Fig. 1: Restoration of Let-7b by sulindac sulfide (SS) attenuates K-Ras-driven tumorigenesis.

A In the absence of SS, mutant-K-Ras activates the RAF−MEK−ERK signaling pathway, leading to phosphorylation and activation of ERK. Activated ERK induces the expression of genes that promote oncogenic transformation. Consequently, the expression of the RNA-binding protein LIN28B is induced, which inhibits the maturation of pri-let-7b into pre-let-7b in the nucleus and into mature microRNA Let-7b in the cytoplasm. Reduced Let-7b levels relieve repression of K-Ras mRNA, reinforcing the oncogenic loop and promoting tumorigenesis. B In the presence of SS, ERK phosphorylation and LIN28B expression are inhibited, thereby restoring Let-7b biogenesis. Elevated levels of Let-7b bind K-Ras mRNA and suppress its expression, breaking the oncogenic loop and reducing transformation. ERK extracellular signal-regulated kinase, K-Ras Kirsten rat sarcoma viral oncogene homolog, Let-7b lethal-7b, LIN28B lin-28 RNA-binding post-transcriptional regulator B, MEK mitogen-activated protein kinase kinase, pre-let-7b precursor let-7b, pri-let-7b primary let-7b transcript, RAF rapidly accelerated fibrosarcoma, SS sulindac sulfide. Created in BioRender (https://BioRender.com/ks3yqge).