Biomarkers Expression in Cervical Cancer and High Grade Squamous Intraepithelial Lesions

Abstract

Objectives: The finding of new prognostic factors in human cervix cancer is necessary to improve present conventional treatments. The aim of the present study was to determine the expression and evaluate the prognostic value of hypoxia-inducible factor-1(HIF-1α), vascular endothelial growth factor (VEGF) and eritropoyetin receptor (EpoR) in cervix cancer stages IIA-IIB and in preinvasive high grade squamous intraepithelial lesions (HSIL) Methods: The study included 70 patients with cervix cancer, FIGO stages IIA-IIB, 28 patients with HSIL and normal cervix (n = 28). HIF-1α, VEGF and EpoR expression were analyzed in tissue samples by immunohistochemistry using commercial antibodies. Expression and overexpression of the tumor markers were quantified according to German Immunoreactive Score. Results: HIF-1α, EpoR and VEGF overexpression was detected in 30%, 37% and 51% of cancer patients respectively. Patients with HSIL showed enhanced expression only of EpoR and VEGF (39.2% and 71.4%) while VEGF was overexpressed in 21% of the specimen. No correlation was found between VEGF and EpoR with disease-free overall survival (OS), tumor recurrences or prognostic factors. Only overexpression of HIF-1 was associated with less median survival measured up to 24 months, unless it was not maintained a long time. Conclusion: Although any of the markers could be considered as independent prognostic factor for cervix cancer patients, our data showed a significant increase in their expression from the premalignant lesion up to the invasive stages of tumor progression.

Deregulation of LIMD1–VHL–HIF-1α–VEGF pathway is associated with different stages of cervical cancer

“…High/medium expression of HIF-1α and VEGF in proliferating basal-parabasal layers of normal-cervix were seen compared to spinous layer (Table1). Similar, high/medium expression of VEGF was reported earlier in the basal-parabasal layers of normal cervical epithelium contrary to low expression of HIF-1α (6).No significant difference in expression profiles of these genes in normal cervical epithelium were seen with respect to HPV16 infection. Thus, it can be suggested that high expression of HIF-1α and its target protein VEGF in basal-parabasal layers of normal cervical epitheliums might be due to the reduced expression of VHL.…”

“…Unlike expression pattern of LIMD1 and VHL during different stages of CACX, the expression of HIF-1α and VEGF were high as seen in basal-parabasal layers of normal-cervix (Table 1,Figure 1). Similar expression profiles of HIF-1α and VEGF have also been reported in CACX, HNSCC and colorectal cancer(6,22,23). The inverse correlation of LIMD1 and VHL expression with that of HIF-1α and VEGF was validated by demethylation experiments using 5-aza-dC in HeLa and SiHa cell lines(Figure 3).…”

“…Low expression of VHL is observed in basal-parabasal layers of normal cervical epithelium and CACX (8), However to date, no studies have investigated LIMD1 expression in normal cervix and CACX. On the contrary, high/medium expression of HIF-1α transcriptional target, VEGF was reported in basal-parabasal layers of normal-cervix and in CIN/CACX (6).…”

“…It has been suggested that hr-HPV infection in the basal stem cells of squamocolumnar junction of the normal-cervix induces some cellular stress, resulting in changes in cellular differentiation/proliferation and induction of cellular transformation (4,5). Among different stress response genes, HIF-1α expression is highly increased in CIN/CACX compared to its expression in normal-cervix (6). The stability of HIF-1α is regulated by the tumor suppressor genes LIMD1 and its interacting partner VHL (7).…”