Raf Kinase Inhibitor Protein Research Articles

Raf-1 kinase inhibitor protein: an important molecule for modulating inflammatory responses? (P1188)

Abstract Systemic inflammatory response syndrome is a costly burden for health care systems both nationally and globally. SIRS results from the systemic release of exorbitant quantities of proinflammatory cytokines, which leads to severe complications including acute lung injury, multiple organ dysfunction syndrome, and even death. RKIP is a regulator of MAPK and NF-κB signaling cascades which are both critical for production of the cytokines responsible for SIRS initiation. Using a T cell dependent mouse model of SIRS, we have shown that RKIP is necessary for the synthesis of pathologic quantities of IFNγ from antigen specific CD8+ T cells, but not CD4+ T cells, which is due to an intrinsic signaling defect downstream of the TCR in RKIP-/- T cells. Importantly, RKIP deficient mice were able to mount a productive response to vaccination, suggesting that RKIP may be critical for cytokine production during serial TCR triggering in SIRS, but less so during primary T cell responses (data submitted for publication). Additionally, we have found that RKIP may also play a role in antigen presenting cell function. This is evidenced by a rapid, but transient, inability to detect RKIP by western blot after stimulation of splenocytes with TLR ligands. Although an exact molecular mechanism underlying RKIP’s effects is presently unclear, we are currently utilizing cutting-edge PF 2D proteomic mapping to further elucidate its role within the signaling machinery of immune cells.

Geographic analysis of RKIP expression and its clinical relevance in colorectal cancer

Background:This study evaluates the geographic expression pattern of Raf-1 Kinase Inhibitor Protein (RKIP) in colorectal cancer (CRC) in correlation with clinicopathological and molecular features, markers of epithelial-mesenchymal transition (EMT) and survival outcome.Methods:Whole-tissue sections of 220 well-characterised CRCs were immunostained for RKIP. NF-κB and E-Cadherin expression was assessed using a matched multi-punch tissue microarray. Analysis of mismatch repair (MMR) protein expression, B-Raf and KRAS mutations was performed. RKIP expression in normal mucosa, tumour centre, invasion front and tumour buds was each assessed for clinical relevance.Results:RKIP was diffusely expressed in normal mucosa and progressively lost towards tumour centre and front (P<0.0001). Only 0.9% of tumour buds were RKIP-positive. In the tumour centre, RKIP deficiency predicted metastatic disease (P=0.0307), vascular invasion (P=0.0506), tumour budding (P=0.0112) and an invasive border configuration (P=0.0084). Loss of RKIP correlated with NF-κB activation (P=0.0002) and loss of E-Cadherin (P<0.0001). Absence of RKIP was more common in MMR-deficient cancers (P=0.0191), while no impact of KRAS and B-Raf mutation was observed. RKIP in the tumour centre was identified as a strong prognostic indicator (HR (95% CI): 2.13 (1.27–3.56); P=0.0042) independently of TNM classification and therapy (P=0.0474).Conclusion:The clinical relevance of RKIP expression as an independent prognostic factor is restricted to the tumour centre. Loss of RKIP predicts features of EMT and correlates with frequent distant metastasis.

Immunocytochemical Detection of Raf Kinase Inhibitor Protein and Human Papillomavirus Profiling of Normal and Abnormal Cervical ThinPrep Samples

Objectives: This study investigates the potential value of Raf kinase inhibitor protein (RKIP) as a marker of normal squamous cells in ThinPrep slides. RKIP was evaluated for its ability to distinguish between normal and abnormal cervical samples in the context of human papillomavirus (HPV) infections. Study Design: A total of 316 ThinPrep samples were taken from women with normal and abnormal cervices. ThinPrep slides were Papanicolaou stained and reported. Residual samples were used for RKIP immunostaining and HPV PCR-based sequencing. Results: RKIP expression was seen in both nuclei and cytoplasm in 83.7% of samples. RKIP expression was highest (84.6%) in samples with a diagnosis of high-grade squamous intraepithelial lesion (HSIL) or worse; expression was lower in low-grade squamous intraepithelial lesions (73%) and was lowest in samples with normal cytology (p = 0.0023). A total of 74% of HPV-infected ThinPrep samples were immunopositive, and 67% of samples that did not harbor HPV were also immunopositive (p = 0.414). Sensitivity and specificity of RKIP were 84.6 and 34.6%, respectively, for the detection of samples with HSIL or worse. Conclusions: This study showed that RKIP expression may be of some value as a marker for abnormal cervical cells. Combined RKIP expression and HPV testing could improve the identification of samples with abnormal cytology.

