TMEPAI/PMEPA1 enhances tumorigenic activities in lung cancer cells.
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.
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Thanh Thao
TT
Vo Nguyen
Yukihide
Y
Watanabe
Aya
A
Shiba
Masayuki
M
Noguchi
Susumu
S
Itoh
Mitsuyasu
M
Kato
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D047368:Tumor Burden
D008565:Membrane Proteins; C412868:PMEPA1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
Antibody; TGF-β; TMEPAI; lung cancer; tumorigenesis