Gene Summary

Gene:MIA; MIA SH3 domain containing
Aliases: CD-RAP
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:melanoma-derived growth regulatory protein
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
MIA is implicated in:
- cell proliferation
- extracellular space
- growth factor activity
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
MelanomaMIA and Melanoma View Publications17

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MIA (cancer-related)

Sasahira T, Bosserhoff AK, Kirita T
The importance of melanoma inhibitory activity gene family in the tumor progression of oral cancer.
Pathol Int. 2018; 68(5):278-286 [PubMed] Related Publications
Oral squamous cell carcinoma has a high potential for locoregional invasion and nodal metastasis. Consequently, early detection of such malignancies is of immense importance. The melanoma inhibitory activity (MIA) gene family comprises MIA, MIA2, transport and Golgi organization protein 1 (TANGO), and otoraplin (OTOR). These members of the MIA gene family have a highly conserved Src homology 3 (SH3)-like structure. Although the molecules of this family share 34-45% amino acid homology and 47-59% cDNA sequence homology, those members, excluding OTOR, play different tumor-associated functions. MIA has a pivotal role in the progression and metastasis of melanoma; MIA2 and TANGO have been suggested to possess tumor-suppressive functions; and OTOR is uniquely expressed in cochlea of the inner ear. Therefore, the definite functions of the MIA gene family in cancer cells remain unclear. Since the members of the MIA gene family are secreted proteins, these molecules might be useful tumor markers that can be detected in the body fluids, including serum and saliva. In this review, we described the molecular biological functions of the MIA gene family in oral cancer.

Uslu U, Schliep S, Schliep K, et al.
Comparison of the Serum Tumor Markers S100 and Melanoma-inhibitory Activity (MIA) in the Monitoring of Patients with Metastatic Melanoma Receiving Vaccination Immunotherapy with Dendritic Cells.
Anticancer Res. 2017; 37(9):5033-5037 [PubMed] Related Publications
BACKGROUND: In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed.
PATIENTS AND METHODS: We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging.
RESULTS: When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression.
CONCLUSION: S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy.

Arnolds O, Zhong X, Tuo Yip K, et al.
NMR-based Drug Development and Improvement Against Malignant Melanoma - Implications for the MIA Protein Family.
Curr Med Chem. 2017; 24(17):1788-1796 [PubMed] Related Publications
The Melanoma Inhibitory Activity (MIA) protein is strongly expressed and secreted by malignant melanoma cells and was shown to promote melanoma development and invasion. The MIA protein was the first extracellular protein shown to adopt an Src homology 3 (SH3) domain-like fold in solution that can bind to fibronectin type III domains. Together with MIA, the homologous proteins OTOR (or FDP), MIA-2, and TANGO (or MIA-3) constitute a protein family of non-cytosolic and - except for fulllength TANGO and TANGO1-like (TALI) - extracellular SH3-domain containing proteins. Members of this protein family modulate collagen maturation and export, cartilage development, cell attachment in the extracellular matrix, and melanoma metastasis. These proteins may thus serve as promising targets for drug development against malignant melanoma. For the last twenty years, NMR spectroscopy has become a powerful technique in medicinal chemistry. While traditional high throughput screenings only report on the activity or affinity of low molecular weight compounds, NMR spectroscopy does not only relate to the structure of those compounds with their activity, but it can also unravel structural information on the ligand binding site on the protein at atomic resolution. Based on the molecular details of the interaction between the ligand and its target protein, the binding affinities of initial fragment hits can be further improved more efficiently in order to generate lead structures that exhibit significant therapeutic effects. The NMR-based approach promises to greatly contribute to the quest for low molecular weight compounds that ultimately could yield drugs to treat skin-related diseases such as malignant melanoma more effectively.

Yip KT, Zhong X, Seibel N, et al.
Human melanoma inhibitory protein binds to the FN12-14 Hep II domain of fibronectin.
Biointerphases. 2017; 12(2):02D415 [PubMed] Free Access to Full Article Related Publications
The heparin binding site (Hep II) of fibronectin plays a major role in tumor cell metastasis. Its interaction with heparan sulfate proteoglycans occurs in a variety of physiological processes including focal adhesion and migration. The melanoma inhibitory activity (MIA) is an important protein that is functionally involved in melanoma development, progression, and tumor cell invasion. After its secretion by malignant melanoma cells, MIA interacts with fibronectin and thereby actively facilitates focal cell detachment from surrounding structures and strongly promotes tumor cell invasion and the formation of metastases. In this report, the authors have determined the molecular basis of the interaction of MIA with the Hep II domain of fibronectin based on nuclear magnetic resonance spectroscopic binding assays. The authors have identified the type III modules 12 to 14 of fibronectin's Hep II as the major MIA binding sites. These results now provide a new target protein-protein binding interface for the discovery of novel antimetastatic agents against malignant melanoma in the future.

Thean LF, Wong YH, Lo M, et al.
Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients.
PLoS One. 2017; 12(3):e0173772 [PubMed] Free Access to Full Article Related Publications
Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3'UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms.

