Research IndicatorsGraph generated 13 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MIF (cancer-related)
Liu W, Liu SY, He YB, et al.MiR-451 suppresses proliferation, migration and promotes apoptosis of the human osteosarcoma by targeting macrophage migration inhibitory factor.
Biomed Pharmacother. 2017; 87:621-627 [PubMed
] Related Publications
Previous studies have shown that MiR-451 plays an important role in human osteosarcoma carcinogenesis, but the underlying mechanism by which MiR-451 affects the osteosarcoma has not been fully understood. This study intends to uncover the mechanism by which MiR-451 functions as a tumor suppressor. The expression of MiR-451 in osteosarcoma tissues and osteosarcoma cell lines was monitored by real-time PCR. The proliferation ability was examined by MTT and cell cycle assay. The migration and apoptosis of cells were monitored by migration assay and flow cytometry, respectively. Moreover, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was examined by tube formation assay. The effect of MiR-451 on MIF was determined by luciferase assays and Western blot assay. The results showed that MiR-451 expression level was significantly reduced in the osteosarcoma compared with normal bone tissues. Overexpression of MiR-451 significantly attenuated the proliferation and migration, and induced the apoptosis of osteosarcoma cells. Furthermore, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was assayed and the decreased angiogenic ability was detected compared to the controls. Finally, we demonstrated that MiR-451 overexpression inhibited the malignant behavior of osteosarcoma by downregulating MIF. These findings suggest that MiR-451 may act as a tumor suppressor in osteosarcoma. MiR-451 inhibited cell proliferation, migration and angiogenesis and promoted apoptosis of human osteosarcoma cells, at least partially, by inhibiting the expression of MIF. MiR-451/MIF may be a novel therapeutic target in treatment of osteosarcoma.
Han L, Liu B, Jiang L, et al.MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha.
Tumour Biol. 2016; 37(10):13205-13214 [PubMed
] Related Publications
Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERα) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRα), a nuclear receptor overexpressed in ERα negative breast cancer. Targeted inhibition of ERRα by si-RNA increased miR-497 expression while overexpression of ERRα inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRα by binding to the 3'UTR region of ERRα. Luciferase assay and ChIP assay confirmed that ERα directly regulated the transcription of miR-497, suggesting that loss of ERα lowered miR-497 level in ERα negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRα expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERα negative breast cancer. Taken together, our findings suggested that, in ERα negative breast cancer, the low level of ERα reduced miR-497 expression, which promoted ERRα expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.
The aim of the present study was to investigate the expression of c-erbB-2 and macrophage migration inhibitory factor (MIF) in endometrial cancer and to elucidate the significance of the early diagnosis and prognosis of endometrial cancer. The gene copy number of c‑erbB‑2 and MIF was characterized by reverse transcription quantitative polymerase chain reaction and the reactivity was assessed by immunohistochemistry in 70 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. A correlation between age, tumor stage, grade, myometrial invasion and lymph node metastasis was observed. The mRNA expression of c‑erbB‑2 and MIF was high in endometrial carcinoma. The positive expression rate of MIF protein in normal endometrium, atypical hyperplasia and endometrial carcinoma significantly increased along with the degree of aggravation of the disease by 20 (3/15), 45 (9/20) and 70% (35/50), respectively. The positive expression of MIF and c‑erbB‑2 was highest in endometrial cancer and a significantly higher level of protein was observed in tumors at stage I, stage G1, with a depth of myometrial invasion <0.4 cm and no lymph node metastasis. The protein expression of c‑erbB‑2 in endometrial cancer was higher in tumors at the G2‑3 phase, clinical stage III‑IV, lymph node metastasis, and had no association with the depth of myometrial invasion and age. MIF and c‑erbB‑2 were correlated with the occurrence and the development of endometrial cancer, and thus can be used for the early diagnosis and prognosis of endometrial cancer. The present study laid the foundation for identifying new treatments for endometrial cancer.
Huberfeld G, Vecht CJSeizures and gliomas--towards a single therapeutic approach.
Nat Rev Neurol. 2016; 12(4):204-16 [PubMed
] Related Publications
Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.
Lv W, Chen N, Lin Y, et al.Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis.
Cancer Lett. 2016; 375(2):245-55 [PubMed
] Related Publications
Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-κB phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1-dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer.
Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rγ(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.
Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancers without effective targeted therapies. Mifepristone (MIF), a drug regularly used for abortion, has been reported to have anti-tumor activity in multiple hormone-dependent cancers, including luminal type breast cancers. In this study, we showed that MIF suppressed tumor growth of the TNBC cell lines and patient-derived xenografts in NOD-SCID mice. Furthermore, MIF reduced the TNBC cancer stem cell (CSC) population through down-regulating KLF5 expression, a stem cell transcription factor over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Interestingly, MIF suppresses the expression of KLF5 through inducing the expression of miR-153. Consistently, miR-153 decreases CSC and miR-153 inhibitor rescued MIF-induced down-regulation of the KLF5 protein level and CSC ratio. Taken together, our findings suggest that MIF inhibits basal TNBC via the miR-153/KLF5 axis and MIF may be used for the treatment of TNBC.
Wang Z, Xue Y, Wang P, et al.MiR-608 inhibits the migration and invasion of glioma stem cells by targeting macrophage migration inhibitory factor.
Oncol Rep. 2016; 35(5):2733-42 [PubMed
] Related Publications
Glioma stem cells (GSCs) contribute to the malignant biological behavior of these tumors and have also been shown to be resistant to radiation and chemotherapy. Recently, a variety of microRNAs (miRNAs) has been found to present altered expression and to play an important oncogenic role or tumor-suppressive function in cancer stem cells (CSCs). microRNA-608 (miR-608) is one of the newly discovered microRNAs, and its biological functions remain unclear. Human macrophage migration inhibitory factor (MIF) is a well known oncogene associated with tumor recurrence and the poor prognosis of gliomas. In the present study, we found that miR-608 negatively regulated the gene expression of MIF at the post‑transcriptional level and plays a tumor-suppressive role by targeting MIF in GSCs. We found that miR-608 expression was significantly downregulated and the expression levels of the MIF gene and protein showed an increase in the GSCs. miR-608 overexpression significantly attenuated the proliferation, migration and invasion, and induced the apoptosis of GSCs. The dual-luciferase reporter system revealed that the 3'UTR of MIF is a direct target of miR-608, and miR-608 negatively regulates the gene expression of MIF at the post-transcriptional level by targeting its 3'UTR. Furthermore, we demonstrated that miR-608 overexpression inhibited the malignant behavior of GSCs by downregulating MIF. Western blot results showed that the inhibition of MIF resulted in the inactivation of the PI3K/AKT and JNK pathways. These results demonstrate that miR-608 acts as a potential tumor suppressor and provide insight into new therapeutic targets for malignant glioma.
BACKGROUND: As a kind of versatility of cytokines, overexpression of macrophage migration inhibitory factor (MIF) and vascular endothelial growth factor-C (VEGF-C) have been reported in a wide variety of tumors. However, the correlation and mechanism between MIF and VEGF-C are still not clear. As an important signal transduction system, MAPK signaling pathways participate in a variety of biological behavior of cells. The purposes of this study are to study the relationship between MIF and VEGF-C and discuss the role of MAPK signal pathway in the relationship.
METHODS: In this study, we first knocked down the MIF using small interfering RNA (siRNA) and built the stable low expression MIF breast cancer cells (siRNA-MIF-MCF-7) and the negative control cells (siRNA-NC-MCF-7). And then, we evaluated the expression of MIF using Western blot to confirm the effect of transfection. Using real-time fluorescent quantitative polymerase chain reaction and enzyme-linked immunosorbent experiment, we respectively examined the different expression of VEGF-C between siRNA-MIF-MCF-7 and siRNA-NC-MCF-7 and breast cancer cells MCF-7. Moreover, we investigated the expression of p38 MAPK, P-p38 MAPK, p44/42 MAPK, and P-p44/42 MAPK in the three kinds of cells by Western blot to analyze the regulatory mechanism to VEGF-C.
RESULTS: We found that MIF siRNA markedly reduced the expression of MIF. And the expression level of VEGF-C, p38 MAPK, P-p38-MAPK, p44/42-MAPK, and P-p44/42 MAPK in siRNA-MIF-MCF-7 cells had different degree of decrease compared with siRNA-NC-MCF-7 cells and MCF-7 cells.
CONCLUSIONS: These results suggest that MIF can regulate the expression of VEGF-C in breast cancer cells. And its regulatory mechanism may work by activating the MAPK signaling pathway.
Jin Y, Dai ZUSO1 promotes tumor progression via activating Erk pathway in multiple myeloma cells.
