Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma

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.

MEIS1 knockdown may promote differentiation of esophageal squamous carcinoma cell line KYSE‐30

“…MEIS1 silencing in ESC cell line KYSE‐30 has resulted in overexpression of SOX2 as a stemness factor. Such results may proposed suppressive role of MEIS1 on SOX2 gene expression in ESCC to inhibit stemness state progression (Rad et al, ). It has been illustrated that MEIS1 silencing in mouse embryonic carcinoma suppressed differentiation in neural cells, while its ectopic expression induced differentiation via expression of neural progenitor markers including GLAST, BLBP, SOX1, and Nestin (Yamada, Urano‐Tashiro, Tanaka, Akiyama, & Tashiro, ).…”

“…On the other hand, MEIS1 ectopic expression in gastric cancer (GC) cells not only suppressed critical cancer cell properties including cell proliferation, colony formation, anchorage independent growth, epithelial mesenchymal transition (EMT), migration, and invasion, but also induced apoptosis and cell cycle arrest at G1/S transition in vitro (Song et al, 2017). In addition, an inverse association between MEIS1 and SRY (sex determining region Y)-box 2 (SOX2) in ESCC tumor samples was reported (Rad et al, 2016). MEIS1 silencing in ESC cell line KYSE-30 has resulted in overexpression of SOX2 as a stemness factor.…”

The homeodomain transcription factor MEIS1 triggers chemokine expression and is involved in CD8+ T‐lymphocyte infiltration in early stage ovarian cancer

“…Contrary to its well defined role in leukemias, the impact of MEIS1 on solid tumors is quite ambiguous. For instance, MEIS1 downregulation in esophageal squamous cell carcinoma (ESCC) correlates with metastasis, lymph node involvement, and high tumor stage . Similarly, low MEIS1 expression associates with poor prognosis in prostate cancer, while in non‐small cell lung cancer (NSCLC) cells downregulation of MEIS1 results in increased proliferation and forced overexpression of MEIS1 inhibits cell proliferation .…”

“…For instance, MEIS1 downregulation in esophageal squamous cell carcinoma (ESCC) correlates with metastasis, lymph node involvement, and high tumor stage. 38 Similarly, low MEIS1 expression associates with poor prognosis in prostate cancer, while in increased proliferation and forced overexpression of MEIS1 inhibits cell proliferation. 29,30 On the other hand, MEIS1 is overexpressed in neuroblastoma and required for skin tumorigenesis.…”

Contribution of LATS1 and LATS2 promoter methylation in OSCC development

“…The down-regulation of tumor suppressor genes is preceded through various epigenetic modifications, mutations, loss of heterozygosities and deletions (Perez-Sayans et al 2009). The epigenetic suppression of genes take place through methylation of CpG islands or histone modifications such as methylation of histone 3, lysine 27 (H3K27) (Rad et al 2016).…”