Nikolin B, Djan I, Trifunovic J, et al.
MIA, S100 and LDH as important predictors of overall survival of patients with stage IIb and IIc melanoma.
J BUON. 2016 May-Jun; 21(3):691-7 [PubMed] Related Publications
PURPOSE: Melanoma represents the most severe form of skin cancer. Detection of specific tumor markers is an important step in disease diagnosis and treatment, contributing to personalized therapy. The purpose of this study was to evaluate the potential of MIA, S-100 and LDH as biomarkers for the estimation of overall survival and disease-free survival rate in patients with stage IIa, IIb vs stage IIc melanoma.
METHODS: Selected biomarkers MIA, S-100 and LDH were prospectively evaluated in 80 patients with melanoma. Patients were divided in two groups according to tumor thickness. The first group (group A) consisted of patients with primary tumor thickness between 2.0 - 4.0 mm (N=40), i.e. IIa and IIb stage of disease (16 males; 40%, and 24 females; 60%). The second group (group B) consisted of 40 patients with primary tumor thickness over 4.0 mm, i.e. IIc stage, which is considered as high risk group (26 males; 65%, and 14 females 35%). Statistical analyses were performed to estimate overall survival and disease-free survival in both patient groups.
RESULTS: In group A a significant difference in overall survival was found among MIA1, MIA2 and MIA3 scores, while the other 2 markers didn't show significant differences. In group B statistically significant differences in overall survival were found regarding all three biomarkers. Statistically significant differences in disease-free survival were found for MIA1 score compared to MIA2 and MIA3 scores. Also, very significant difference was detected in patients with S-100 below 0.106 and above 0.106. The same was confirmed for normal and increased LDH level in group B for disease-free survival.
CONCLUSION: MIA score, S100 protein and LDH in the IIC group B patients might be useful in the prediction of overall survival and disease free survival.

Sasahira T, Kirita T, Nishiguchi Y, et al.
A comprehensive expression analysis of the MIA gene family in malignancies: MIA gene family members are novel, useful markers of esophageal, lung, and cervical squamous cell carcinoma.
Oncotarget. 2016; 7(21):31137-52 [PubMed] Free Access to Full Article Related Publications
Melanoma inhibitory activity (MIA) gene family members include MIA, MIA2, and Transport and Golgi organization protein 1 (TANGO). Although MIA gene family members have several tumor-related functions, their detailed roles in malignancies remain poorly elucidated. In this study, 477 tumor specimens were subjected to immunohistochemical screening to evaluate MIA gene family expression. For a validation analysis, we also examined the association between MIA gene family expression and clinicopathological factors in 66 cases of esophageal cancer, 145 cases of lung cancer, and 126 cases of cervical cancer. The frequency of MIA gene family expression was higher among squamous cell carcinomas than among other tumor types subjected to screening. In the validation analysis, MIA gene family staining was observed frequently in esophageal and lung cancers associated with nodal and/or distant metastasis. In cervical cancers, MIA and TANGO immunostaining also correlated with tumor progression and metastasis. Furthermore, MIA2 expression levels in invasive cervical cancer were upregulated relative to those in cervical intraepithelial neoplasia 3. A disease-free survival analysis revealed that MIA-, MIA2, or TANGO-positive patients had a significantly shorter disease-free survival than did those patients who were negative. Our results suggest that MIA, MIA2, and TANGO may be useful diagnostic and therapeutic molecular targets in human malignancies.

Sasahira T, Nishiguchi Y, Fujiwara R, et al.
Storkhead box 2 and melanoma inhibitory activity promote oral squamous cell carcinoma progression.
Oncotarget. 2016; 7(18):26751-64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Storkhead box protein 2 (STOX2) is a transcriptional factor associated with pre-eclampsia with fetal growth restriction. We recently reported that melanoma inhibitory activity (MIA) promotes oral squamous cell carcinoma (OSCC) progression. However, the relationship between STOX2 and MIA remains unknown in malignancies.
METHODS: We used immunohistochemistry and PCR to investigate MIA and STOX2 expression in OSCC. We also performed functional analysis in human OSCC cells.
RESULTS: MIA and STOX2 mRNA levels were higher in OSCCs than in normal oral epithelial cells, and upregulation of STOX2 was significantly correlated with overexpression of MIA. Immunostaining for STOX2 was associated with nodal metastasis (P = 0.0002) and MIA expression (P < 0.0001). Furthermore, MIA expression (P = 0.0035) and STOX2 expression (P = 0.0061) were associated with poor outcome in OSCCs. In vitro analysis using OSCC cells revealed that MIA increased expression of STOX2 by paracrine manner. Moreover, STOX2 accelerated OSCC cell growth, invasion, suppressed apoptosis, and enhanced resistance to paclitaxel, cisplatin, and 5-FU.
CONCLUSIONS: Our results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in OSCCs.

Alegre E, Zubiri L, Perez-Gracia JL, et al.
Circulating melanoma exosomes as diagnostic and prognosis biomarkers.
Clin Chim Acta. 2016; 454:28-32 [PubMed] Related Publications
BACKGROUND: Malignant melanoma is an aggressive cancer with an increasing incidence. Exosomes are actively secreted microvesicles, whose characteristics reflect those of the cell they are originated in. The aim of this study was to identify and evaluate the presence of the melanoma biomarkers MIA, S100B and tyrosinase-related protein 2 (TYRP2) in exosomes and their potential clinical utility.
METHODS: Serum samples were obtained from stage IV melanoma patients, melanoma-free patients and healthy controls. Exosomes were precipitated and TYRP2, MIA and S100B concentrations were quantified in serum, exosomes, and exosome-free serum.
RESULTS: Both MIA and S100B were detected in exosomes and correlated significantly with serum concentrations (S100B: r=0.968; MIA: r=0.799; p<0.001). MIA and S100B concentrations in exosomes were significantly higher in melanoma patients than in healthy controls and disease-free patients. However, TYRP2 concentrations in exosomes did not differ between these three groups. ROC curves analysis rendered AUCs for MIA of 0.883 (p<0.01) and of 0.840 for S100B (p<0.01). Patients with exosome MIA concentration higher than 2.5 μg/L showed shorter median survival related to those with lower level (4 versus 11 months; p<0.05).
CONCLUSIONS: MIA and S100B can be detected in exosomes from melanoma patients and their quantification presents diagnostic and prognostic utility.