Biomed Pharmacother. 2016; 78:264-71 [PubMed
] Related Publications
OBJECTIVE: This study aimed to explore the influence of USO1 on multiple myeloma (MM) cell proliferation and apoptosis and the related molecular mechanism.
METHODS: The expression of USO1 and MIF in MM tissues and cells, normal bone marrow tissues and cells were determined by qRT-PCR and western blot assay. The cell proliferation and apoptosis of MM cells before and after knockdown of USO1 were determined by MTT assay and flow cytometry, respectively. Before and after knockdown of USO1, the expression of the proliferation-related genes cyclin D1, Mcm2 and PCNA in MM cells was determined by qRT-PCR and western blot assay. The protein level of p-Erk1/2 and MIF was determined by western blot assay and ELISA, respectively.
RESULTS: The expression levels of USO1 and MIF in MM tissues and cells were much higher than those in normal bone marrow tissues and cells. Knockdown of USO1 resulted in the inhibited ability of cell proliferation and induced cell apoptosis. The expression of cyclin D1, Mcm2, PCNA and p-Erk1/2 decreased significantly after knockdown of USO1 as well as the decreased MIF secretion.
CONCLUSION: USO1 gene may be a promising target for the therapy of human MM and its diagnosis marker.
The expression and functions of microRNA-451 have been studied in many human cancers. However, up to date, there is no study of microRNA-451 in renal cell carcinoma. In the present study, we aimed to investigate the expression, biological functions and molecular mechanisms of microRNA-451 in renal cell carcinoma. microRNA-451 expression level in renal cell carcinoma tissues and cell lines was measured using quantitative Real-time PCR. By using CCK8 assay, cell migration and invasion assay, we explored the functions of microRNA-451 in renal cell carcinoma. Dual-Luciferase report assay, quantitative Real-time PCR and western blot were performed to explore the molecular mechanisms of microRNA-451 functions in renal cell carcinoma. Functional assays were also performed to explore the effects of endogenous MIF in renal cell carcinoma. In this study, we showed for the first time that microRNA-451 was significantly down-regulated in renal cell carcinomas tissues and cell lines. microRNA-451 expression level was correlated with histological grade and lymph node metastasis. In addition, microRNA-451 inhibited proliferation, migration and invasion of renal cell carcinomas cells. Moreover, MIF was identified as a target of microRNA-451, and down-regulation of MIF could mimic the suppressive functions of microRNA-451 in renal cell carcinomas, suggesting that microRNA-451 might be a novel therapeutic strategy for the treatment of renal cell carcinomas.
Gataullina S, Lemaire E, Wendling F, et al.Epilepsy in young Tsc1(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex.
Epilepsia. 2016; 57(4):648-59 [PubMed
] Related Publications
OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC).
METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin.
RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases.
SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.
Pasqualon T, Lue H, Groening S, et al.Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells.
Biochim Biophys Acta. 2016; 1863(4):717-26 [PubMed
] Related Publications
Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinases involved in this process. Finally, MIF induced the chemotactic migration of A549 cells, wound closure and invasion into matrigel without affecting cell proliferation. These MIF-induced responses were abrogated by heparin or by silencing of syndecan-1. Thus, our study indicates that syndecan-1 on epithelial tumor cells promotes MIF binding and MIF-mediated cell migration. This may represent a relevant mechanism through which MIF enhances tumor cell motility and metastasis.
Pancreatic cancer is one of most aggressive forms of cancer. After clinical detection it exhibits fast metastatic growth. Heat shock protein 27 (HSP27; HSPB1) has been characterized as a molecular chaperone which modifies the structures and functions of other proteins in cells when they are exposed to various stresses, such as chemotherapy. While the administration of gemcitabine, an anti-tumor drug, has been the standard treatment for patients with advanced pancreatic cancer, accumulating evidence shows that HSP27 plays a key role in the chemosensitivity to gemcitabine. In addition, phosphorylated HSP27 induced by gemcitabine has been associated with the inhibition of pancreatic cancer cell growth. In this review, we summarize the role of phosphorylated HSP27, as well as HSP27, in the regulation of chemosensitivity in pancreatic cancer.
Liu G, Xu Z, Hao DMicroRNA‑451 inhibits neuroblastoma proliferation, invasion and migration by targeting macrophage migration inhibitory factor.
