Dissociation of MIF‐rpS3 Complex and Sequential NF‐κB Activation Is Involved in IR‐Induced Metastatic Conversion of NSCLC

Abstract

Frequent relapse and spreading of tumors during radiotherapy are principal obstacles to treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to investigate how macrophage migration inhibitory factor (MIF) which is expressed at high levels in metastatic and primary lung cancer cells could regulate NSCLC metastasis in response to ionizing radiation (IR). The results indicated that MIF and ribosomal protein S3 (rpS3) were shown to be connected to inflammation, proliferation, and metastasis of NSCLC via IR-induced activation of the NF-κB pathway. Under unirradiated conditions, MIF physically established a complex with rpS3. MIF-rpS3 dissociation induced by IR activated NF-κB and made the expression of target genes of this factor transactivated in two NSCLC cell lines, A549, and NCI-H358. We also found that IR-induced dissociation of this complex led to increased secretion of pro-inflammatory cytokines and modulated the expression of epithelial-mesenchymal transition marker proteins. Finally, the effects of IR-induced dissociation of the MIF-rpS3 complex on tumor metastasis were confirmed by in vivo xenograft studies. Taken together, the present study revealed that dissociation of the MIF-rpS3 complex and subsequent activation of NF-κB is a critical post-IR exposure event that accounts for IR-induced metastatic conversion of NSCLC.

Macrophage Migration Inhibitory Factor Secretion Is Induced by Ionizing Radiation and Oxidative Stress in Cancer Cells

“…Interestingly, while we observed MIF secretion in several cell lines after IR, others have not seen such decreases in cellular MIF. Youn et al have recently investigated the effect of radiation on interaction of MIF with rp53 in A549, and NCI-H358 lung cancer cells, and did not observe decreases in cellular MIF following exposure [ 42 ]. This contradiction suggests genetic parameters may lead to differences in MIF levels or secretion that could further illuminate the mechanism of MIF secretion.…”

TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts

“…After treatments appropriate for each experiment, Western blotting was performed as previously described 51 . Whole cell lysates and tissue lysates were obtained in lysis buffer (20 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 0.5% sodium deoxycholate, 10 mM PMSF, 5 μg/mL Leupeptin, 1 μg/mL Aprotinin, and 1 μg/mL Pepstatin A).…”

TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial–mesenchymal transition

“…23 After cells with the indicated treatments had reached 70% confluency in RPMI-1640 medium supplemented with 1% FBS, the monolayers were scratched using a 200 μl pipette tip. Cells were then further incubated for 24 or 48 h. Photomicrographs were taken at × 100 using an Olympus IX71 inverted microscope (Olympus Optical Co Ltd).…”