Odashiro M, Hans Filho G, Pereira PR, et al.
Melanoma inhibitory activity in Brazilian patients with cutaneous melanoma.
An Bras Dermatol. 2015 May-Jun; 90(3):327-32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanoma inhibitory activity is a protein secreted by melanoma cells and has been used as a tumor marker. Increased Melanoma inhibitory activity serum levels are related to metastatic disease or tumor recurrence. Currently there are no studies on Melanoma inhibitory activity and cutaneous melanoma involving Brazilian patients.
OBJECTIVE: To evaluate the performance and feasibility of measuring Melanoma inhibitory activity levels in Brazilian patients with cutaneous melanoma.
METHODS: Blood was obtained from ten patients with proved metastatic cutaneous melanoma (Group 1), 15 patients resected for cutaneous melanoma without metastasis (Group 2) and 5 healthy donors (Group 3). Melanoma inhibitory activity was measured using a commercially available ELISA kit.
RESULTS: There was a statistically significant difference of Melanoma inhibitory activity levels between patients with and without metastasis (p=0.002), and between patients with metastasis and healthy donors (p=0.002). There was no difference between patients without metastasis and healthy donors (p=0.443).
CONCLUSION: Melanoma inhibitory activity is a tumor marker for cutaneous melanoma and the Melanoma inhibitory activity-ELISA test can be easily performed. Patients with metastasis have increased Melanoma inhibitory activity serum levels when compared to patients without metastasis and healthy donors.

Sasahira T, Kirita T, Kuniyasu H
Update of molecular pathobiology in oral cancer: a review.
Int J Clin Oncol. 2014; 19(3):431-6 [PubMed] Related Publications
Head and neck cancer including oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the world. OSCC has a high potential for local invasion and nodal metastasis, and the overall 5-year survival rate has not significantly changed during the past 30 years. Recent research has elucidated the detailed molecular mechanisms of carcinogenesis, tumor progression, and metastasis of OSCC. It is generally accepted that OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens such as alcohol, smoking, viral infections, and inflammation. The molecular mechanisms of carcinogenesis, tumor progression, and metastasis of head and neck cancer have been elucidated by recent advances in molecular biology. However, many unsolved questions remain. In this review, we describe the current molecular biological findings such as human papillomavirus infection, epithelial-mesenchymal transition, microRNA, and our novel molecular pathological findings of OSCC.

Graf SA, Busch C, Bosserhoff AK, et al.
SOX10 promotes melanoma cell invasion by regulating melanoma inhibitory activity.
J Invest Dermatol. 2014; 134(8):2212-2220 [PubMed] Related Publications
The transcription factor SOX10 (SRY (sex determining region Y)-box 10) has a key role in the embryonic development of melanocytes. Recently, it has been suggested that SOX10 is highly relevant for melanoma development and survival. However, the distinct functions and downstream targets of SOX10 in melanoma remain widely unknown. In this study, we inhibited SOX10 via RNA interference in different human melanoma cell lines and found a significantly reduced invasion capacity in vitro and in the chick embryo model. At later time points, SOX10 inhibition reduced proliferation and induced cell death. We identified melanoma inhibitory activity (MIA) as a direct target gene of SOX10, which is an essential protein for melanoma cell migration and invasion. Expression levels of SOX10 and MIA strictly correlated in melanoma cell lines, and SOX10 inhibition reduced MIA expression and promoter activity. Direct binding of SOX10 to the MIA promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. Ectopic expression of MIA in SOX10-inhibited melanoma cells restored the invasion capacity, supporting the hypothesis that MIA is responsible for SOX10-mediated melanoma cell invasion. Our data provide evidence for a critical role of SOX10 in melanoma cell invasion through the regulation of MIA and highlight its role as a therapeutic target in melanoma.

Riechers A, Bosserhoff AK
Melanoma inhibitory activity in melanoma diagnostics and therapy - a small protein is looming large.
Exp Dermatol. 2014; 23(1):12-4 [PubMed] Related Publications
Malignant melanoma is a highly aggressive cancer with a very poor prognosis after the onset of metastasis. We have previously demonstrated that the protein melanoma inhibitory activity (MIA) is involved in the metastasis of and immunosuppression in malignant melanoma. Recently, we further established MIA as a therapeutic target to inhibit metastatic spread in malignant melanoma. We could show that an inhibition of MIA by a synthetic peptide decreased both the number of metastases as well as immunosuppression in a murine model of malignant melanoma. To control recurrence after surgical resection of a primary lesion, it is paramount to have diagnostic tools available that can detect a relapse due to the strong metastatic potential of melanoma. This follow-up is maintained with periodic re-examinations. Due to high cost and the associated radiation exposure, radiology examinations are avoided if possible. The analysis of prognostic markers in patient serum is therefore attractive. In this review, we focus on the quantitative analysis of the MIA protein as a prognostic tool because it has proven to be a useful serum marker for documenting disease progression of malignant melanoma. The MIA quantification assay itself is readily performed using an ELISA kit and common laboratory equipment. Because analysing MIA serum levels in combination with other established markers such as S100B improves their prognostic value, we feel that the quantification of MIA in the serum, among other markers, should be performed as a general standard of care in patients at risk of developing metastatic melanoma.

