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BMC Cancer. 2015 Nov 4;15:843. doi: 10.1186/s12885-015-1855-z.

Macrophage migration inhibitory factor - a therapeutic target in gallbladder cancer.

Author information

1
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. tejaswini@ibioinformatics.org.
2
Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. tejaswini@ibioinformatics.org.
3
Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile. pamela.leal@ufrontera.cl.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pamela.leal@ufrontera.cl.
5
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mustafa@jhmi.edu.
6
Adrienne Helis Malvin Research Foundation, New Orleans, LA, 70130, USA. mustafa@jhmi.edu.
7
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. remya@ibioinformatics.org.
8
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. santosh4ever@gmail.com.
9
Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. santosh4ever@gmail.com.
10
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. gajanan@ibioinformatics.org.
11
Manipal University, Madhav Nagar, Manipal, 576104, India. gajanan@ibioinformatics.org.
12
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. sneha@ibioinformatics.org.
13
YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India. sneha@ibioinformatics.org.
14
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. nazia@ibioinformatics.org.
15
Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India. nazia@ibioinformatics.org.
16
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. vishalakshi@ibioinformatics.org.
17
Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. vishalakshi@ibioinformatics.org.
18
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. arun@ibioinformatics.org.
19
School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India. arun@ibioinformatics.org.
20
Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), CITO, Pontificia Universidad Católica de Chile, Santiago, Chile. pgarciam@uc.cl.
21
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. nandinipatankar@gmail.com.
22
Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. bipin@am.amrita.edu.
23
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. rguerre3@jhmi.edu.
24
Lab Surgpath, Mumbai, 400034, India. sanjay.hpr@gmail.com.
25
Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior, 474011, India. pk_tiwari@hotmail.com.
26
School of Studies in Zoology, Jiwaji University, Gwalior, India. pk_tiwari@hotmail.com.
27
Department of Pathology, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India. vani.santosh@gmail.com.
28
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. dsidrans@jhmi.edu.
29
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. keshav@ibioinformatics.org.
30
Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. keshav@ibioinformatics.org.
31
YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India. keshav@ibioinformatics.org.
32
NIMHANS-IOB Proteomics and Bioinformatics Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India. keshav@ibioinformatics.org.
33
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. harsha@ibioinformatics.org.
34
YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India. harsha@ibioinformatics.org.
35
Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), CITO, Pontificia Universidad Católica de Chile, Santiago, Chile. jcroas@gmail.com.
36
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pandey@jhmi.edu.
37
Departments of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pandey@jhmi.edu.
38
Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pandey@jhmi.edu.
39
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pandey@jhmi.edu.
40
Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. aditi@ibioinformatics.org.
41
Manipal University, Madhav Nagar, Manipal, 576104, India. aditi@ibioinformatics.org.
42
YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India. aditi@ibioinformatics.org.

Abstract

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.

PMID:
26530123
PMCID:
PMC4632274
DOI:
10.1186/s12885-015-1855-z
[Indexed for MEDLINE]
Free PMC Article

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