RKIP: Much more than Raf Kinase inhibitory protein

From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease.

Raf kinase inhibitor protein (RKIP) and phospho-RKIP expression in melanomas

Melanoma, a cancer notorious for its high potential to metastasize, arises from melanocytes, cells dedicated to melanin production and located in the basal layer of the epidermis. Raf-1 kinase inhibitor protein (RKIP) is an inhibitory molecule that down-regulates the effects of the Ras/Raf/MEK/ERK signaling pathway. The aim of this study was to examine the expression of RKIP and pRKIP in melanomas at different stages. We evaluated the RKIP and pRKIP protein by immunohistochemistry in control skin, pigmented nevi and melanomas, and through Western blotting in human normal melanocytes and in four different melanoma-derived cell lines (WM35, A375, M14, and A2058). Our results demonstrated a correlation between the expression of RKIP and pRKIP, and metastatic ability in melanoma cells. This raises the possibility to analyze both RKIP and pRKIP in all melanomas. Down-regulation of both RKIP and pRKIP expression could represent a useful marker of metastatic melanoma. On the contrary for non-metastatic melanoma, especially in Clark I and II, low RKIP and high pRKIP expression could be indicative. In conclusion, the observed negative correlation of the RKIP and pRKIP expression in metastatic melanomas indicates that expression of these proteins may become a prognostic marker for the progression of human cutaneous melanoma. We propose that the investigation of both RKIP and pRKIP may provide a useful tool indicative for metastatic or non-metastatic melanoma in different Clark's level melanomas. Further studies are required to verify the molecular background of the observed RKIP and pRKIP variations.

Abstract 606: Inhibition of epithelial to mesenchymal transition and advancement of therapeutic effect in oral cancer by the flavonoid compound, Quercetin: pivotal roles of Snail repression and RKIP induction.

Abstract Oral squamous cell carcinoma (OSCC) is prevalent worldwide, and survival in OSCC has not improved significantly in the last few decades. Cancer prevention using natural products has become an integral part of cancer control. Quercetin is a plant-derived flavonoid known to possess anti-inflammatory property, but its use as a chemopreventive substance has been reviewed quite recently. Several reports have assessed the pro-apoptotic action of Quercetin in cancer cells similar to many other flavonoids, although the mechanisms involved are not clear. We here reported that Quercetion-mediated sensitization may result from modulation of the EMT inducer Snail and the EMT suppressor/ immunosurveillance cancer gene product Raf-1 kinase inhibitory protein (RKIP). Quercetin regulated EMT, invasion, cell survival and apoptosis via inhibition of NF-κB inactivation as well as leaded to the induction of RKIP through downregulation of its transcriptional repressor Snail. Quercetin-induced RKIP upregulation potentiates further modulated mitochondria-mediated apoptosis, thus leading to enhance therapeutic effect. These findings demonstrate the role of Quercetin in the regulation of EMT via inhibition of NF-κB and Snail and induction of RKIP and also identified Quercetin as targets for resistance via NF-κB/Snail/RKIP circuitry. Citation Format: Yun-Ching Chang, Shih-Hwa Chiou, Shin Nieh. Inhibition of epithelial to mesenchymal transition and advancement of therapeutic effect in oral cancer by the flavonoid compound, Quercetin: pivotal roles of Snail repression and RKIP induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 606. doi:10.1158/1538-7445.AM2013-606

ERK Phosphorylation Is Not Increased in Papillary Thyroid Carcinomas with BRAFV600E Mutation Compared to That of Corresponding Normal Thyroid Tissues

