circ-FBXW7 expression in an YTHDF3 repression-dependent manner. I Let-7d and circ-FBXW7 formed a negative feedback loop. J Enforcing circ-FBXW7, Let-7d, or inhibiting YTHDF3 all decreased the self-renewal ability of resistant H1975OR and HCC827OR cells, with Capmatinib used as a positive control. K Upregulation of circ-FBXW7 and Let-7d reduced the stem cell population, while inhibition of YTHDF3 increased stem cells expressing the ALDH1A1 surface marker