Sanmamed MF, Fernández-Landázuri S, Rodríguez C, et al.
Relevance of MIA and S100 serum tumor markers to monitor BRAF inhibitor therapy in metastatic melanoma patients.
Clin Chim Acta. 2014; 429:168-74 [PubMed] Related Publications
BRAF V600 mutation has been reported in more than 50% of melanoma cases and its presence predicts clinical activity of BRAF inhibitors (iBRAF). We evaluated the role of MIA, S100 and LDH to monitor iBRAF efficiency in advanced melanoma patients presenting BRAF V600 mutations. This was a prospective study of melanoma patients harboring the BRAF V600 mutation and treated with iBRAF within a clinical trial (dabrafenib) or as part of an expanded access program (vemurafenib). MIA, S100 and LDH were analyzed in serum at baseline, and every 4-6 weeks during treatment. Eighteen patients with melanoma stages IIIc-IV were enrolled with 88.8% of response rate to iBRAF. Baseline concentrations of all the tumor markers correlated with tumor burden. MIA and S100 concentrations decreased significantly one month after the beginning of treatment and, upon progression, their concentrations increased significantly above the minimum levels previously achieved. MIA levels lower than 9 μg/L one month after the beginning of treatment and S100 concentrations lower than 0.1 μg/L at the moment of best response were associated with improved progression-free survival. In conclusion, MIA and S100 are useful to monitor response in melanoma patients treated with iBRAF.

Schmid R, Meyer K, Spang R, et al.
Melanoma inhibitory activity promotes melanoma development through activation of YBX1.
Pigment Cell Melanoma Res. 2013; 26(5):685-96 [PubMed] Related Publications
Melanoma inhibitory activity (MIA), a small soluble secreted protein, is functionally important for progression of malignant melanoma. We recently revealed that p54(nrb) acts as a mediator of MIA action. In this study, we characterize the transcriptional regulation of p54(nrb) by MIA to explain MIA's molecular action. We identified one highly conserved region in the p54(nrb) promoter that is necessary and sufficient for MIA-dependent activation. Functional promoter analysis identified the transcription factor YBX1 as the mediator of MIA activation of p54(nrb) transcription. We screened the genome for further potential MIA-regulated genes carrying the element in their promoter regions. Integrating our sequence data with expression data from human melanomas identified a list of 23 potential MIA-YBX1 targets in melanomas. In summary, we present for the first time effects of MIA on transcriptional regulation. Uncovering new potential downstream effectors working via activation of YBX1 supports the important role of MIA in melanoma.

Henry L, Fabre C, Guiraud I, et al.
Clinical use of p-proteasome in discriminating metastatic melanoma patients: comparative study with LDH, MIA and S100B protein.
Int J Cancer. 2013; 133(1):142-8 [PubMed] Related Publications
Plasmatic proteasome (p-proteasome) has recently been described as a new marker for metastatic melanoma. The objective of this study was to compare the diagnostic and prognostic values of p-proteasome with three other melanoma serological markers: S100B protein, melanoma inhibitory activity protein (MIA) and lactate dehydrogenase (LDH) in the plasma of 121 stage I-IV melanoma patients. Laboratory analyses were performed by standardized ELISA (p-proteasome, MIA), immunoluminometric assay (S100B) and colorimetry (LDH). We found that all markers were relevant for discriminating metastatic from nonmetastatic patients but p-proteasome displayed the highest diagnostic accuracy. P-proteasome and S100B were the most sensitive (58.1%) and p-proteasome and MIA the most specific (98.7 and 100%) in detecting metastatic disease. P-proteasome and S100B had the highest area under receiver operating characteristics curve, 0.811 (95% CI: 0.725-0.897) and 0.822 (95% CI: 0.738-0.906), respectively. These two markers were the best in detecting patients with lymph node metastases. S100B, MIA and LDH diagnostic accuracy was increased when these markers were combined with p-proteasome. As shown with univariate analysis, shorter progression-free and overall survival rates were significantly associated with elevated plasma levels of each markers. The multivariate Cox regression analysis identified p-proteasome as the only independent predictor of a poorer progression-free survival (p = 0.030). In conclusion, this comparative study established that p-proteasome quantification in combination with other melanoma biomarkers is an attractive approach for the biological follow-up of melanoma patients.

