Deletion of macrophage migration inhibitory factor inhibits murine oral carcinogenesis: Potential role for chronic pro‐inflammatory immune mediators

Abstract

Oral cancer kills about 1 person every hour, each day in the United States and is the 6th most prevalent cancer worldwide. The pro-inflammatory cytokine ‘macrophage migration inhibitory factor’ (MIF) has been shown to be expressed in oral cancer patients, yet its precise role in oral carcinogenesis is not clear. In this study, we examined the impact of global Mif deletion on the cellular and molecular process occurring during oral carcinogenesis using a well-established mouse model of oral cancer with the carcinogen 4-nitroquinoline-1-oxide (4NQO). C57BL/6 Wild-type (WT) and Mif knock-out mice were administered with 4NQO in drinking water for 16 weeks, then regular drinking water for 8 weeks. Mif knock-out mice displayed fewer oral tumor incidence and multiplicity, accompanied by a significant reduction in the expression of pro-inflammatory cytokines Il-1β, Tnf-α, chemokines Cxcl1, Cxcl6 and Ccl3 and other molecular biomarkers of oral carcinogenesis Mmp1 and Ptgs2. Further, systemic accumulation of myeloid-derived tumor promoting immune cells was inhibited in Mif knock-out mice. Our results demonstrate that genetic Mif deletion reduces the incidence and severity of oral carcinogenesis, by inhibiting the expression of chronic pro-inflammatory immune mediators. Thus, targeting MIF is a promising strategy for the prevention or therapy of oral cancer.

Tumor-Associated Macrophages in the Development of 4-Nitroquinoline-1-Oxide-Induced Tongue Squamous Cell Carcinoma in a Mouse Model

“…We speculated that the large number of TAMs in human tongue cancer tissue may be an epiphenomenon that reflects an inflamed tumor microenvironment in which many types of immune cells can be found [20] , and that an animal SCC model like the 4NQO-treated mouse may be less associated with inflammation. Deletion of the expression of a proinflammatory cytokine, macrophage migration inhibitory factor, reduces the incidence and severity of oral carcinogenesis by inhibiting the expression of inflammatory cytokines and the infiltration of tumor-promoting immune cells in the same 4NQO mouse model as the one we used [21] . We consider that the absence of macrophage migration inhibitory factor might cause a decrease in tumor-promoting immune cells other than TAMs, such as regulatory T cells [9,22] , and that, at the least, TAMs are not an essential factor for carcinogenesis of the tongue in these 4NQO-treated mice.…”

Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC

“…In addition to mounting an effective immune response at the tumor site, our data highlights the importance of an appropriate anti-tumor immune response at the sentinel lymph node, in order to prevent the seeding and establishment of HNSCC cells at metastatic sites (47,48). It is now well known that lymphatic metastasis is an active process, which is regulated at several steps.…”

Identification and Validation of Novel Long Non-coding RNA Biomarkers for Early Diagnosis of Oral Squamous Cell Carcinoma

“…We retrospectively collected a total of 262 samples from three publicly available datasets from the Gene Expression Omnibus (GEO) database, 1 including 167 OSCC samples and 45 normal oral tissues from GSE30784 dataset 2 (Chen et al, 2008), 26 OSCC samples and 12 control samples from GSE9844 dataset 3 (Ye et al, 2008), and six OSCC samples and six adjacent non-involved oral tissue from GSE74530 dataset 4 (Oghumu et al, 2016). The largest sample dataset GSE30784 was used as a discovery dataset and the other two datasets were used as independent testing datasets.…”