Mol Med Rep. 2016; 13(3):2253-60 [PubMed
] Related Publications
Neuroblastoma (NB) is the most prevalent type of extracranial solid tumour in young children. To improve current understanding of the mechanisms, which modulate cancer cell proliferation, invasion and migration, investigations have focused on microRNAs (miRs), a class of small non‑coding RNAs, which post‑transcriptionally regulate gene expression during various crucial cell processes. The present study aimed to investigate the role of miR‑451 in NB. Human NB tissue and adjacent normal tissue were surgically removed, and the expression of miR‑451, and development and pathological characteristics of NB were investigated. The expression of miR‑451 was reduced in the NB tissue, compared with that in the adjacent tissue, and correlations between the reduction in miR‑451 and unfavourable variables included tumour size (P=0.0081), differentiation (P=0.0217), lymph node metastasis (P=0.0489), tumour‑node‑metastasis stage (0.0220) and distant metastases (P=0.0201). Transfection of the SK‑N‑SH and GI‑LA‑N NB cell lines with miR‑451 inhibited cell growth, invasion and migration. Furthermore, the present study demonstrated that macrophage migration inhibitory factor (MIF) was regulated directly by miR‑451 and was a critical mediator of the biological effects of miR‑451 in NB. The re‑expression of MIF markedly reversed the carcinogenic inhibitory property of miR‑451. These data provide a more detailed understanding of the essential role of miR‑451 in NB, which relies on regulation of the expression of MIF.
Interferon gamma (IFN-γ) is the major immune mediator that prevents toxoplasmic encephalitis in murine models. The lack of IFN-γ secretion causes reactivation of latent T. gondii infection that may confer a risk for severe toxoplasmic encephalitis. We analyse the effect of IFN-γ on immune mediator production and parasite multiplication in human nerve cells infected by tachyzoites of two T. gondii strains (RH and PRU). IFN-γ decreased the synthesis of MCP-1, G-CSF, GM-CSF and Serpin E1 in all cell types. It decreased IL-6, migration inhibitory factor (MIF) and GROα synthesis only in endothelial cells, while it increased sICAM and Serpin E1 synthesis only in neurons. The PRU strain burden increased in all nerve cells and in contrast, RH strain replication was controlled in IFN-γ-stimulated microglial and endothelial cells but not in IFN-γ-stimulated neurons. The proliferation of the PRU strain in all stimulated cells could be a specific effect of this strain on the host cell.
Twenty-five years ago marked the publication of the first report describing a functional contribution by the cytokine, macrophage migration inhibitory factor (MIF), to tumor-associated angiogenesis and growth. Since first appearing, this report has been cited 304 times (as of this writing), underscoring not only the importance of this landmark study but also the importance of MIF in tumor neovascularization. Perhaps more importantly, this first link between MIF and stromal cell-dependent tumor angiogenesis presaged the subsequent identification of MIF in mediating protumorigenic contributions to several solid tumor stromal cell types, including monocytes, macrophages, T lymphocytes, NK cells, fibroblasts, endothelial progenitors and mesenchymal stem cells. This retrospective review will broadly evaluate both past and present literature stemming from this initial publication, with an emphasis on cellular sources, cellular effectors, signal transduction mechanisms and the clinical importance of MIF-dependent tumor vascularization.
Macrophage migration inhibitory factor (MIF) is closely associated with tumorigenesis. The present study aimed to investigate the effects of MIF on the proliferation, migration and colony formation of oral squamous cell carcinoma (OSCC), and to quantify the protein expression levels of MIF in OSCC tissue samples. Firstly, small interfering (si)RNA was used to knock down the gene expression of MIF in Tca8113, HN5 and SCC25 OSCC cells. Secondly, proliferation, migration and colony formation of the OSCC cells were determined by MTT, transmigration and colony formation assays, respectively. Western blotting was performed to detect changes in the protein expression levels of the epithelial mesenchymal transition markers, Twist‑related protein 1 (Twist1), matrix metalloproteinase (MMP)‑2 and MMP‑9. Finally, immunohistochemistry was used to examine the protein expression of MIF in OSCC tissue samples. The results demonstrated that siRNA against MIF significantly downregulated the expression levels of MIF in all OSCC cells, and decreased their proliferation and migration ability. Colony formation ability was also inhibited in the OSCC cells following transfection with MIF siRNA. Furthermore, western blotting demonstrated that the protein expression of Twist1 was decreased similarly to those of MIF. The protein expression of MMP‑2 revealed no change, whereas that of MMP‑9 decreased. The protein expression of MIF was detected in OSCC tissue samples with staining predominantly located in the cell membrane and cytoplasm. The present study demonstrated that MIF may be important in the pathogenesis and progression of OSCC, and indicated its potential therapeutic value.
