Using a lung cancer model, it has been reported that the TGF–β/Smad signaling pathway leads to the phosphorylation of Smad2 and Smad3; in hypoxia, HIF-1α binds to Smad3 phosphorylated, inducing the expression of c-Myc, which induces the expression of protein machinery to alternative splicing targeting PKM2, which in turn activates glycolysis [74]. The gene discussed is HIF1A; the disease is lung cancer.