Transcriptional analysis of CXCR4, DNMT3A, DNMT3B and DNMT1 gene expression in primary advanced uterine cervical carcinoma

Abstract

Abstract. The development of cervical cancer requires genetic and epigenetic factors which result in the persistence of a malignant phenotype. Cervical cancer exhibits also some unique differences from other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue with over-expression of HIF-1 (hypoxia-inducible factor-1) transcription factor, which targets the transcription of over 70 genes involved in many aspects of cancer biology. One of the genes, which could be induced by HIF-1 is chemokine (C-X-C motif) receptor 4 (CXCR4). CXCR4 could also be epigenetically regulated by methylation of CpG dinucleotides located in the promoter region. Here, we examined the CXCR4, DNMT3A, DNMT3B and DNMT1 transcript levels in cancer tissue (n=30) and non-cancer, normal uterine cervical tissue (n=30) from a Polish cohort. We also compared the methylation status of CXCR4 promoter region in cancer and normal tissue samples. Our result showed significantly higher levels of CXCR4, DNMT3A, DNMT3B and DNMT1 transcript (p=0.0058, 0.0163, 0.0003 and <0.0001, respectively) levels in cancer tissue as compared to normal samples. We did not observe DNA methylation in the CXCR4 promoter region in either control or cancer tissue samples. CXCR4 has a functional hypoxia response element (HRE) in the promoter region, located -1.3 kb from the transcription start site. Our work shows for the first time that HIF-1A could promote the induction of CXCR4 gene expression (Spearman's correlation coefficient = 0.515, p=0.003) in patients with primary advanced

Epigenetic Silencing of CXCR4 Promotes Loss of Cell Adhesion in Cervical Cancer

“…Similar negative correlations between CXCR4 expression and promoter methylation have been shown in pancreatic cancer [19] and melanoma cells [34]. Our result is contradictory to the previous report of Łuczak et al [18] that CXCR4 promoter is not methylated in CC biopsy samples. The dietary intake is known to influence the pattern of global and targeted methylation of genome (reviewed by Alshatwi and Shafi) [35].…”

“…Exploring the autocrine and paracrine signaling, Tsujikawa et al [16] have demonstrated that chemokine CCL22 produced by cancer cells themselves (autocrine) or by other types of cells, for example, macrophage (paracrine), increased the cell motility of CCR4 + head and neck squamous cell carcinoma cells in vitro . CXCR4 has been shown to be upregulated in many of the solid tumors including cervical cancer (CC) [17, 18]. Also, downregulation of CXCR4 has been demonstrated in pancreatic cancer cell [19] and CD34 + cells [20] of patients with primary myelofibrosis due to promoter hypermethylation.…”

Inhibition of bladder cancer invasion by Sp1‐mediated BTG2 expression via inhibition of DNA methyltransferase 1

“…Moreover, the negative correlation between expression of DNMT1 and DNMT3a versus BTG2 in MIBC ( Table 1) further indicates a role for BTG2 expression in muscle invasion of bladder cancer, and its regulation by DNMTs. It is known that expression of tumor suppressor genes in cancer tissues and cells is regulated by DNA methylation of the promoter region by DNMT1, DNMT3a or DNMT3b [45][46][47][48]. Due to significant individual human variations, absolute values of DNMTs and BTG2 expression in human, normalized against GAPDH expression, did not reveal any significant correlations between their expression.…”

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

“…A study showed that DNMT1 and DNMT3A mRNA levels were higher in human kidney tumor tissues than in adjacent normal tissues (Robertson et al, 1999), and the expression of DNMT1 and DNMT3A proteins was higher in RCC tumors than in nontumor tissues (Li et al, 2014b). High DNMT1 and DNMT3A expression also was found in poorly differentiated retinoblastoma (Qu et al, 2010) and advanced uterine cervical carcinoma (Luczak et al, 2012). Cao et al reported that DNMT1 and DNMT3A expression was higher in human gastric carcinoma tissues than in adjacent normal gastric epithelial tissues, and DNMT3A expression was significantly related to poor survival (Cao et al, 2014).…”