Schmidt J, Riechers A, Stoll R, et al.
Targeting melanoma metastasis and immunosuppression with a new mode of melanoma inhibitory activity (MIA) protein inhibition.
PLoS One. 2012; 7(5):e37941 [PubMed] Free Access to Full Article Related Publications
Melanoma is the most aggressive form of skin cancer, with fast progression and early dissemination mediated by the melanoma inhibitory activity (MIA) protein. Here, we discovered that dimerization of MIA is required for functional activity through mutagenesis of MIA which showed the correlation between dimerization and functional activity. We subsequently identified the dodecapeptide AR71, which prevents MIA dimerization and thereby acts as a MIA inhibitor. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy demonstrated the binding of AR71 to the MIA dimerization domain, in agreement with in vitro and in vivo data revealing reduced cell migration, reduced formation of metastases and increased immune response after AR71 treatment. We believe AR71 is a lead structure for MIA inhibitors. More generally, inhibiting MIA dimerization is a novel therapeutic concept in melanoma therapy.

Palmer SR, Erickson LA, Ichetovkin I, et al.
Circulating serologic and molecular biomarkers in malignant melanoma.
Mayo Clin Proc. 2011; 86(10):981-90 [PubMed] Free Access to Full Article Related Publications
The worldwide incidence of malignant melanoma has been increasing during the past decade and is a public health concern because this disease accounts for up to 90% of deaths from cutaneous malignancies. It remains a devastating disease with few therapeutic options once in an advanced stage. Current methods of detection, prognostication, and monitoring of melanoma focus on clinical, morphologic, and histopathologic characteristics of measurable tumor. Although this information provides some insight into disease behavior and outcome, melanoma is still an unpredictable disease. Significant effort has been put into finding an informative serologic biomarker. However, the marker remains elusive, and investigations continue. Using the PubMed database, we reviewed the published literature on serologic melanoma biomarkers and present a synopsis of the extensive investigations that have been performed thus far, provide some insight into why most have failed to become incorporated into routine clinical use, and present an overview of innovative methods currently being explored.

Essler M, Link A, Belloni B, et al.
Prognostic value of [18F]-fluoro-deoxy-glucose PET/CT, S100 or MIA for assessment of cancer-associated mortality in patients with high risk melanoma.
PLoS One. 2011; 6(9):e24632 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To assess the prognostic value of FDG PET/CT compared to the tumor markers S100B and melanoma inhibitory activity (MIA) in patients with high risk melanoma.
METHODS: Retrospective study in 125 consecutive patients with high risk melanoma that underwent FDG PET/CT for re-staging. Diagnostic accuracy and prognostic value was determined for FDG PET/CT as well as for S100B and MIA. As standard of reference, cytological, histological, PET/CT or MRI follow-up findings as well as clinical follow-up were used.
RESULTS: Of 125 patients, FDG PET/CT was positive in 62 patients. 37 (29.6%) patients had elevated S100B (>100 pg/ml) and 24 (20.2%) had elevated MIA (>10 pg/ml) values. Overall specificities for FDG PET/CT, S100B and MIA were 96.8% (95% CI, 89.1% to 99.1%), 85.7% (75.0% to 92.3%), and 95.2% (86.9% to 98.4%), corresponding sensitivities were 96.8% (89.0% to 99.1%), 45.2% (33.4% to 55.5%), and 36.1% (25.2% to 48.6%), respectively. The negative predictive values (NPV) for PET/CT, S100B, and MIA were 96.8% (89.1% to 99.1%), 61.4% (50.9% to 70.9%), and 60.6% (50.8% to 69.7%). The positive predictive values (PPV) were 96.7% (89.0% to 99.1%), 75.7% (59.9% to 86.6%), and 88.0% (70.0% to 95.8%). Patients with elevated S100B- or MIA values or PET/CT positive findings showed a significantly (p<0.001 each, univariate Cox regression models) higher risk of melanoma associated death which was increased 4.2-, 6.5- or 17.2-fold, respectively.
CONCLUSION: PET/CT has a higher prognostic power in the assessment of cancer-associated mortality in melanoma patients compared with S100 and MIA.

Díaz-Lagares A, Alegre E, Arroyo A, et al.
Evaluation of multiple serum markers in advanced melanoma.
Tumour Biol. 2011; 32(6):1155-61 [PubMed] Related Publications
The aim of this retrospective study was to analyse in advanced melanoma the potential tumor markers S-100B, melanoma inhibiting activity protein (MIA) and YKL-40 compared to LDH. Serum levels of S-100B, MIA, LDH and YKL-40 were measured in 110 patients with advanced melanoma (36 in stage IIIB/C and 74 in stage IV), in 66 disease-free patients and in 65 healthy controls. Results show that S-100B, MIA and LDH levels were significantly higher in patients with advanced melanoma than in disease-free patients or healthy controls. The combination of S-100B plus MIA had the best diagnostic sensitivity, and the addition of LDH did not further increase this sensitivity. MIA was an independent prognostic factor of overall survival. Patients with both S-100B and MIA elevated had a significant shorter survival than those with both S-100B and MIA under the cut-off. YKL-40 levels did not differentiate patients with advanced melanoma from controls. We concluded that the combination of MIA plus S-100B showed a better prognostic value in advanced melanoma compared to LDH.

