Expression of inhibitors of apoptosis family protein in 7,12‐dimethylbenz[a]anthracene‐induced hamster buccal‐pouch squamous‐cell carcinogenesis is associated with mutant p53 accumulation and epigenetic changes

Abstract

Fifty outbred Syrian golden hamsters were equally divided into three experimental groups and two control groups. The pouches of the experimental groups were painted bilaterally with a 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) solution thrice a week for 3, 7 and 14 weeks. One of the control groups was applied with mineral oil while another control group remained untreated throughout the experiment. Neither survivin nor cIAP2 could be detected in any of the control tissues, whereas survivin and cIAP2 were found to be significantly increased in 3-, 7- and 14-week DMBA-treated pouches compared with the control pouches. Expression of XIAP, cIAP1 and NAIP were noted for both the control and 3-, 7- and 14-week DMBA-treated pouches, but levels were found to be significantly elevated in the experimental groups compared with the control pouches. p53 was not detected in any control tissues, but was significantly increased in 3-, 7- and 14-week DMBA-treated pouches. Direct sequencing revealed a point mutation (C-->G) of p53 for pouch tissues treated with DMBA for 3 and 7 weeks, and there was a wide variation in the p53 sequence of the 14-week DMBA-treated pouch tissues, as compared with the control tissues. The control tissues had a survivin- and cIAP2-methylated allele, whereas the DMBA-treated tissues showed no evidence of survivin- and cIAP2-methylation. Neither the control nor DMBA-treated pouches showed evidence of XIAP-, cIAP1- or NAIP-methylation. Our results suggest that the expression of inhibitors of apoptosis family in DMBA-induced hamster buccal-pouch squamous-cell carcinogenesis may be modulated by both genetic (mutant p53) and epigenetic mechanisms.

Expression of inhibitor of apoptosis family proteins in human oral squamous cell carcinogenesis

“…We observed significant protein overexpression of the 5 IAP family members (survivin, XIAP, cIAP1, cIAP2, and NAIP) in oral potentially malignant disorders as compared to normal oral mucosa, indicating that IAP expression is an early event in human oral carcinogenesis. This finding is also compatible with our results from a previous animal study using an HBPCM 13…”

“…In this study, no significant statistical differences were noted in a comparison of the clinical characteristics of the patients with OSCC in which expression of the 5 IAP members was observed, although some IAPs, such as cIAP1 and particularly survivin , have been found to be related to clinical outcomes in previous studies 32–34, 45. On the other hand, the cIAP1 and cIAP2 genes are located on human chromosome 11q, whereas the NAIP , survivin , and XIAP genes are situated on human chromosomes 5q, 17q, and Xq, respectively,13 all of which are regions of high incidence of chromosomal abnormalities associated with carcinomas of the head and neck, including OSCC 46–49…”

“…One form of epigenetic modification is known as DNA methylation, in which hypomethylation leading to oncogene activation occurs, whereas hypermethylation causes tumor suppressor gene silencing 11. Hypomethylation of IAP genes in HBPCM has recently been demonstrated,12, 13 but, nevertheless, the regulation of IAP family members by an epigenetic mechanism is still a promising area for investigation in human oral squamous cell carcinogenesis.…”

The role of neuronal apoptosis inhibitory protein (NAIP) in acute myeloid leukemia patients

“…NAIP protein was present only in samples with prostatic neoplasm, and this protein expression was in more than 60% of cells [33]. Normal prostatic cells displayed a lack of NAIP protein expression; unfortunately, NAIP expression was not correlated with clinical and pathological parameters [34].…”

Epigenetic Mechanisms in Oral Carcinogenesis

“…In one study, increased Survivin expression was associated with a more aggressive and invasive tumor phenotype [10]. Using the hamster buccal pouch mucosa as an experimental model for oral carcinogenesis, Chen et al observed that mineral oil-treated animals had normal Survivin methylated alleles, while the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals had buccal pouch carcinomas with a hypomethylated Survivin allele [11,12]. The results of these studies indicate that hypomethylation of the Survivin gene appears to be an important step in the process of OSCC carcinogenesis.…”