BACKGROUND: Poor 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.
METHODS: Proteomic 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.
RESULTS: The 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.
CONCLUSIONS: Our findings support the role of MIF in tumor aggressiveness and suggest its potential application as a therapeutic target for gallbladder cancer.
Wang K, Liang Q, Wei L, et al.MicroRNA-608 acts as a prognostic marker and inhibits the cell proliferation in hepatocellular carcinoma by macrophage migration inhibitory factor.
Tumour Biol. 2016; 37(3):3823-30 [PubMed
] Related Publications
Human hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Research on HCC has recently focused on microRNAs (miRNAs) that play crucial roles in cancer development and progression of HCC. In this study, we aimed to analyze the expression and function of a metastasis-associated microRNA-608 (miR-608) in HCC. Samples of human HCC and matched adjacent normal tissues were surgically removed, and miR-608 expression and the pathological characteristics of HCC were investigated. In this study, we found that miR-608 expression was significantly reduced in HCC and its expression levels were highly associated with tumor size, differentiation, clinical stage, and overall and disease-free survival of HCC. Overexpression of miR-608 in HCC cell lines HepG2 and SK-Hep-1 inhibited cell proliferation by G1 arrest. Macrophage migration inhibitory factor (MIF), a potential target gene of miR-608, was inversely correlated with miR-608 expression in HCC tissues and cell lines. Furthermore, we demonstrated that MIF was directly regulated by miR-608 and the restoration of MIF expression reversed the inhibitory effects of miR-608 on HCC cell proliferation. Taken together, these findings collectively demonstrate that miR-608 exerts its anti-cancer function by directly targeting MIF in HCC, indicating a potential novel prognostic biomarker and therapeutic target for HCC.
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine involved in many cellular processes and in particular carcinogenesis. Here, we review the experimental and clinical published data on MIF and its pathways in breast cancer. Experimental data show that MIF is overexpressed in breast cancer cells (BCC) due, at least partly, to its stabilization by HSP90 and upregulation by HIF-1α. MIF interacts with its main receptor CD74 and its co-receptor CXCR-4, both overexpressed, promoting cell survival by PI3K/Akt activation, a possible link with EGFR and HER2 pathways and inhibition of autophagy. Besides these auto- and paracrine effects on BCC, MIF interacts with BCC microenvironment by several mechanisms: immunomodulation by increasing the prevalence of immune suppressive cells, neo-angiogenesis by its link to HIF-1, and finally BCC transendothelial migration. Clinical studies show higher levels of MIF in breast cancer patients serum compared to healthy volunteers but without obvious clinical significance. In breast cancer tissue, MIF and CD74 are overexpressed in the cancer cells and in the stroma but correlations with classical prognostic factors or survival are elusive. However, an inverse correlation with the tumor size for stromal MIF and a positive correlation with the triple receptor negative tumor status for stromal CD74 seem to be showed. This set of experimental and clinical data shows the involvement of MIF pathways in breast carcinogenesis. Several anti-MIF targeted strategies are being explored in therapeutic goals and should merit further investigations.
Zhang M, Yan L, Kim JAModulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment.
Cancer Gene Ther. 2015; 22(10):463-74 [PubMed
] Related Publications
Macrophage migration inhibitory factor (MIF) has been identified as a major gene product upregulated in breast cancer cells-tissues upon the accumulation of macrophages. However, regulatory role of MIF in tumor microenvironment is not well understood. Previously, we have developed small interfering RNA (siRNA)-loaded nanoparticle system to effectively reduce MIF expression in both breast cancer cells and macrophages. Using this nanoparticle system, in this study we demonstrated that the siRNA-induced MIF reduction in murine mammary cancer line 4T1 and human breast cancer line MDA-MB-231 resulted in significant reduction of cell proliferation and increase of apoptosis; the siRNA-induced MIF reduction in tumor-associated macrophages resulted in a significant reduction of surface expression of CD74 and CD206 and a significant increase of surface expression of major histocompatibility complex II, as well as intracellular expression of tumor necrosis factor-α and interleukin-2. A direct injection of the MIF-siRNA-loaded nanoparticles into 4T1 tumor in mice resulted in effective reduction of intratumoral MIF. This led to a reduction of tumor growth and metastasis. This also resulted in a reduction of circulating myeloid-derived suppressive cells both in number and in suppressive function. CD4 T-cell infiltration to tumor was increased. More importantly, this not only slowed the growth of treated 4T1 tumor, but also delayed the growth and metastasis of a contralateral untreated 4T1-luc tumor, suggesting the development of systemic antitumor responses. This study demonstrates for the first time that the siRNA-mediated intratumoral MIF reduction can induce antitumoral immune response via reducing systemic immune suppression.