Kolanczyk M, Mautner V, Kossler N, et al.
MIA is a potential biomarker for tumour load in neurofibromatosis type 1.
BMC Med. 2011; 9:82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is a frequent genetic disease characterized by multiple benign tumours with increased risk for malignancy. There is currently no biomarker for tumour load in NF1 patients.
METHODS: In situ hybridization and quantitative real-time polymerase reaction were applied to investigate expression of cartilage-specific genes in mice bearing conditional inactivation of NF1 in the developing limbs. These mice do not develop tumours but recapitulate aspects of NF1 bone dysplasia, including deregulation of cartilage differentiation. It has been recently shown that NF1 tumours require for their growth the master regulator of cartilage differentiation SOX9. We thus hypothesized that some of the cartilage-specific genes deregulated in an Nf1Prx1 mouse model might prove to be relevant biomarkers of NF1 tumours. We tested this hypothesis by analyzing expression of the SOX9 target gene product melanoma-inhibitory activity/cd-rap (MIA) in tumour and serum samples of NF1 patients.
RESULTS: Increased expression of Mia was found in Nf1-deficient cartilage in mice. In humans, MIA was expressed in all NF1-related tumours and its serum levels were significantly higher in NF1 patients than in healthy controls. Among NF1 patients, MIA serum levels were significantly higher in those with plexiform neurofibromas and in those with large number of cutaneous (> 1,000) or subcutaneous (> 100) neurofibromas than in patients without such tumours. Most notably, MIA serum levels correlated significantly with internal tumour burden.
CONCLUSIONS: MIA is a potential serum biomarker of tumour load in NF1 patients which could be useful in following the disease course and monitoring the efficacy of therapies.

Hofmann MA, Schicke B, Fritsch A, et al.
Impact of lymph node metastases on serum level of melanoma inhibitory activity in stage III melanoma patients.
J Dermatol. 2011; 38(9):880-6 [PubMed] Related Publications
Melanoma patients in stage III have a considerable recurrence rate. The 10-year survival in this stage depends on the number and size of affected nodes. Currently, there is no optimal serum marker for early detection of relapse available. The goal of the study was to assess the utility of melanoma inhibitory activity (MIA) serum marker in the follow up and primary diagnosis of stage III melanoma patients. One hundred and thirty-eight melanoma patients in stage III at time of primary diagnosis were analyzed at time of primary diagnosis and during periodical routine follow up both for serum MIA using an enzyme-linked immunosorbent assay and for serum lactate dehydrogenase (LDH). Results were correlated with the positivity of the sentinel lymph node (SLN) and the number of lymph node metastases in the completion lymph node dissection at time of primary diagnosis. During follow up, the overall survival time was assessed using the Kaplan-Meier method in terms of elevated MIA (>12 ng/mL) values. Regarding SLN status, significant differences of MIA values (P = 0.024) and LDH (P = 0.007) were found, both within the normal cut-off. Having lymph node metastases in the completion lymph node dissection, significantly higher MIA values (12.55 ng/mL [±0.48], P < 0.0001) were found. In patients with three or more tumor-positive nodes, MIA values were significantly higher when compared to patients with one or two affected nodes (P = 0.024). In the routine follow-up, stage III patients with an MIA value of more than 12 ng/mL had a five times higher risk for developing recurrences (P < 0.0001). Patients with relapsing disease had a significantly (P < 0.0001) higher mean MIA value (13.76 ng/mL) compared to patients without relapse (7.52 ng/mL). The MIA serum marker can be helpful in patients undergoing lymph node dissection. Furthermore, during follow up, patients showing relapsing diseases can have an elevated MIA value.

Schiffner S, Zimara N, Schmid R, Bosserhoff AK
p54nrb is a new regulator of progression of malignant melanoma.
Carcinogenesis. 2011; 32(8):1176-82 [PubMed] Related Publications
Nuclear RNA-binding protein p54(nrb) and its murine homolog NonO are known to be involved in a variety of nuclear processes including transcription and RNA processing. Melanoma inhibitory activity (MIA) has been shown to play an essential role in the progression of malignant melanoma and to influence melanoma-associated molecules and pathways in the early tumor formation steps. Interestingly, recent studies suggest that MIA is a regulator of p54(nrb). Here, we show that p54(nrb) is strongly expressed and localized in the nucleus of both melanoma cell lines and melanoma tissue samples compared with normal human melanocytes or normal skin, respectively. Furthermore, all tested melanoma cell lines revealed strong p54(nrb) promoter activity. Treatment with MIA-specific small interfering RNAs showed an influence of MIA on p54(nrb) expression on both messenger RNA (mRNA) and protein level. Knockdown of p54(nrb) protein in melanoma cell lines led to reduced proliferation rates and to a strong decrease in their migratory potential. In addition, attachment to laminin and poly-l-lysine was significantly increased. We could identify Connexin-43 (Cx-43) as a downstream target molecule of p54(nrb) as knockdown of p54(nrb) resulted in enhanced Cx-43 mRNA and protein levels. As a confirmation of these findings, melanoma cell lines showed very low Cx-43 expression levels compared with melanocytes. Our results demonstrate that p54(nrb) is highly expressed in malignant melanoma and, as a MIA target molecule, it seems to be involved in the development and progression of malignant melanoma.

