TMEPAI/PMEPA1 is a transmembrane
protein that was originally identified as a prostatic
RNA, the synthesis of which is induced by
testosterone or its derivatives. We have recently identified TMEPAI as a direct target gene of
transforming growth factor-β (TGF-β)/Smad signaling that participates in negative feedback control of the duration and intensity of TGF-β/Smad signaling. TMEPAI is constitutively and highly expressed in many types of
cancer and is associated with poor prognosis. Here, we report that TMEPAI is highly expressed in the
lung adenocarcinoma cell lines Calu3, NCI-H23, and RERF-LC-KJ. Expression of TMEPAI in these
cancer cells was significantly suppressed by a TGF-β receptor
kinase antagonist, SB208, and by TGF-β
neutralizing antibodies. These results suggest that constitutive expression of TMEPAI in these
cancer cells depends on autocrine TGF-β stimulation. Knockdown of TMEPAI in Calu3 and NCI-H23 cells enhanced levels of Smad2 phosphorylation and significantly suppressed cell proliferation in the presence of TGF-β, indicating that highly expressed TMEPAI suppresses levels of Smad phosphorylation in these
cancer cells and reduces the growth inhibitory effects of TGF-β/Smad signaling. Furthermore, knockdown of TMEPAI in Calu3 and NCI-H23 cells suppressed sphere formation in vitro and
tumor formation in s.c. tissues and in lungs after tail vein injection in NOD-SCID mice in vivo. Together, these experiments indicate that TMEPAI promotes tumorigenic activities in
lung cancer cells.