AIM: To investigate macrophage migration inhibitory factor (MIF) expression and its clinical relevance in gastric cancer, and effects of MIF knockdown on proliferation of gastric cancer cells.
METHODS: Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry (IHC) semiquantitatively, and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Two pairs of siRNA targeting the MIF gene (MIF si-1 and MIF si-2) and one pair of scrambled siRNA as a negative control (NC) were designed and chemically synthesized. All siRNAs were transiently transfected in AGS cells with Oligofectamine(TM) to knock down the MIF expression, with the NC group and mock group (Oligofectamine(TM) alone) as controls. At 24, 48, and 72 h after transfection, MIF mRNA was analyzed by RT-PCR, and MIF and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot. The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium (MTT) assay and colony forming assay.
RESULTS: The tissue microarray was informative for IHC staining, in which the MIF expression in gastric cancer tissues was higher than that in adjacent non-cancer normal tissues (P < 0.001), and high level of MIF was related to poor tumor differentiation, advanced T stage, advanced tumor stage, lymph node metastasis, and poor patient survival (P < 0.05 for all). After siRNA transfection, MIF mRNA was measured by real-time PCR, and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group, MIF expression was knocked down successfully in gastric cancer cells, and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection, and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific siRNA compared with the control siRNA and mock groups (P < 0.001 for all).
CONCLUSION: MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.
Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2(-/-) mouse embryonic fibroblasts, Pten(-/-) mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knock-out mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-κB. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-κB-BEX2-VEGF signaling pathway contributes to hyperactive mTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway.
Hypoxia-inducible factor 1α (HIF1α) is a transcription factor that regulates the adaptation of cells to hypoxic microenvironments, for example inside solid tumours. Stabilisation of HIF1α can also occur in normoxic conditions in inflamed tissue or as a result of inactivating mutations in negative regulators of HIF1α. Aberrant overexpression of HIF1α in many different cancers has led to intensive efforts to develop HIF1α-targeted therapies. However, the role of HIF1α is still poorly understood in chronic inflammation that predisposes the colon to carcinogenesis. We have previously reported that the transcription of HIF1α is upregulated and that the protein is stabilised in inflammatory lesions that are caused by the non-steroidal anti-inflammatory drug (NSAID) sulindac in the mouse proximal colon. Here, we exploited this side effect of long-term sulindac administration to analyse the role of HIF1α in colon inflammation using mice with a Villin-Cre-induced deletion of Hif1α exon 2 in the intestinal epithelium (Hif1α(ΔIEC)). We also analysed the effect of sulindac sulfide on the aryl hydrocarbon receptor (AHR) pathway in vitro in colon cancer cells. Most sulindac-treated mice developed visible lesions, resembling the appearance of flat adenomas in the human colon, surrounded by macroscopically normal mucosa. Hif1α(ΔIEC) mice still developed lesions but they were smaller than in the Hif1α-floxed siblings (Hif1α(F/F)). Microscopically, Hif1α(ΔIEC) mice had significantly less severe colon inflammation than Hif1α(F/F) mice. Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1α(ΔIEC) mice. However, immunohistochemistry analysis revealed a defect of E-cadherin protein expression in sulindac-treated Hif1α(ΔIEC) mice. Sulindac sulfide treatment in vitro upregulated Hif1α, c-JUN and IL8 expression through the AHR pathway. Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.
