FOXP4 modulates tumor growth and independently associates with miR-138 in non-small cell lung cancer cells

Abstract

Family of forkhead box transcription factors, including forkhead box P4 (FOXP4), plays an important role in oncogenesis. The current study is to evaluate the role of FOXP4 in regulating human non-small cell lung cancer (NSCLC). Quantitative RT-PCR and Western blot were performed to evaluate the gene and protein expressions of FOXP4 in six NSCLC cell lines and 55 NSCLC patients. Lentivirus of small hairpin RNA (FOXP4-shRNA) was used to downregulate FOXP4 in NSCLC cell lines A549 and H1703 cells. Its effect on NSCLC growth, invasion, and cell cycle were evaluated by cell proliferation assay, migration assay, and cell cycle assay, respectively. Dual luciferase assay and Western blot were used to examine whether microRNA-138 (miR-138) was an upstream regulator of FOXP4. The dependence of FOXP4 on miR-138 associated signaling pathway was evaluated by ectopically overexpressing enhancer of zeste homolog 2 (EZH2), a known miR-138 target in NSCLC. FOXP4 was highly expressed in both NSCLC cell lines and NSCLC patients. FOXP4 downregulation by FOXP4-shRNA markedly reduced cancer cell growth and invasion, as well as induced cell cycle arrest in A549 and H1703 cells. MiR-138 was confirmed to be an upstream regulator of FOXP4 and directly regulated FOXP4 expression in A549 and H1703 cells. FOXP4 downregulation-mediated inhibition on cancer cell growth and invasion was independent on overexpressing EZH2, another direct target of miR-138 in NSCLC. Our data demonstrated that FOXP4 was a critical regulator in NSCLC and independently associated with miR-138 regulation.

Genome-wide association study of subclinical interstitial lung disease in MESA

“…FOXP4 encodes a transcription factor (forkhead box P4) expressed in proximal and distal airway epithelium as well as in subepithelial mesenchyme during lung development [20]. FOXP4 is also expressed in CD4+ and CD8+ T cells and appears to contribute to cytokine production and memory T cell responses [21], and a recent study reported FOXP4 as an important regulator of non-small cell lung cancer cells [22]. The specific role of this locus in disease pathogenesis requires further elucidation.…”

Up‐regulation of microRNA‐491‐5p suppresses cell proliferation and promotes apoptosis by targeting FOXP4 in human osteosarcoma

“…Furthermore, knockdown of FOXP4 was shown to markedly reduce the proliferation and invasion capabilities of A549 and H1703 cells and induce cell cycle arrest. These findings further confirm that FOXP4 is target gene for miR‐138 …”

MicroRNAs as regulators and mediators of forkhead box transcription factors function in human cancers

“…Huang et al showed that FOXP3 downregulates miR-142-3p to keep the adenylyl cyclase (AC) 9 / cAMP pathway active in T REG cells [152]. In addition, miR-138 is an upstream regulator of FOXP4 and directly regulates FOXP4 expression in NSCLC [153]. Similarly, it was also found that miR-338-3p inhibits HCC cell growth by targeting FOXP4 [154].…”