Background. An association between a BRAFV600E mutation and upregulation of mitogen-activated protein kinase (MAPK) pathways in human papillary thyroid carcinoma (PTC) tissues has not been demonstrated well outside of in vitro studies. The aims of this study were to evaluate the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) in human PTCs with BRAFV600E mutations compared to that of corresponding normal thyroid tissue and to determine the expressions of Raf kinase inhibitor protein (RKIP) and MAPK phosphatase 3 (MKP-3), possible regulators of ERK1/2 activation. Methods. We analyzed the presence of BRAFV600E mutation and the expressions of BRAF, total ERK, p-ERK, RKIP, and MKP-3 in 33 PTCs and corresponding normal thyroid gland tissues using western blot analysis. Results. BRAFV600E mutation was found in 28 (84.8%) of 33 PTCs, 96.4% (27/28) of which showed decreased p-ERK activity, while 75% (21/28) showed increased MKP-3 expression. There were significant differences in p-ERK and MKP-3 expressions between BRAFV600E (+) PTCs and normal thyroid glands (p < 0.001). There were no differences in expressions of BRAF, total ERK, and RKIP between PTCs and normal thyroid tissue, irrespective of the presence of BRAFV600E mutation. Conclusions. In human BRAFV600E (+) PTCs, ERK phosphorylation is decreased compared to normal thyroid glands and the observed decrease in ERK1/2 MAPK phosphorylation in BRAFV600E (+) PTCs may be associated with increased MKP-3 activity.

RKIP Inhibition in Cervical Cancer Is Associated with Higher Tumor Aggressive Behavior and Resistance to Cisplatin Therapy

Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the leading etiological factor. The raf kinase inhibitory protein (RKIP) has been associated with tumor progression and metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being highly expressed in non-neoplastic tissues (54% of the samples; 73/135), and expressed at low levels in the cervix invasive carcinomas (∼15% (19/124). Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors. Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy resistance of cervical cancer.

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.

Inhibition of G-protein-coupled Receptor Kinase 2 (GRK2) Triggers the Growth-promoting Mitogen-activated Protein Kinase (MAPK) Pathway

Inhibition of G-protein-coupled receptor kinase 2 (GRK2) is an emerging treatment option for heart failure. Because GRK2 is also indispensable for growth and development, we analyzed the impact of GRK2 inhibition on cell growth and proliferation. Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect the proliferation of cultured cells. In contrast, upon xenograft transplantation of cells into immunodeficient mice, the dominant-negative GRK2-K220R or a GRK2-specific peptide inhibitor increased tumor mass. The enhanced tumor growth upon GRK2 inhibition was attributed to the growth-promoting MAPK pathway because dual inhibition of the GRK2 and RAF-MAPK axis by the Raf kinase inhibitor protein (RKIP) did not increase tumor mass. The MAPK cascade contributed to the cardioprotective profile of GRK2 inhibition by preventing cardiomyocyte death, whereas dual inhibition of RAF/MAPK and GRK2 by RKIP induced cardiomyocyte apoptosis, cardiac dysfunction, and signs of heart failure. Thus, cardioprotective signaling induced by GRK2 inhibition is overlapping with tumor growth promotion.

RKIP regulates MAP kinase signaling in cells with defective B-Raf activity

MAP kinase (MAPK) signaling results from activation of Raf kinases in response to external or internal stimuli. Here, we demonstrate that Raf kinase inhibitory protein (RKIP) regulates the activation of MAPK when B-Raf signaling is defective. We used multiple models including mouse embryonic fibroblasts (MEFs) and primary keratinocytes from RKIP- or Raf-deficient mice as well as allografts in mice to investigate the mechanism. Loss of B-Raf protein or activity significantly reduces MAPK activation in these cells. We show that RKIP depletion can rescue the compromised ERK activation and promote proliferation, and this rescue occurs through a Raf-1 dependent mechanism. These results provide formal evidence that RKIP is a bona fide regulator of Raf-1. We propose a new model in which RKIP plays a key role in regulating the ability of cells to signal through Raf-1 to ERK in B-Raf compromised cells.