Klingenstein A, Haritoglou I, Schaumberger MM, et al.
Receiver operating characteristic analysis: calculation for the marker 'melanoma inhibitory activity' in metastatic uveal melanoma patients.
Melanoma Res. 2011; 21(4):352-6 [PubMed] Related Publications
The serological marker melanoma inhibitory activity (MIA) has been shown to be significantly higher in the serum of patients suffering from metastatic uveal melanoma than in progression-free patients. The objective of this study was to calculate a meaningful receiver operating characteristic (ROC) curve for MIA based on a large patient collective and to find an appropriate threshold value. MIA tumor marker levels of 503 outpatients suffering from uveal melanoma were evaluated using enzyme-linked immunosorbent assay. Fifty-four patients had confirmed metastases and 449 patients showed no overt metastatic disease at the time the blood sample was taken. ROC analysis was performed and the area under the curve (AUC) was calculated. Metastatic patients showed significantly higher MIA levels (median 11.69 ng/ml) than patients in the group without overt metastatic disease (median 6.97 ng/ml) (the Mann-Whitney test, P<0.001). The AUC was 0.84 (95% confidence interval: 0.76-0.91). The ROC resulting from our study can be applied for test comparison by means of AUC. The AUC value of 0.84 for MIA demonstrates the accurate performance of the test. On the basis of this ROC curve, we propose a MIA threshold value for uveal melanoma patients of 8.3 ng/ml (with a corresponding sensitivity of 82% and specificity of 77%, positive predictive value of 0.30 and negative predictive value of 0.97). In patients with higher MIA serum levels, further diagnostics should be initiated.

Kluger HM, Hoyt K, Bacchiocchi A, et al.
Plasma markers for identifying patients with metastatic melanoma.
Clin Cancer Res. 2011; 17(8):2417-25 [PubMed] Free Access to Full Article Related Publications
PURPOSE: With the rising incidence of melanoma, more patients are undergoing surveillance for disease recurrence. Our purpose was to study levels of proteins that might be secreted in the blood of patients with metastatic melanoma that can be used for monitoring these individuals.
METHODS: Genome-wide gene expression data were used to identify abundantly expressed genes in melanoma cells that encode for proteins likely to be present in the blood of cancer patients, based on high expression levels in tumors. ELISA assays were employed to measure proteins in plasma of 216 individuals; 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease split into equal-sized training and test cohorts.
RESULTS: Levels of seven markers, CEACAM (carcinoembryonic antigen-related cell adhesion molecule), ICAM-1 (intercellular adhesion molecule 1), osteopontin, MIA (melanoma inhibitory activity), GDF-15 (growth differentiation factor 15), TIMP-1 (tissue inhibitor of metalloproteinase 1), and S100B, were higher in patients with unresected stage IV disease than in patients with resected stage I/II disease. About 81% of the stage I/II patients in the training set had no marker elevation, whereas 69% of the stage IV patients had elevation of at least one marker (P < 0.0001). Receiver operating characteristic curves for the markers in combination in these two patient populations had an area under curve (AUC) of 0.79 in the training set and 0.8 in the test set. A CART (Classification and Regression Trees) model developed in the training set further improved the AUC in the test set to 0.898.
CONCLUSIONS: Plasma markers, particularly when assessed in combination, can be used to monitor patients for disease recurrence and can compliment currently used lactate dehydrogenase and imaging studies; prospective validation is warranted.

Hendler K, Pe'er J, Kaiserman I, et al.
Trends in liver function tests: a comparison with serum tumor markers in metastatic uveal melanoma (part 2).
Anticancer Res. 2011; 31(1):351-7 [PubMed] Related Publications
AIM: To compare trends in liver function test (LFT) levels over consecutive visits before detection of liver metastasis (LM) from uveal melanoma (UM) with such trends in the serum tumor markers S-100β, melanoma inhibitory activity (MIA), osteopontin (OPN), and tissue polypeptide-specific antigen (TPS).
PATIENTS AND METHODS: Blood was drawn from 32 patients with metastatic UM and 43 disease-free (DF) patients semi-annually for levels of S-100β, MIA, OPN, and TPS. Abdominal ultrasonography (US) and LFTs were used to detect LM. Median LFT levels were calculated at 6-month intervals prior to the clinical detection of LM. Trends in LFT levels over consecutive visits in the groups were compared with trends in the tumor markers for these groups.
RESULTS: Only LDH gave a statistically significant difference between the trends of the metastasis and DF groups (p=0.0041). When calculating the lead time, all of the elevations were non-significant except for gamma glutamyltransferase which showed a statistically significant elevation at time 0, the time of detection of metastasis. LDH showed a rise at 0-6 months before detection, but this was not significant. For the tumor markers, steeper trendlines were shown for the metastasis group for MIA and S-100β, and most of the markers showed a lead time of more than six months, although this was statistically significant only for OPN.
CONCLUSION: Following the dynamics of tumor markers and LFTs may help to find metastatic disease in UM patients before the metastases are detectable by imaging, enabling earlier treatment.

