Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma

Abstract

Senescence and apoptosis are two key mechanisms that protect against cancer development. Many cell cycle regulators, such as p14 ARF , p15INK4b and p16 INK4a , are important in G1 cell cycle arrest and oncogene-induced senescence. The bcl-2 protein is one of the key components that control apoptosis, while the p53 protein plays key roles in both mechanisms. The genes of these key regulator proteins are often mutated or deleted in various malignancies. It is unknown how senescence and apoptosis are regulated in one of the most common tumors of the female genital tract, cervical squamous cell carcinoma (SCC). In this study the, expression of senescence, apoptosis and proliferation markers in normal cervical epithelium, cervical intraepithelial neoplasia (CIN) and SCC are characterized via immunohistochemical staining for p14INK4b , p16 INK4a , bcl-2, p53 and Ki-67 in tissue microarray blocks containing 20 samples each of normal cervix, moderate-to-severe cervical dysplasia (CIN II-III) and invasive SCC. Samples are derived from 60 total cases of cervical biopsies and cervical conizations. Results showed that the proliferation marker, Ki-67, is markedly increased, and the senescence markers, p15 INK4b, p16INK4a and p14 ARF are overexpressed in both dysplasia and carcinoma. P53 immunostain is negative in all normal cervical tissue, and positive in dysplasia and carcinoma. Although the expression of bcl-2 is increased in dysplasia, this marker is negative in approximately half of SCC cases. These results suggest that some senescence pathways are activated and are still maintained in cervical dysplasia and carcinoma. However proliferation is increased and carcinogenesis is not thwarted, leading to eventual development of cervical cancer. Other mechanisms, such as those that account for the apparent overexpression of p53 and paradoxical loss of bcl-2 expression in some SCC cases, as well as additional senescence and apoptotic pathways, may play key roles carcinogenesis of cervical SCC. Keywords: senescence; apoptosis; carcinogenesis; cervical squamous; carcinoma Squamous cell carcinoma (SCC) of the uterine cervix is the second most common malignant tumor of the female genital tract. It is well known that the human papilloma virus (HPV) is the single most important etiologic agent in the pathogenesis of cervical carcinoma. However, not all women who are infected with the high-risk HPV (HPV subtypes 16 and 18) develop cervical carcinoma. It often takes years or decades before persistent dysplasia eventually develops into invasive cervical SCC. This suggests that other cofactors must be present in the pathogenic pathway between cervical dysplasia (CIN) and carcinoma.There are two basic cellular mechanisms by which cells with accumulated somatic mutations are prevented from cancer development: apoptosis and senescence. Senescence is a form of growtharrested state described first in cultured fibroblasts where metabolically active cells undergo stable cell cycle arrest at the G1 phase.1-4 This is induced by a variety of str...

Immunohistochemical Expression of Apoptosis Regulators in Squamous Cell Carcinoma of the Cervix and Their Association with Human Papillomavirus 16/18 Subtypes

“…These findings are comparable with those of Grace et al (92.6% in HPV + and 38.1% in HPV-) (18). The findings of Feng et al (19), Giarnieri et al (24) and Win et al (21) were comparable with our HPV positive group results, which could be related to the higher prevalence of high risk HPV in their population. Regarding the well-known effect of high risk HPV E6 protein in p53 ubiquitination and inactivation, it seems that the inactivated and stabilised p53 preserves its IHC antibody target epitope.…”

“…Paradoxical overexpression of p53 could be interpreted by inactivation and stabilisation of the p53 protein against the Mouse double minute 2 homolog (MDM2) degradation effect mediated by the E6 protein of high risk HPVs. Conversely, Bcl2 may be negative in almost half of the cases, which could be related to direct obstruction of p53 through E6 oncoprotein (19). On the other hand, overexpression of p53 in the majority of cases and Bcl2 and Bax expression in half of the cases of cervical SCC have been demonstrated (20)(21)(22)(23).…”

“…In the case of high risk HPV types associated with cervical cancer, the relative thickness of these layers increases with the grade of neoplasia, while the extent of epithelial differentiation decreases. In such cases, high risk HPVs may be responsible for overexpression of the p53 tumour suppressor and Bcl2 anti-apoptotic factor (18,19). Paradoxical overexpression of p53 could be interpreted by inactivation and stabilisation of the p53 protein against the Mouse double minute 2 homolog (MDM2) degradation effect mediated by the E6 protein of high risk HPVs.…”

Evaluation Of P16, P27, Cycline D1, Bcl-2 Expressions In Uterine Cervical Intraepithelial Neoplasia and Skuamous Cell Carcinoma

“…Doğurganlık çağı süresince kadınların çoğu bir veya daha çok HPV tipi ile enfekte olmakta ancak enfekte kadınların çok azında önce displazi, sonrasında kansere dönüşüm izlenmektedir. HPV infeksiyonunun latent kalmasını, prekansere veya kansere doğru gelişimini diğer kokarsinojenler, bireyin bağışıklık durumu, beslenme gibi birçok faktör etkiler (2,3) .…”

p16INK4a and p14ARF mRNA expression in Pap smears is age-related

“…14,15 Cervical cancer was shown to be strongly associated with p16 INK4a and p14 ARF expression by immunohistochemical studies. 11,[16][17][18][19] Immunohistochemical staining for p16 INK4a became the most widely accepted surrogate biomarker in cervical cancer screening. p16 INK4a has the advantage to detect any high-risk HPV infection in conjunction with uncontrolled, malignant cell replication.…”