Fig. 6. Proposed model for the miR-449b-TGFBI/TGFβ1 pathway.

a In normal cells, the secretion of TGFBI into the ECM leads to competition between TGFBI and latent TGFβ1 (ECM-sequestered) for the binding of αvβ3/5 integrins. TGFBI-αvβ3/5 binding activates the tumor suppressor PTEN (dotted arrow; uncharacterized mechanism), suppressing AKT activation. This binding also prevents excess conversion of latent TGFβ1 into active TGFβ1, thereby modulating endocytosis of active TGFβ1 and its receptors, and maintaining homeostasis. b In NPC, miR-449b is overexpressed and downregulates TGFBI expression. Consequently, with less TGFBI in the ECM, this facilitates PTEN inhibition, as well as increased binding of latent TGFβ1 to αvβ3/5 integrins (via its LAP domain), promoting the release of active TGFβ1. As more active TGFβ1 binds to its receptors, it becomes internalized, resulting in increased activation of both canonical and noncanonical TGFB signaling, as demonstrated by the EMT-like phenotype acquired by the cells, as well as activation of AKT; two features known to be involved in chemoresistance⁵³