Barak V, Kaiserman I, Frenkel S, et al.
The dynamics of serum tumor markers in predicting metastatic uveal melanoma (part 1).
Anticancer Res. 2011; 31(1):345-9 [PubMed] Related Publications
AIM: To examine the kinetics of the tumor marker levels: osteopontin (OPN), S-100β, melanoma inhibitory activity (MIA) and tissue polypeptide-specific antigen (TPS), and to evaluate their potential for predicting earlier liver metastasis in patients with uveal melanoma (UM).
PATIENTS AND METHODS: Forty-three UM patients who remained disease-free (DF) for at least 10 years, 32 patients with metastatic UM and 53 healthy controls were enrolled. Median and mean levels of the tumor markers OPN, S-100β, MIA and TPS at the time periods of 0-6, 6-12, 12-18, 18-24 and >24 months prior to confirmation of metastasis by liver ultrasound, CT scan and biopsy, served in a box and whiskers analysis and were compared by Students t-test. Trends of changes in marker levels of DF and metastatic UM groups were calculated and compared by ANOVA.
RESULTS: The lead-time for predicting metastasis was: 12-18 months both for OPN (p=0.005) and MIA (p=0.37), for S-100β 18-24 months first increase (p=0.5) followed by a second one 0-6 months (p=0.01) and for TPS 18-24 months (p=0.1). The gradient of the trendlines for the metastatic group was significantly steeper for MIA (p=0.02) and S-100β (p=0.018) than for the DF group and not statistically significant for OPN (p=0.168). For TPS, the trendline was negative. The overall increase in the levels of OPN and S-100β was significant, while for TPS and MIA, it was not.
CONCLUSION: Significant increases in OPN and S-100β levels were demonstrated by a major lead time. Trendlines of the metastasis group were steeper than of the DF group predicting liver metastasis. The routine use of those markers in the follow up of UM patients, can enable earlier diagnosis of liver metastasis and effective therapeutic intervention, with an impact on survival.

Schmidt J, Friebel K, Schönherr R, et al.
Migration-associated secretion of melanoma inhibitory activity at the cell rear is supported by KCa3.1 potassium channels.
Cell Res. 2010; 20(11):1224-38 [PubMed] Related Publications
Malignant melanoma, characterized by invasive local growth and early formation of metastases, is the most aggressive type of skin cancer. Melanoma inhibitory activity (MIA), secreted by malignant melanoma cells, interacts with the cell adhesion receptors, integrins α(4)β(1) and α(5)β(1), facilitating cell detachment and promoting formation of metastases. In the present study, we demonstrate that MIA secretion is confined to the rear end of migrating cells, while in non-migrating cells MIA accumulates in the actin cortex. MIA protein takes a conventional secretory pathway including coat protein complex I (COPI)- and coat protein complex II (COPII)-dependent protein transport to the cell periphery, where its final release depends on intracellular Ca(2+) ions. Interestingly, the Ca(2+)-activated K(+)-channel, subfamily N, member 4 (KCa3.1), known to be active at the rear end of migrating cells, was found to support MIA secretion. Secretion was diminished by the specific KCa3.1 channel inhibitor TRAM-34 and by expression of dominant-negative mutants of the channel. In summary, we have elucidated the migration-associated transport of MIA protein to the cell rear and also disclosed a new mechanism by which KCa3.1 potassium channels promote cell migration.

Sasahira T, Kirita T, Kurihara M, et al.
MIA-dependent angiogenesis and lymphangiogenesis are closely associated with progression, nodal metastasis and poor prognosis in tongue squamous cell carcinoma.
Eur J Cancer. 2010; 46(12):2285-94 [PubMed] Related Publications
We examined the role of angiogenesis/lymphangiogenesis and the relationship between melanoma inhibitory activity (MIA) and angiogenesis or lymphangiogenesis in oral squamous cell carcinoma (OSCC). One hundred and one formalin-fixed, paraffin-embedded specimens of primary OSCC were evaluated for microvessel density (MVD), lymphovessel density (LVD), expression of vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D and MIA. Fresh frozen 18 samples of primary OSCC were further examined for the expression of VEGF, VEGF-C, VEGF-D and MIA protein by enzyme-linked immunosorbent assay (ELISA). In in vitro analysis, we studied the change of VEGF, VEGF-C and VEGF-D expression after MIA siRNA treatment. Higher MVD, LVD and VEGF expression levels were closely associated with tumour progression, nodal metastasis and poor prognosis. Expression levels of VEGF-C and VEGF-D were only related with nodal metastasis. MIA expression was significantly associated with MVD, LVD, VEGF, VEGF-C and VEGF-D expression by immunohistochemistry and ELISA assay. VEGF, VEGF-C, VEGF-D and MIA expression levels of metastatic tongue cancer HSC-3 cells were higher than those with no metastatic HSC-4 cells, and VEGF, VEGF-C and VEGF-D expression levels were decreased by MIA siRNA treatment in both cells. MIA-dependent angiogenesis/lymphangiogenesis might be a useful therapeutic target in progressive and metastatic OSCC.

Dumitraşcu G, Constantin C, Manda G, et al.
Serum markers in skin melanoma--preliminary study.
Roum Arch Microbiol Immunol. 2009 Jul-Sep; 68(3):125-35 [PubMed] Related Publications
Skin melanoma presents the strongest metastatic capacity and the highest mortality rate of all types of skin cancer, being one of the most aggressive forms of human cancer. Although melanoma represents only 4% of skin cancers, it accounts for 80% of skin cancer deaths. The aim of this study was the investigation of two specific serum markers for melanoma: S100B and melanoma inhibitory activity in relation to disease development. The longitudinal study was performed on 51 patients diagnosed with skin melanoma and 72 healthy volunteers. For serum S100B and MIA measurement standard ELISA was used. The serum concentration of S100B was found significantly different from normal values only in patients in stage IV, in contrast to MIA, where significant differences occurred as early as stage II. The dynamics of the studied serum markers was in accordance with the skin melanoma evolution, especially for serum MIA. Only both increased S100B and MIA serum levels can indicate the disease evolution towards advanced stages and appearance of the metastatic processes.

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