Rad Abolfazl, Farshchian Moein, Forghanifard Mohammad Mahdi, Matin Maryam M, Bahrami Ahmad Reza, Geerts Dirk, A'rabi Azadeh, Memar Bahram, Abbaszadegan Mohammad Reza
Department of Biochemistry and Nutrition, Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Tumour Biol. 2016 Feb;37(2):1715-25. doi: 10.1007/s13277-015-3780-9. Epub 2015 Aug 28.
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.
已知三氨基酸环延伸（TALE）类髓系嗜亲性病毒整合位点1（MEIS1）同源框基因在正常发育和肿瘤发展中起关键作用。与其在血液系统癌症中已被充分描述的癌症干性特性不同，其在食管癌鳞状细胞癌（ESCC）等实体瘤中的作用知之甚少。在此，我们分析了ESCC患者中MEIS1的表达及其临床相关性，并在ESCC样本和KYSE-30 ESCC细胞系中研究了其与SOX2自我更新主转录因子的相关性。MEIS1 mRNA和蛋白表达在ESCC疾病中显著降低（P<0.05）。MEIS1 mRNA表达与肿瘤细胞向淋巴结转移之间的负相关性显著（P = 0.004）。此外，MEIS1蛋白水平与淋巴结受累呈负相关（P = 0.048），与高肿瘤分期（III/IV期，P = 0.030）呈负相关。MEIS1启动子中低水平的DNA甲基化表明这种抑制不依赖于甲基化。我们表明EZH2的下调显著恢复了MEIS1的表达。此外，我们研究发现MEIS1的下调与SOX2表达增加同时发生。据我们所知，这是关于ESCC中MEIS1基因的首次报道。MEIS1与转移、肿瘤分期的负相关性，EZH2在甲基化中的作用，以及其与干性因子SOX2表达的相关性，使我们预测MEIS1在ESCC中具有癌症干性特性。