Molecular Mechanisms and Modulation of Key Pathways Underlying the Synergistic Interaction of Sorafenib with Erlotinib in Non-Small-Cell-Lung Cancer (NSCLC) Cells

Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key pathways in NSCLC progression such as EGFR, K-Ras and VEGFR. The sorafenib-erlotinib combination showed clinical activity and acceptable safety. Therefore, we evaluated mechanisms underlying sorafenib-erlotinib interaction in seven NSCLC cell lines selected for their heterogeneous pattern of EGFR and Raf-kinase-inhibitor protein (RKIP) expression, and EGFR/K-Ras mutations. Pharmacologic interaction was studied using MTT/SRB assays and the combination index (CI) method, while effects on EGFR, Erk1/2 and Akt phosphorylation, cell cycle and apoptosis were studied with western-blot, ELISA, and flow cytometry. Intracellular drug concentrations were measured with LC-MS/MS, whereas kinase activity profiles were generated on tyrosine kinase peptide substrate arrays. Synergism was detected in all cell lines, with CIs < 0.6 in K-Ras mutated A549, SW1573 and H460, as well as in H1975 (EGFR-T790M) cells. Sorafenib slowed cell cycle progression and induced apoptosis, which was significantly increased in the combination. Moreover, sorafenib reduced Akt/ERK phosphorylation in erlotinib-resistant cells, associated with significant RKIP up-regulation. No direct drug interaction was detected by LC-MS/MS measurement, while lysates from A549 and H1975 cells exposed to erlotinib+sorafenib showed a significant inhibition in the phosphorylation of 16 overlapping peptides, including sites from RAF, VEGFR2, PDGFR, CDK2 and SRC, suggesting new markers to identify NSCLC patients who are likely to respond to this treatment. In conclusion, several mechanisms, including apoptosis-induction, modulation of expression/phosphorylation of RKIP and crucial kinases contribute to erlotinib-sorafenib synergistic interaction and should be evaluated in future trials for the rational development of this combination in NSCLC.

Raf kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in Dukes' B colorectal cancer patients

There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients.This demonstrates the potential utility of RKIP in identifying 'high-risk' Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

BackgroundRaf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC).MethodsStaining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis.ResultsWe found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p < 0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p < 0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p = 0.0599) as well as high-grade peritumoral (p = 0.0048) and intratumoral budding (p = 0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p = 0.0089).ConclusionsThe progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.

Overexpression of RKIP Inhibits Cell Invasion in Glioma Cell Lines through Upregulation of miR-98

Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.

Rituximab regulates the expression of the Raf kinase inhibitor protein via NF-κB in renal tissue of rats with diabetic nephropathy

This study aimed to investigate the expression levels of the Raf kinase inhibitor protein (RKIP) and NF-κB in renal tissues of diabetic nephropathy (DN) rats, and to determine the underlying molecular targets of rituximab (RTX), with the goal of developing new clinical treatment selection for DN. Sprague-Dawley rats were randomly divided into a normal group (N), a DN group (M), and an RTX treatment group (D). Blood glucose and 24-h urine protein levels of rats were determined. The expression levels of RKIP and NF-κB in glomerular tissues were determined by immunohistochemistry staining and Western blotting. Comparisons between the M and N groups revealed that the concentrations of blood glucose and 24-h urine protein were significantly increased by DN (P < 0.01), and the expression levels of RKIP and NF-κB were significantly decreased and increased (P < 0.05), respectively. In the D group, the expression levels of RKIP and NF-κB were, respectively, upregulated and downregulated by RTX, and the concentrations of 24-h urine protein were also decreased by RTX. These results suggest that expression levels of RKIP might be regulated by RTX via NF-κB. This pathway could play an important role in the development and pathogenesis of DN. Therefore, RTX could be selected for clinical treatment of DN.

