Loss of RKIP expression during the carcinogenic evolution of endometrial cancer

Aims Endometrial cancer is one of the most common cancers in women worldwide, but there is a lack of diagnostic markers for early detection of these tumours. The raf kinase inhibitory protein (RKIP) negatively regulates the Raf/MEK/ERK pathway, and the downregulation of RKIP is associated with tumour progression and metastasis in several human neoplasms. The aim of this study was to assess the expression levels of RKIP in endometrial cancer and determine whether this expression correlates with clinical outcome in these patients.Methods Tissue microarrays constructed using tissue samples from 209 endometrial adenocarcinomas, 49 endometrial polyps and 48 endometrial hyperplasias were analysed for RKIP expression by immunohistochemistry.Results The authors found that RKIP expression decreases significantly during malignant progression of endometrial cancer; it is highly expressed in non-neoplastic tissues (polyps 79.6%; hyperplasias 87.5%) and expressed at very low levels in endometrioid adenocarcinomas (29.7%). No correlations were observed between RKIP expression, clinicopathological data and survival.Conclusion This study demonstrated for the first time that RKIP expression is lost during the carcinogenic evolution of endometrial tumours and that the loss of RKIP expression is associated with a malignant phenotype. Functional studies are needed to address the biological role of RKIP downregulation in endometrial cancer.

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

Gastric cancer is a leading cause of cancer-related mortality, and the presence of lymph node metastasis an important prognostic factor. Downregulation of RKIP has been associated with tumor progression and metastasis in several types of neoplasms, being currently categorized as a metastasis suppressor gene. Our aim was to determine the expression levels of RKIP in gastric tissues and to evaluate its impact in the clinical outcome of gastric carcinoma patients. RKIP expression levels were studied by immunohistochemistry in a series of gastric tissues. Overall, we analysed 222 non-neoplastic gastric tissues, 152 primary tumors and 42 lymph node metastasis samples. We observed that RKIP was highly expressed in ∼83% of non-neoplastic tissues (including normal tissue and metaplasia), was lost in ∼56% of primary tumors and in ∼90% of lymph node metastasis samples. Loss of RKIP expression was significantly associated with several markers of poor clinical outcome, including the presence of lymph node metastasis. Furthermore, the absence of RKIP protein constitutes an independent prognostic marker for these patients. In conclusion, RKIP expression is significantly lost during gastric carcinoma progression being almost absent in lymph node metastasis samples. Of note, we showed that the absence of RKIP expression is associated with poor outcome features of gastric cancer patients, this being also an independent prognostic marker.

Low RKIP expression associates with poor prognosis in bladder cancer patients

Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle-invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer. © 2013 Springer-Verlag Berlin Heidelberg.