Deletions in chromosome 4 differentially associated with the development of cervical cancer: evidence of slit2 as a candidate tumor suppressor gene

Abstract

The aim of this study was to locate the candidate tumor suppressor genes (TSGs) loci in the chromosomal 4p15-16, 4q22-23 and 4q34-35 regions associated with the development of uterine cervical carcinoma (CA-CX). Deletion mapping of the regions by microsatellite markers identified six discrete areas with high frequency of deletions, viz. 4p16.2 (D1: 40%), 4p15.31 (D2: 35-38%), 4p15.2 (D3: 37-40%), 4q22.2 (D4: 34%), 4q34.2-34.3 (D5: 37-59%) and 4q35.1 (D6: 40-50%). Significant correlation was noted among the deleted regions D1, D2 and D3. The deletions in D1, D2, D5 and D6 regions are suggested to be associated with the cervical intraepithelial neoplasia (CIN), and deletions in the D2, D3, D5 and D6 regions seems to be associated with progression of CA-CX. The deletions in the D2 and D6 regions showed significant prognostic implications (P = 0.001; 0.02). The expression of the candidate TSG SLIT2 mapped to D2 region gradually reduced from normal cervix uteri -->CIN --> CA-CX. SLIT2 promoter hypermethylation was seen in 28% CIN samples and significantly increased with tumor progression (P = 0.04). Significant correlation was seen between SLIT2 deletion and its promoter methylation (P = 0.001), indicating that both these phenomena could occur simultaneously to inactivate this gene. Immunohistochemical analysis showed reduced expression of SLIT2 in cervical lesions and CA-CX cell lines. Although no mutation was detected in the SLIT2 promoter region (-432 to + 55 bp), CC and AA haplotypes were seen in -227 and -195 positions, respectively. Thus, it indicates that inactivation of SLIT2-ROBO1 signaling pathway may have an important role in CA-CX development.

Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis

“…By promoter region CpG island hypermethylation and allele loss, SLIT2 is reportedly inactivated in various cancer cell lines and primary lung, breast, intestinal, cervical and hepatocellular carcinomas, gliomas and lymphocytic leukemia, suggesting that SLIT2 may act as a candidate tumor suppressor gene [45][46][47][48][49][50][51]. Notably, Slit2 is also found to enhance E-cad-mediated cell-cell adhesion of breast cancer MCF-7 cells [52] and to increase E-cad expression through downregulation of its transcriptional repressor, Snail, in lung cancer [53].…”

Calcium-binding protein S100P and cancer: mechanisms and clinical relevance

“…Some fatal disease-related genes are also mapped to 4p16, such as non-syndromic oral clefts (Ingersoll et al 2010), Ellis-van Creveld syndrome (Cagdas et al 2008;Polymeropoulos et al 1996), Huntington disease (Norremolle et al 2009), Wolf-Hirschhorn syndrome (Zollino et al 2008), Familial Wolfram syndrome (Zenteno et al 2008), Crohn's disease (Raelson et al 2007) and cervical cancer (Singh et al 2007). …”

RBSP3 is frequently altered in premalignant cervical lesions: Clinical and prognostic significance

“…Deletion status of RB1 was determined using an intragenic, polymorphic microsatellite marker (D13S153) in the same samples as above. Scoring of loss of heterozygosity (LOH) and microsatellite size alteration (MA) for informative/noninformative markers were done according to the standard protocols (Ichimura et al, 2000;Dasgupta et al, 2002;Singh et al, 2007). (Details in Supporting Information).…”