This study aims to investigate the regulative effects of microRNA-451a (miR-451a) on cell proliferation and sensitivity to tamoxifen in breast cancer cells. In cell culture experiments, the lentiviral vectors of pHBLV-miR-451a and pHBLV-miR-451a sponge were constructed and used to transfect MCF-7 and LCC2 cells. The transfection efficiency was tested by fluorescent observation, and cell lines with stable over- or downregulated expression of miR-451a were established. The expression of miR-451a and the target gene macrophage migration inhibitory factor (MIF) were detected by real-time reverse transcriptase polymerase chain reaction and/or western blot. Moreover, MTT assay, colony formation, and Transwell invasion assays were also performed. Data showed that the recombinant lentiviral vectors were constructed correctly, and the virus titer was 1 × 10(8) CFU/mL. The stable transfected cells were obtained. Overexpression of miR-451a downregulated MIF expression in mRNA and protein levels and inhibited cell proliferation, colony formation, and invasion of breast cancer cells. Downregulation of miR-451a upregulated MIF expression and increased breast cancer cell growth, invasion, and tamoxifen sensitivity. In summary, the miR-451a/MIF pathway may play important roles in the biological properties of breast cancer cells and may be a potential therapeutic target for breast cancer.
The profiling of cancer cell secretomes is considered to be a good strategy for identifying cancer-related biomarkers, but few studies have focused on identifying low-molecular-mass (LMr) proteins (<15 kDa) in cancer cell secretomes. Here, we used tricine-SDS-gel-assisted fractionation and LC-MS/MS to systemically identify LMr proteins in the secretomes of five oral cavity squamous cell carcinoma (OSCC) cell lines. Cross-matching of these results with nine OSCC tissue transcriptome datasets allowed us to identify 33 LMr genes/proteins that were highly upregulated in OSCC tissues and secreted/released from OSCC cells. Immunohistochemistry and quantitative real-time PCR were used to verify the overexpression of two candidates, HMGA2 and MIF, in OSCC tissues. The overexpressions of both proteins were associated with cervical metastasis, perineural invasion, deeper tumor invasion, higher overall stage, and a poorer prognosis for post-treatment survival. Functional assays further revealed that both proteins promoted the migration and invasion of OSCC cell lines in vitro. Collectively, our data indicate that the tricine-SDS-gel/LC-MS/MS approach can be used to efficiently identify LMr proteins from OSCC cell secretomes, and suggest that HMGA2 and MIF could be potential tissue biomarkers for OSCC.
Wang CD, Li TM, Ren ZJ, et al.Contribution of Macrophage Migration Inhibitory Factor -173G/C Gene Polymorphism to the Risk of Cancer in Chinese Population.
Asian Pac J Cancer Prev. 2015; 16(11):4597-601 [PubMed
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BACKGROUND: Macrophage migration inhibitory factor (MIF) -173G/C (rs755622) gene polymorphism has been associated with cancer risk. Previous studies have revealed that MIF -173G/C gene polymorphism may increase cancer in the Chinese population, while results of individual published studies remain inconsistent and inconclusive.We performed this meta-analysis to derive a more precise estimation of the relationship.
MATERIALS AND METHODS: We conducted a search on PubMed, Embase, MEDLINE, Cochrane Library ,Chinese National Knowledge Infrastructure (CNKI), Wanfang, Weipu on Dec 31, 2014.Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. A total of eight studies including 2,186 cases and 2,285 controls were involved in this meta-analysis.
RESULTS: The pooled results indicated the significant association between MIF -173G/C polymorphism and the risk of cancer for Chinese population (CC + CG vs GG: OR=1.14, 95%CI=1.02-127, pheterogeneity<0.01; P =0.023; CC vs CG+GG: OR=1.12, 95%CI=1.02- 1.23, pheterogeneity< 001; P =0.017;CC vs GG: OR=1.18, 95%CI=1.04-1.33, pheterogeneity<001; P =0.008; CG vs GG:OR=1.03, 95%CI=0.91-1.15, pheterogeneity<001; P =0.656; C vs G:OR=1.24, 95%CI=1.14-1.25, pheterogeneity<001; P <001). Subgroup analysis showed that in patients with "solid tumors", heterogeneity was very large (OR=0.94,95%CI=0.83-1.06,pheterogeneity=0.044; p=0.297). Within "non-solid tumors", the association became even stronger (OR=6.62, 95 % CI=4.32-10.14, pheterogeneity<0.001; p <0.001).
CONCLUSIONS: This study suggested that MIF ?173G/C gene polymorphism may increase increase cancer in the Chinese population.Furthermore, more larger sample and representative population-based casees and well-matched controls are needed to validate our results.
Melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. IFN-γ produced by immune cells has a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including IL-6, IL-8, and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ-stimulatory conditions would be an effective therapeutic approach for melanoma.
Costa-Silva B, Aiello NM, Ocean AJ, et al.Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
Nat Cell Biol. 2015; 17(6):816-26 [PubMed
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Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.