Functional disruption of macrophage migration inhibitory factor (MIF) suppresses proliferation of human H460 lung cancer cells by caspase-dependent apoptosis

Abstract

BackgroundMacrophage migration inhibitory factor (MIF) is important in regulating cell proliferation and apoptosis in both normal and cancerous cells, and may be important in cancer progression and metastasis. In human non-small cell lung cancer (NSCLC), the underlying mechanisms responsible for MIF-dependent regulation of cellular proliferation, and cell death remain poorly appreciated.MethodsThe human H460 lung cancer cell-line was treated with an optimally determined dose of 50 pmol/ml MIF siRNA, following which cell proliferation, cell cycle and apoptosis were analyzed. Additionally, known pathways of apoptosis including expression of Annexin-V, enhanced production of caspases-3 and −4 and expression of the Akt signaling protein were assessed in an attempt to provide insights into the signaling pathways involved in apoptosis following disruption of MIF expression.ResultsSpecific siRNA sequences markedly decreased MIF expression in H460 cells by 2 to 5-fold as compared with the negative control. Moreover, MIF miRNA dampened not only cellular proliferation, but increased the frequency of apoptotic cells as assessed by cell-surface Annexin-V expression. Entry of cells into apoptosis was partly dependent on enhanced production of caspases −3 and −4 while not affecting the expression of either caspase-8 or the Akt signaling pathway.ConclusionsIn a model of NSCLC, knockdown of MIF mRNA expression dampened H460 proliferation by mechanisms partly dependent on entry of cells into apoptosis and enhanced production of caspase-3 and −4. MIF expression may thus be important in NSCLC progression. Targeting MIF may have clinical utility in the management of human lung cancer.

Prognostic role of macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the lung

“…reported that knockdown of MIF resulted in a substantial decrease in migratory potential of lung adenocarcinoma cells. Another study showed that knockdown of MIF dampened cell proliferation by enhancing apoptosis in lung cancer cell . Goto et al .…”

“…Another study showed that knockdown of MIF dampened cell proliferation by enhancing apoptosis in lung cancer cell. 20 Goto et al 11 reported that MIF expression was inversely correlated with miR-451 expression, and MIF expression and phosphorylated Akt expression after transfection of miR-451-mimic was suppressed, as were cell proliferation and migration in NSCLC cell lines. Moreover, they found that SCC and highgrade tumor showed a lower expression of miR-451 than adenocarcinoma and low-grade tumor in NSCLC.…”

MicroRNA-451 inhibits neuroblastoma proliferation, invasion and migration by targeting macrophage migration inhibitory factor

“…Furthermore, the present study confirmed MIF as a direct target gene of miR-451, and showed that miR-451 negatively regulated the expression of MIF expression by directly targeting the 3'UTR of MIF mRNA in the NB cells. MIF is considered to be a multifunctional cytokine, secreted by a variety of cells, including macrophages, lymphocytes, eosinophils, epithelial cells and endothelial cells (25). It is predominantly immunoregulatory, serving important roles in inflammation, and in cell-mediated and innate immunity (26)(27)(28).…”

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

“…The proangiogenic factor, PDGFaa, was shown to act as a survival factor, to inhibit apoptosis, to increase vessel density [45], and to stimulate reorganization of actin [46]. The pro-inflammatory factor, MIF, was shown to promote metastases by (i) initiating the NF-ĸB signaling cascade resulting in the secretion of pro-inflammatory cytokines such as IL-8, TNF-α, IL-1, and IL-6 ,(ii) promoting MMPs activity, (iii) increasing tumor-infiltration of myeloid-derived suppressor cells [47][48], (iv) promoting EMT [49], and (v) exerting pro-survival [50] and anti-apoptotic activities [51]. Overall, these PT secreted factors are likely to promote metastatic progression in micrometastatic niches, 5 especially when autocrine release of growth supporting factors is insufficient.…”