Mp85-16 study of altered ratios of protein kinase ck2 catalytic subunits and regulatory subunit (ck2beta) in renal cell carcinoma. relation with epitelial-to-mesenchymal transition markers (il-6/stat3)

INTRODUCTION AND OBJECTIVES: Epitelial-to-mesenchymal transition (EMT) is a well characterised process linked to tumour progression and metastasis in a number of carcinomas. EMT enables carcinoma cells to lose cell to cell contacts and endows them with stem cell-like properties to invade and initiate metastasis. Recent reports have identified EMT as potentially playing a significant role in RCC disease recurrence, invasion and metastasis. Several signalling pathways like HIF/2 and IL-6/STAT, are well known inducers of the EMT phenotype. Protein kinase CK2 is a constitutively active serine/threonine kinase consisting of two catalytic subunits (CK2alpha/alpha’) and two regulatory subunits (CK2Beta) and is present in the nucleus and cytoplasm of all eukaryotic cells. The imbalance of CK2 catalytic and regularory subunits, due to underexpression of CK2Beta subunit, has been correlated with the expression of EMT markers. In clear cell renal cell carcinoma (ccRCC), the alterations in the ratios between CK2 subunits during the neoplasic process seems to participate at different stages of tumour progression METHODS: We analyzed the expression and distribution of CK2 subunits in samples of clear cell renal carcinomas (ccRCC) and renal healthy tissue from the same patients by immunohistochemistry on TMAs and Western-blot in a total of 98 patients. Tumour registry data and patient outcome were retrospectivelly collected and correlates with clinicopathological data (F€ urhman grade, pT stage and Risk group) and with IL-6/STAT inmunoexpression RESULTS: We observed an increase of CK2 in tumors. Regarding the subcellular distribution in normal tissue CK2alpha is predominantly cytoplasmic whereas tumors markedly increased in the core, with only a slight decrease in the cytoplasm, indicating nuclear overexpression CK2alpha tumors. CK2Beta changes are more discreet and its nuclear accumulation in tumors could be due to translocation from the cytoplasm, which is a marked decrease. Using 786-O cells, derived ccRCC pVHL deficient, and 786-O cells stably transfected with an expression vector pVHL, we have observed that the presence of VHL not decrease but it increases CK2alpha levels by altering the ratio between CK2alpha/CK2Beta. It was observed higher survival in the subset patients with underexpression of CK2sBeta although log-rank was not significant (0,301). The combination of overexpression of STAT3 and underexpression ok CK2Beta seems to provide a higher survival hazard ratio of 4,252 (95% IC, 1,182-18.413) CONCLUSIONS: The results indicate CK2alpha overexpression in clear cell renal cell carcinoma by a mechanism that does not appear due to inactivation of VHL. In patients with underexpression of IL-6/STAT3, CK2Beta was no able to discriminate any behaviour, but the patients defined as poor prognostic when STAT3 was overexpressed has similar survival than those that had underexpression of STAT3. The combination of overexpression of STAT3 and underexpression of CK2Beta provided a higher survival rate