Interferon regulatory factor 4 (IRF4) is overexpressed in human non-small cell lung cancer (NSCLC) and activates the Notch signaling pathway

Abstract

The transcription factor, interferon regulatory factor 4 (IRF4), serves an essential role in the regulation of immune responses, and has been reported to act as a diagnostic and prognostic marker for various hematological malignancies. The present study aimed to investigate whether IRF4 could exert effects on human non-small cell lung cancer (NSCLC) and to explore the underlying mechanism. The mRNA and protein expression of IRF4 was detected in NSCLC tissues using reverse-transcription quantitative polymerase chain reaction and western blotting, respectively. In the in vitro experiment, IRF4 expression was knocked down or overexpressed using lentivirus in human lung adenocarcinoma A549 and lung squamous cell carcinoma LC-AI cell lines. Cell proliferation and colony number were analyzed using MTT and colony formation assays, respectively. The expression levels of IRF4 mRNA and protein were significantly higher in NSCLC tissues (n=54) compared with that in adjacent non-tumor tissues. Similarly, the expression levels of Notch1 and Notch2 mRNA were significantly higher in NSCLC tissues. Furthermore, the expression level of IRF4 mRNA was positively correlated with the levels of Notch1 and Notch2 mRNA in NSCLC tissues. Consequently, using NSCLC cell lines, it was demonstrated that the knockdown of IRF4 expression significantly reduced the cell proliferation rate and colony formation, whereas IRF4-overexpression significantly increased them. Notably, the IRF4 knockdown significantly decreased the expression levels of Notch1 and Notch2 mRNA, and phosphorylated protein kinase B (AKT), whereas IRF4 overexpression resulted in the opposite. The results of the present study indicate that IRF4 is overexpressed and serves as a tumor promoter in human NSCLC, at least partially, through activating the Notch-Akt signaling pathway.

The impact of the RASSF1C and PIWIL1 on DNA methylation: the identification of GMIP as a tumor suppressor

“…In contrast to A4GALT, CIB2, and PSMA1, high expression of IRF4 is associated with higher lung cancer patient survival. This appears to be inconsistent with published findings that IRF4 acts as an oncogene in NSCLC cell lines [30]. Like CIB2, IRF4 function in lung cancer remains to be clearly determined.…”

IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

“…We observed that the combination of pomalidomide with the BET family antagonist JQ1 has additive effects in four of five pomalidomide-insensitive cell lines. Further analyses, as well as in vivo studies, are needed to confirm the efficacy of IMiDs and BET-bromodomain inhibitors combination therapy in ALCL and other tumors with de-regulated IRF4 [ 67 ]. Importantly, our data confirm the study by Weilemann et al, that demonstrated a key role of IRF4 in ALCL, irrespective of ALK status [ 38 ].…”

Genetic and environmental factors underlying keratinocyte carcinoma risk

“…The two largest genetic-association studies of SCC (18) and BCC (22) identified multiple risk loci near pigmentation genes (for SCC SLC45A2, IRF4, TYR, HERC2, DEF8, and RALY; for BCC MC1R, IRF4, TYRP1, HERC2, LPP, and BNC2), supporting the well-established role of lighter pigmentation, and its interaction with UV radiation exposure, in the risk of KC. The association of genetic variants in regions of FOXP1 and IRF4 also implicate Notch signaling (30)(31)(32) in both SCC and BCC susceptibility. Patients with Bloom, Werner, and Rothmund-Thomson syndromes are at increased risk of BCC and SCC, implicating chromosomal instability as another shared KC risk factor (14,15).…”