These results suggest a novel mechanism for the loss of TβRII expression and TGF-β-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-β/miR-145/c-Myc/miR-20a/TβRII.
To test this hypothesis, we compared the effects of deleting the murine homolog of this receptor (Tgfbr2) in a mouse model of mutant K-ras-induced lung carcinoma, which normally induces the formation of multifocal tumors of low invasive potential.
Mutations in the tumor suppressor gene transforming growth factor beta (TGFB) Type II receptor (TGFBR2) are frequently found in many cancers with microsatellite instability, but are less common in lung cancer.
Because different histone modifications may play crucial roles in the epigenetic alterations, we further studied links with silencing of the TGFbetaRII gene promoter in six lung cancer cell lines.
We show in the present study that most lung cancer cell lines have lost the growth-inhibitory response to TGF-beta signal, and that those with TGF-beta unresponsiveness can be divided into two major groups, TGF-beta type II receptor (TGFbetaRII)(+)/Smad7(+) and TGFbetaRII(-)/Smad7(-), suggesting the heterogeneous mechanisms underlying the TGF-beta responsiveness.