Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma
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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.
KeywordsESCC Downregulation MEIS1 SOX2
Esophageal squamous cell carcinoma
Embryonic stem cells
Cancer stem cell
Myeloid ecotropic viral integration site 1
Myeloid/lymphoid or mixed lineage leukemia
Leukemia stem cell
Pre-B cell leukemia homeobox
Three amino acid loop extension
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
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.
- 4.Sadjadi A, Marjani H, Semnani S, Nasseri-Moghaddam S. Esophageal cancer in Iran: a review. Middle East J Cancer. 2010;1:11–20.Google Scholar
- 20.Forghanifard MM, Khales SA, Javdani-Mallak A, Rad A, Farshchian M, Abbaszadegan MR. Stemness state regulators SALL4 and SOX2 are involved in progression and invasiveness of esophageal squamous cell carcinoma. Med Oncol. 2014;31:1–8.Google Scholar
- 25.Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
- 27.Forghanifard MM, Gholamin M, Farshchian M, Moaven O, Memar B, Forghani MN, et al. Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: Identification of specific tumor marker and potential targets for immunotherapy. Cancer Biol Ther. 2011;12:191–7.CrossRefPubMedGoogle Scholar
- 33.Barde I, Salmon P, Trono D. Production and titration of lentiviral vectors. Curr Protoc Neurosci. 2010;4:4.21.Google Scholar