Differences in the expression of five senescence markers in oral cancer, oral leukoplakia and control samples in humans

Abstract

Abstract. Oncogene-induced senescence (OIS) may be a response to oncogenic activation, acting as a natural barrier against carcinogenesis at a premalignant stage. Thus, numerous cells in premalignant lesions enter senescence, but none or few in malignant tumours. This event could be due to the loss of senescence pathway effectors, including p16 (INK4a)-pRb or ARF-p53. The aim of this study was to characterize and compare the expression of certain senescent markers between oral precancer and cancer tissue samples. The expression of cyclin D1, Rb, maspin, p53 and mouse double minute 2 (MDM2) was analyzed in 20 paraffin-embedded tissue samples of normal oral mucosa (NOM), 14 samples of oral leukoplakia without dysplasia (OLD-), 11 samples of leukoplakia with dysplasia (OLD+) and 15 samples of oral squamous cell carcinoma (OSCC) by immunohistochemistry in tissue arrays. The expression of p16-pRb pathway markers, cyclin D1, maspin and Rb, was more frequent in OLD+ samples than in OSCC samples, although a statistical significance was only observed for maspin (P=0.036). Cyclin D1 expression was also significantly more frequent in OLD-samples vs. NOM samples. For the ARF-p53 pathway, the expression of p53 and MDM2 was significantly more frequent in the OLD-samples compared to in the NOM ones. These findings may indicate a role for cellular senescence in oral carcinogenesis, considering maspin as a reliable senescence marker and prognostic factor in oral premalignant lesions.

Combinations of SERPINB5 gene polymorphisms and environmental factors are associated with oral cancer risks

“…Moreover, gene-to-gene interactions significantly increased the risk of oral cancer susceptibility among participants with TC or CC of rs17071138 , CT or TT of rs3744941 , and CT or CC of rs8089104 polymorphisms of SERPINB5 . It was demonstrated that oncogene-induced senescence contributed to repressing aberrant proliferation of oral squamous cells at risk of neoplastic transformation [11, 12]. SERPINB5 is a potential senescence marker in oral precancerous lesions for its response to oncogene-induced senescence, and increased SERPINB5 expression plays a critical role in protecting cells against oral cancer [1, 2, 4, 11, 12].…”

“…It was demonstrated that oncogene-induced senescence contributed to repressing aberrant proliferation of oral squamous cells at risk of neoplastic transformation [11, 12]. SERPINB5 is a potential senescence marker in oral precancerous lesions for its response to oncogene-induced senescence, and increased SERPINB5 expression plays a critical role in protecting cells against oral cancer [1, 2, 4, 11, 12]. We suggest that genetic polymorphisms of TC heterozygotes of rs17071138 T/C and CC homozygotes of SERPINB5 rs8089104 T/C can decrease promoter activity resulting from alterations in transcription factor binding, which could diminish the production of SERPINB5 [17].…”

“…We suggest that genetic polymorphisms of TC heterozygotes of rs17071138 T/C and CC homozygotes of SERPINB5 rs8089104 T/C can decrease promoter activity resulting from alterations in transcription factor binding, which could diminish the production of SERPINB5 [17]. Such an occurrence of genetic variants or gene-gene interactions obstructing the senescence response for regulating cell cycle arrest and triggering cell apoptosis consequently induces transformation from precancerous cells to malignant cells and increases the susceptibility to oral cancer [1, 2, 4, 11, 12, 21, 22]. …”

“…Cellular senescence and apoptosis in oral cancer and oral precancerous cells are considered strong mechanisms for tumor suppression through their control of the proliferative potential of premalignant or malignant cells [11]. It was reported that repression of premalignant cell proliferation can be triggered by oncogene-induced senescence (OIS), and SERPINB5 was suggested to be an effector of oncogene-induced senescence, which acts as a natural barrier against transformation from a premalignant lesion to carcinoma in oral leukoplakia with dysplasia [12]. Gene expression of SERPINB5 was significantly higher in tissues of normal oral mucosa than in oral leukoplakic tissues with dysplasia and in oral squamous cell carcinoma tissues; however, there were no significantly different expression levels between tissues of normal oral mucosa and leukoplakia without dysplasia [12].…”

“…It was reported that repression of premalignant cell proliferation can be triggered by oncogene-induced senescence (OIS), and SERPINB5 was suggested to be an effector of oncogene-induced senescence, which acts as a natural barrier against transformation from a premalignant lesion to carcinoma in oral leukoplakia with dysplasia [12]. Gene expression of SERPINB5 was significantly higher in tissues of normal oral mucosa than in oral leukoplakic tissues with dysplasia and in oral squamous cell carcinoma tissues; however, there were no significantly different expression levels between tissues of normal oral mucosa and leukoplakia without dysplasia [12]. A loss of SERPINB5 expression was correlated with an increased invasive potential in a human oral squamous cell carcinoma (OSCC) cell line [1, 4].…”