Macrophage migration inhibitory factor - a therapeutic target in gallbladder cancer

Abstract

BackgroundPoor prognosis in gallbladder cancer is due to late presentation of the disease, lack of reliable biomarkers for early diagnosis and limited targeted therapies. Early diagnostic markers and novel therapeutic targets can significantly improve clinical management of gallbladder cancer.MethodsProteomic analysis of four gallbladder cancer cell lines based on the invasive property (non-invasive to highly invasive) was carried out using the isobaric tags for relative and absolute quantitation labeling-based quantitative proteomic approach. The expression of macrophage migration inhibitory factor was analysed in gallbladder adenocarcinoma tissues using immunohistochemistry. In vitro cellular assays were carried out in a panel of gallbladder cancer cell lines using MIF inhibitors, ISO-1 and 4-IPP or its specific siRNA.ResultsThe quantitative proteomic experiment led to the identification of 3,653 proteins, among which 654 were found to be overexpressed and 387 were downregulated in the invasive cell lines (OCUG-1, NOZ and GB-d1) compared to the non-invasive cell line, TGBC24TKB. Among these, macrophage migration inhibitory factor (MIF) was observed to be highly overexpressed in two of the invasive cell lines. MIF is a pleiotropic proinflammatory cytokine that plays a causative role in multiple diseases, including cancer. MIF has been reported to play a central role in tumor cell proliferation and invasion in several cancers. Immunohistochemical labeling of tumor tissue microarrays for MIF expression revealed that it was overexpressed in 21 of 29 gallbladder adenocarcinoma cases. Silencing/inhibition of MIF using siRNA and/or MIF antagonists resulted in a significant decrease in cell viability, colony forming ability and invasive property of the gallbladder cancer cells.ConclusionsOur findings support the role of MIF in tumor aggressiveness and suggest its potential application as a therapeutic target for gallbladder cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1855-z) contains supplementary material, which is available to authorized users.

Prognostic significance of macrophage migration inhibitory factor expression in cancer patients

“…[ 4 ] Recent studies showed that MIF is overexpressed in many solid cancers and is closely related in the tumor cell proliferation, angiogenesis and tumorigenesis. [ 3 , 5 , 6 ] Moreover, the overexpression of MIF has been associated to tumor progression, metastasis and unfavorable prognosis in gastric, hepatocellular, pancreatic, and lung cancers, and oral squamous cell carcinoma and metastatic melanoma. [ 3 , 7 , 8 ]…”

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

“…Moreover, recent studies imply that MIF could be closely involved in the cell proliferation, angiogenesis and tumorigenesis by activating the MAPK/PI3K/Akt pathways . MIF has been reported to be overexpressed in various cancers, including gastric, esophageal, colorectal, liver, pancreatic, ovarian, breast and prostate cancers . Furthermore, MIF overexpression has been found to be related to a poor prognosis in hepatocellular carcinoma, oral squamous cell carcinoma, metastatic melanoma and pancreatic ductal adenocarcinoma …”

“…6,[8][9][10][11] MIF has been reported to be overexpressed in various cancers, including gastric, esophageal, colorectal, liver, pancreatic, ovarian, breast and prostate cancers. 12,13 Furthermore, MIF overexpression has been found to be related to a poor prognosis in hepatocellular carcinoma, oral squamous cell carcinoma, metastatic melanoma and pancreatic ductal adenocarcinoma. 14 However, the exact role of MIF is not clearly understood in SCC of the lung.…”

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

“…Numerous preclinical and clinical studies have demonstrated that MIF is overexpressed and may correlate with tumor aggressiveness in many different types of human cancers such as prostate , bladder, and kidney cancer [30], cervical cancer [20], ovarian cancer [44,45], breast cancer [29], gastric cancer [29], hepatocellular carcinoma [46], colon cancer [47,48], pancreatic cancer [49,50], gallbladder cancer [51], lung cancer [29,52], melanoma [31], head and neck cancer [29], acute myeloid leukemia [53,54], glioblastoma [15,55,56], and NB [57][58][59][60]. Moreover, elevated MIF expression is correlated with a worse patient overall survival in a large variety of cancers such as breast cancer [29], gastric cancer [29], hepatocellular carcinoma [61], pancreatic cancer [49,50], metastatic melanoma [31], head and neck cancer [29], esophageal squamous cell carcinoma [62], acute myeloid leukemia [53], glioblastoma [29,56], and NB [57].…”