Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol-nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.

There have been significant advances in our understanding of carcinogenesis at the molecular level over the last 25 years. Oncogenes are of major interest as part of our search for knowledge surrounding the aetiology of cancer. There are several oncogenes associated with thyroid cancer. Detailed investigation of the nature and function of these tumour genes has provided important insights into both the tumour biology and the complex biochemical pathways of normal cellular functioning. Our knowledge of oncogene biology offers the hope of better diagnostic, therapeutic and prognostic modalities in our fight against this and other common cancers. Development of specific thyroid tumour markers and gene therapy is now a realistic prospect to supplement our present armamentarium of surgery and radiotherapy. This review aims to outline the pertinent information gained so far from studies of these oncogenes and provides both clinical relevance and fuel for further interest amongst the ENT thyroid community in this exciting area of research.

Background. VEGF exerts its effects by binding to tyrosine kinase receptors, KDR and VEGFR1. KDR is critical for transmitting signals for proliferation of endothelial cells but is also expressed in several non‐endothelial cells suggesting existence of autocrine stimulatory pathways. Study‐design. We investigated VEGF and KDR expression in human thyroid epithelial cells in vitro and thyroid cancers samples ex vivo. Results. Expression of KDR was demonstrated using Taqman RT‐PCR and Western blotting in a human follicular thyroid cancer line (FTC133) and primary thyroid epithelial cells. Further, VEGF‐specific and dose‐dependent activation of KDR‐dependent MAPK signalling and KDR‐dependent mitogenesis was demonstrated. KDR mRNA expression was elevated in thyroid cancers (2.5‐fold, n = 38, P < 0.001), and immunohistochemistry demonstrated stronger phosphorylated‐KDR staining in thyroid cancer cells. Further, we showed that PTTG, an oncogene known to promote angiogenesis, up‐regulates KDR (2.2‐fold, P = 0.006) and VEGF (2.4‐fold, P < 0.001) expression in FTC133 thyroid cells. Next, we examined expression of ID3, known to be important in VEGF‐dependent angiogenesis, and VEGF mRNA expression in a series of thyroid cancers. We observed a strong positive correlation between expression of these genes (R2 = 0.62, P < 0.001). Stimulation of FTC133 cells with exogenous VEGF increased ID3 expression (2.1‐fold, P < 0.001), an effect abrogated by a KDR‐specific inhibitor, suggesting VEGF regulation of ID3 is KDR‐dependent. Conclusion. We suggest the presence of a VEGF‐KDR‐ID3 dependent autocrine pathway in thyroid cells. By up‐regulating both VEGF and KDR expression, we propose that PTTG may promote this autocrine proliferative pathway which may in turn be critical to thyroid cancer progression.

The key mitotic regulator securin is expressed at low levels in fetal brain compared with adult, and modulates the proliferation of human embryonic neuronal N-Tera2 (NT2) cells. We now examine the function and expression of securin's interacting partner separase, along with Rad21, the functional component of cohesin, which is cleaved by separase following interaction with securin. In contrast to securin, the cleaved forms of separase and Rad21 were highly expressed in human fetal cerebral cortex compared with adult. In a murine model of absent securin expression - the PTTG knock-out mouse - separase and Rad21 were over-expressed in multiple brain regions. In addition, cDNA array analysis of other key mitotic regulators additionally identified cyclin C and sestrin 2 to be induced in the brains of securin-null mice compared with wild type. Further, Rad21 mRNA expression was highly correlated with that of securin, separase, cyclin C and sestrin 2 in fetal brains. In embryonic neuronal NT2 cells, siRNA repression of separase failed to significantly alter cell turnover, whereas repression of securin expression resulted in increased levels of the activated forms of Rad21 and separase, and promoted cell proliferation. Our data suggest that the co-ordinated expression of separase, securin and Rad21 is fundamental for the developing brain.