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Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma

  • Original Article
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Tumor Biology

Abstract

The three amino acid loop extension (TALE) class myeloid ecotropic viral integration site 1 (MEIS1) homeobox gene is known to play a crucial role in normal and tumor development. In contrast with its well-described cancer stemness properties in hematopoietic cancers, little is known about its role in solid tumors like esophageal squamous cell carcinoma (ESCC). Here, we analyzed MEIS1 expression and its clinical relevance in ESCC patients and also investigated its correlation with the SOX2 self-renewal master transcription factor in the ESCC samples and in the KYSE-30 ESCC cell line. MEIS1 mRNA and protein expression were significantly decreased in ESCC disease (P < 0.05). The inverse correlation between MEIS1 mRNA expression and tumor cell metastasis to the lymph nodes (P = 0.004) was significant. Also, MEIS1 protein levels inversely correlated to lymph node involvement (P = 0.048) and high tumor stage (stages III/IV, P = 0.030). The low levels of DNA methylation in the MEIS1 promoter showed that this suppression does not depend on methylation. We showed that downregulation of EZH2 restored MEIS1 expression significantly. Also, we investigated that MEIS1 downregulation is concomitant with increased SOX2 expression. To the best of our knowledge, this is the first report on the MEIS1 gene in ESCC. The inverse correlation of MEIS1 with metastasis, tumor staging, and the role of EZH2 in methylation, together with its correlation with stemness factor SOX2 expression, led us to predict cancer stemness properties for MEIS1 in ESCC.

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Abbreviations

EC:

Esophageal carcinoma

ESCC:

Esophageal squamous cell carcinoma

ESC:

Embryonic stem cells

CSC:

Cancer stem cell

MEIS1:

Myeloid ecotropic viral integration site 1

MLL:

Myeloid/lymphoid or mixed lineage leukemia

MSP-PCR:

Methylation-specific PCR

LSC:

Leukemia stem cell

PBX:

Pre-B cell leukemia homeobox

TALE:

Three amino acid loop extension

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Acknowledgments

The authors gratefully acknowledge the scientific and technical support of colleagues at the Division of Human Genetic, Avicenna Research Institute (Mashhad University) and the Department of Biology, Ferdowsi University of Mashhad. In addition, we thank Dr. Heydar Parsaee (Department of Pharmacology, Mashhad University) and Dr. Thomas Mikeska (Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia) for their technical assistances. This study was a MSc thesis and supported by a grant from Mashhad University of Medical Sciences (# 89751).

Conflict of interest

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved beforehand by the local Ethics Committee. Informed, declared consent was obtained from all individual participants included in the study, and is on record. This article does not contain any studies with animals performed by any of the authors.

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Authors and Affiliations

  1. Department of Biochemistry and Nutrition, Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran

    Abolfazl Rad

  2. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Abolfazl Rad, Azadeh A’rabi & Mohammad Reza Abbaszadegan

  3. Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

    Moein Farshchian, Maryam M. Matin & Ahmad Reza Bahrami

  4. Molecular Medicine Research Department, ACECR-Khorasan Razavi branch, Mashhad, Iran

    Moein Farshchian

  5. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran

    Mohammad Mahdi Forghanifard

  6. Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Dirk Geerts

  7. Department of Pathology, Omid Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

    Bahram Memar

  8. Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Reza Abbaszadegan

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  1. Abolfazl Rad
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Correspondence to Mohammad Reza Abbaszadegan.

Additional information

Abolfazl Rad and Moein Farshchian contributed equally to this work.

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Supplemental Figure 1

SOX2 mRNA detection in 50 ESCC and matched adjacent non-tumoral tissue samples. SOX2 mRNA expression is higher in tumor than in adjacent non-tumoral tissue, but this difference does not reach significance. SOX2 mRNA expression was determined with qRT-PCR, with GAPDH as the reference gene. Shown are the 2log median centered mean values, the error bars represent the SD. A two-sided t-test was used to assess the statistical difference between ESCC and adjacent non-tumoral tissue. (TIFF 329 kb)

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Rad, A., Farshchian, M., Forghanifard, M.M. et al. Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma. Tumor Biol. 37, 1715–1725 (2016). https://doi.org/10.1007/s13277-015-3780-9

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  • DOI: https://doi.org/10.1007/s13277-015-3780-9

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