Positive effect of high RKIP expression on reduced distant metastasis by chemotherapy when combined with radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a prospective study

The purpose of this prospective study is to investigate the predictive and prognostic significance of the Raf kinase inhibitory protein (RKIP) in locoregionally advanced nasopharyngeal carcinoma (NPC). Immunohistochemical assays were performed to detect the RKIP protein expression of samples from 212 patients with locoregionally advanced NPC. All patients were assigned randomly into the inductive chemotherapy plus radiation therapy (IC + RT) group, the concurrent chemoradiotherapy (CCRT) group, the inductive chemotherapy plus concurrent chemoradiotherapy (IC + CCRT) group, and the radiation therapy alone (RT) group. The patients in the IC + RT group were treated with IC using 2-3 cycles of cisplatin (80 mg/m(2)) and fluorouracil (500 mg/m(2)), repeated every 3 weeks, followed by radiotherapy. Those in the CCRT group were treated with weekly cisplatin (40 mg/m(2)) for 6-7 cycles during radiotherapy. In the IC + CCRT group, the chemotherapy prior to radiation was similar to the cisplatin-fluorouracil regimen in the IC + RT group, whereas it cisplatin regimen was identical to that in the CCRT group. The results show that RKIP is an independent prognostic factor for 5-year distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). Patients with high RKIP expression benefited more from reduced metastasis in the IC + RT and the IC + CCRT group, with improved OS and PFS in each treatment group compared with that among patients with low RKIP expression. In the high RKIP expression subgroup, chemotherapy combined with radiotherapy improved the DMFS when compared with the RT group, but this effect was not observed in the low RKIP expression subgroup. RKIP was predictive of distant metastasis with good sensitivity and specificity. Clinically, high RKIP expression inhibited distant metastasis in advanced NPC, and its detection might be used to predict distant metastasis with good sensitivity and specificity. The effect of chemotherapy on distant metastasis in combined chemoradiotherapy might be related to the RKIP expression level. Patients with high RKIP expression showed more improved OS and PFS than their low RKIP expression counterparts. Higher RKIP expression improves the DMFS of patients who receive inductive high-dose cisplatin-based chemoradiotherapy, with or without concurrent cisplatin. Low RKIP expression is also a predictive marker for cancer progression and metastasis, which could be used to stratify patients with high risk of metastasis and death.

Novel biomarkers for the prediction of metastasis in colorectal cancer

In patients with metastatic colorectal cancers, multimodal management and the use of biological agents such as monoclonal antibodies have had major positive effects on survival. The ability to predict which patients may be at 'high risk' of distant metastasis could have major implications on patient management. Histomorphological, immunohistochemical or molecular biomarkers are currently being investigated in order to test their potential value as predictors of metastasis. Here, the author reviews the clinical and functional data supporting the investigation of three novel promising biomarkers for the prediction of metastasis in patients with colorectal cancer: tumor budding, Raf1 kinase inhibitor protein (RKIP) and metastasis-associated in colon cancer-1 (MACC1). The lifespan of most potential biomarkers is short as evidenced by the rare cases that have successfully made their way into daily practice such as KRAS or microsatellite instability (MSI) status. Although the three biomarkers reviewed herein have the potential to become important predictive biomarkers of metastasis, they have similar hurdles to overcome before they can be implemented into clinical management: standardization and validation in prospective patient cohorts.

Reduction of Raf Kinase Inhibitor Protein Expression is Associated with Lymph Node Metastasis in Resectable Non-small Cell Lung Cancer

Introduction:Raf kinase inhibitor protein (RKIP) had been identified as one of prognostic indictor in various malignant diseases. Association of RKIP expression and the clinical-pathological features were not investigated in patients with resectable non-small cell lung cancer (NSCLC).Materials and Methodology:159 sectioned samples from surgical NSCLC patients were investigated by immunohistochemistry in order to reveal the associations between RKIP expression and clinical-pathologic features.Results:Statistically, Lower RKIP expression level was found in the group with higher N stage (P<0.01) and higher TNM stage (P<0.05). No significant correlation was observed between RKIP expressions and histologic type (P>0.05) and tumor size (P>0.05).Conclusions:Down expression level of RKIP was found relating to lymph node metastasis in resectable NSCLC patients in this study.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature