Chfr expression is downregulated by CpG island hypermethylation in esophageal cancer

Abstract

Cell cycle progression is monitored by checkpoint mechanisms to ensure the integrity of the genome and the fidelity of sister chromatid separation. Failure of such checkpoint functions results in genomic instability, a condition that predisposes cells to neoplastic transformation and tumor progression. Recently, Scolnick and Halazonetis defined a new mitotic checkpoint that acts at prophase and delays chromosome condensation in response to mitotic stress, and identified a gene, named checkpoint with FHA and ring finger (Chfr), that seems to be required for delaying prophase in human cells. In the present study, we examined human Chfr mRNA expression in 15 human esophageal cancer cell lines and 43 primary esophageal cancers to investigate the potential involvement of Chfr in the pathogenesis of esophageal cancers. We report here that a significant proportion of human esophageal cancer has loss of expression of Chfr gene. Furthermore, we found aberrant hypermethylation of the promoter region of this checkpoint gene in four of 15 (26.7%) esophageal cancer cell lines and in seven of 43 (16.3%) primary cancers.

Promoter hypermethylation of the Chfr gene in neoplastic and non-neoplastic gastric epithelia

“…In contrast, cancer cell lines that lack CHFR enter metaphase without delay, with ectopic expression of CHFR necessary and sufficient to restore cell-cycle delay (Scolnick and Halazonetis, 2000). Recent studies of human tumours have shown that Chfr inactivation can be due to hypermethylation of CpGs in the promoter region (Mizuno et al, 2002;Shibata et al, 2002). However, whether Chfr promoter hypermethylation is involved in gastric cancer has not yet been determined.…”

“…Northern blot analysis of Chfr using RNA from eight colon, osteosarcoma and neuroblastoma cancer cell lines revealed that Chfr expression was absent in three cell lines (Scolnick and Halazonetis, 2000). Loss of Chfr expression due to hypermethylation of a CpG island in the promoter region has been observed in tumour cell lines and primary cancers of the lung, oesophagus and colon (Mizuno et al, 2002;Shibata et al, 2002;Corn et al, 2003;Toyota et al, 2003). Thus, it is possible that Chfr promoter hypermethylation is also involved in gastric carcinogenesis.…”

CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

“…To evaluate the association between CHFR mRNA expression and CHFR immunohistochemical protein expression in NSCLC, we performed laser capture microdissection to collect cancer cells selectively in 20 lung cancer cases (adenocarcinoma, cases 1-10; squamous cell carcinoma, cases [11][12][13][14][15][16][17][18][19][20] as previously reported. 27 Before microdissection, frozen sections were cut into 8-lm-thick slices and stained with Giemsa, then dried with ethanol followed by xylene treatment as previously described, with minor modification.…”

“…After mRNA extraction, reverse transcription and real-time quantitative RT-PCR were carried out in each case. The data were then compared to the immunohistochemical protein expression in matched formalin-fixed and paraffin-embedded tissue (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Various levels of messenger RNA expression of the CHFR were detected in NSCLC (Fig.…”

“…Several groups have demonstrated that CHFR mRNA expression is lost or decreased in human cancers and cancer cell lines, mostly due to hypermethylation of its promoter region or, in a few cases, as a result of missense mutations. [15][16][17][18][19] However, the distribution of CHFR protein expression and the association with clinicopathologic behavior in NSCLC have remained unknown.…”