Cell adhesion molecule 4 suppresses cell growth and metastasis by inhibiting the Akt signaling pathway in non-small cell lung cancer.
Cell adhesion molecule 4 (CADM4) is downregulated in many human cancers. However, CADM4 expression levels in human non-small cell lung cancer (NSCLC) tissues and its roles in NSCLC progression remain unknown. Our study aims to address these issues. We examined CADM4 levels in NSCLC tissues using real-time PCR and western blot. A549 and NCI-H1299 cells were then transfected with pcDNA3.1-CADM4 plasmid or siCADM4 to overexpress or knock down CADM4. Cell proliferation, cell cycle distribution, migration, and invasion were evaluated. NSCLC cells transfected with pcDNA3.1-CADM4 plasmid or siCADM4 were treated with SC79 or LY294002, respectively, to investigate the involvement of the Akt signaling pathway. Male nude mice were subcutaneously injected with stably transfected cells (1 × 106 cells/mice) to observe tumor growth. Stable transfectants were injected into nude mice (1 × 106 cells/mice) via tail vein to observe tumor metastasis. The results showed that CADM4 gene and protein levels in NSCLC tissues were significantly lower than those in corresponding adjacent tissues. CADM4 overexpression markedly inhibited cell proliferation, migration, and invasion. We also found that matrix metalloproteinase 9 (MMP-9) and MMP-2 activities were reduced. Moreover, CADM4 overexpression arrested the cell cycle at G1 phase, with the changes in expression of cell cycle regulators. The Akt signaling pathway was inhibited by CADM4 overexpression. In contrast, CADM4 knockdown showed the opposite effects. Additionally, SC79 and LY294002 reversed the effects of CADM4 overexpression and CADM4 knockdown in vitro, respectively. In xenograft models, CAMD4 overexpression suppressed, while CADM4 knockdown promoted tumor growth, accompanied by changes in Ki67 expression. In in vivo metastasis assay, CADM4 overexpression decreased, while CADM4 knockdown increased numbers of metastatic nodules in lung and liver. These evidences suggest that CADM4 may regulate NSCLC progression via the Akt signaling pathway. CADM4 may be a potential therapeutic target for NSCLC.
['Luo|Fang|F|', 'Zhao|Yi|Y|', 'Liu|Jiwei|J|']
D000085:Acetates D000818:Animals D001578:Benzopyrans D002289:Carcinoma, Non-Small-Cell Lung D015815:Cell Adhesion Molecules D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D002867:Chromones D015536:Down-Regulation D059585:G1 Phase Cell Cycle Checkpoints D055785:Gene Knockdown Techniques D006801:Humans D007136:Immunoglobulins D019394:Ki-67 Antigen D008113:Liver Neoplasms D008297:Male D020778:Matrix Metalloproteinase 2 D020780:Matrix Metalloproteinase 9 D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009025:Morpholines D051057:Proto-Oncogene Proteins c-akt D034741:RNA, Small Interfering D015398:Signal Transduction D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
Cell adhesion molecule 4 metastasis Akt signaling non-small cell lung cancer tumor growth