Reduction in Raf Kinase Inhibitor Protein Expression Is Associated with Increased Ras-Extracellular Signal-Regulated Kinase Signaling in Melanoma Cell Lines

Schuierer, Marion; Bataille, Frauke; Hagan, Suzanne; Kölch, Walter; Bosserhoff, Anja‐Katrin

doi:10.1158/0008-5472.can-03-3861

Cited by 166 publications

(159 citation statements)

References 22 publications

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“…Immunohistochemical analysis has demonstrated that the loss of RKIP expression is a key phenotype for many human cancers, including colorectal cancer, breast cancer, melanoma, prostate cancer and hepatocellular carcinoma, modulating distant metastasis, lymphatic metastasis, vascular infiltration and cancer mortality (45)(46)(47)(48)(49). Consistent with these studies, the present study showed that the incidence of positive RKIP expression in ESCC tissues was significantly less compared with the matched normal tissues, and that it was clinically correlated with lymph node metastasis.…”

Section: Rkip Protein Expression ------------------------------------supporting

confidence: 89%

“…Keller et al reported that RKIP expression was at its highest in normal prostate tissues, decreased in primary prostate cancers and was not detectable in metastatic tissues from prostate cancer (50). In addition, Schuierer et al demonstrated that RKIP expression was decreased concomitantly with the metastasis of melanoma (47). Mechanistic studies have suggested that RKIP is a metastasis suppressor gene that is responsible for blocking several signaling pathways in the metastatic cascade, including MEK, G proteins and NF-κB (51).…”

Section: Rkip Protein Expression ------------------------------------mentioning

confidence: 99%

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Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

et al. 2017

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Abstract. Raf kinase inhibitory protein (RKIP) regulates multiple cellular processes, and its downregulation is associated with distinct human cancers. In the present study, the status of RKIP promoter methylation, as well as its expression and clinical significance in esophageal squamous cell carcinoma (ESCC), were examined. The promoter methylation status in the 5'-CpG island of the RKIP gene and the expression level of the RKIP protein were examined using a modified methylation-specific polymerase chain reaction (MSP) method and immunohistochemical staining, respectively, in 77 ESCC samples and matched paratumor normal tissues. The incidence of RKIP promoter methylation was significantly higher in tumor samples (75.3%) than in the matched normal tissues (27.3%; P<0.001). A higher incidence of promoter methylation was also detected in poorly differentiated cancers (93.5%) compared with well-differentiated cancers (50.0%; P<0.001), as well as in tumor samples with positive lymph node metastasis (86.7%) compared with those with negative lymph node metastasis (59.4%; P<0.001). Consistent with the promoter methylation status, the expression level of RKIP was significantly reduced in cancer tissues (36.4%) compared with matched normal tissues (76.6%; P<0.01), as well as in cancers with positive lymph node metastasis (24.4%) compared with those with negative lymph node metastasis (53.1%; P=0.01). Promoter methylation-induced gene silencing significantly correlated with the down regulation of RKIP and the development of ESCC. The results of the present study suggested that the methylation status of the RKIP promoter, when combined with its expression level, may serve as a biomarker for predicting the biological behaviors of ESCC.

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Section: Rkip Protein Expression ------------------------------------supporting

confidence: 89%

Section: Rkip Protein Expression ------------------------------------mentioning

confidence: 99%

Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

et al. 2017

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“…On the molecular level, RKIP functions by inhibiting the proliferative and survival Raf-MEK-ERK and NF-kB signaling pathways (Chatterjee et al, 2004;Park et al, 2005). Consistent with its demonstrated inhibitory effect on Raf and NF-kB signaling, we and others have shown that the expression levels of RKIP are downregulated in a number of tumors, including highly metastatic prostate, breast and colon cancer, hepatocellular carcinoma, melanomas and insulinomas (Fu et al, 2003;Chatterjee et al, 2004;Schuierer et al, 2004Schuierer et al, , 2006Zhang et al, 2004;Hegan et al, 2005;Al-Mulla et al, 2006;Lee et al, 2006). The importance of RKIP in metastases was highlighted by the finding that restoration of RKIP expression inhibits prostate cancer metastasis in a murine model (Fu et al, 2003(Fu et al, , 2005.…”

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confidence: 58%

Snail is a repressor of RKIP transcription in metastatic prostate cancer cells

et al. 2007

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Diminished expression of the metastasis suppressor protein RKIP was previously reported in a number of cancers. The underlying mechanism remains unknown. Here, we show that the expression of RKIP negatively correlates with that of Snail zinc-transcriptional repressor, a key modulator of normal and neoplastic epithelial-mesenchymal transition (EMT) program. With a combination of loss-of-function and gain-of-function approaches, we showed that Snail repressed the expression of RKIP in metastatic prostate cancer cell lines. The effect of Snail on RKIP was on the level of transcriptional initiation and mediated by a proximal E-box on the RKIP promoter. (Chatterjee et al., 2004;Park et al., 2005). Consistent with its demonstrated inhibitory effect on Raf and NF-kB signaling, we and others have shown that the expression levels of RKIP are downregulated in a number of tumors, including highly metastatic prostate, breast and colon cancer, hepatocellular carcinoma, melanomas and insulinomas (Fu et al., 2003;Chatterjee et al., 2004;Schuierer et al., 2004Schuierer et al., , 2006Zhang et al., 2004;Hegan et al., 2005;Al-Mulla et al., 2006;Lee et al., 2006). The importance of RKIP in metastases was highlighted by the finding that restoration of RKIP expression inhibits prostate cancer metastasis in a murine model (Fu et al., 2003(Fu et al., , 2005. More recent studies have shown that RKIP is also a good prognostic marker of the pathogenesis of human prostate cancer (Fu et al., 2005) and a prognostic indicator for overall survival and disease-free survival in colorectal cancer (Al-Mulla et al., 2006). Collectively, these studies suggest that RKIP is a novel cancer metastasis suppressor and an effector of signal transduction pathways leading to apoptosis. In spite of the abundance of experimental evidence on the deleterious consequences of reduced RKIP expression in tumors, the mechanisms responsible for the downregulation of RKIP in cancer are not completely understood.To set up a system to study the transcription regulation of RKIP, we examined RKIP expression levels in cancer cell lines with different metastatic capacity. In accordance with clinical tumor studies, we observed that expression levels of RKIP proteins progressively decreased in breast and prostate cancer cell lines of increasing metastatic potential. The expression of RKIP is low in invasive and metastatic breast (MB231, MB435 and 578T) and prostate (DU145 and PC3) cell lines and high in noninvasive cell lines like MCF7, BT20 and LNCaP (Figure 1a). Notably, RKIP protein levels correlated well with those of the intercellular adhesion protein E-cadherin (E-cad). E-cad is a well-documented tumor metastasis suppressor protein that is regulated by the Snail and closely related Slug transcription factors (Peinado et al., 2007). Quantitation of RKIP transcript levels in the different cancer cell lines by qRT-PCR demonstrated that they correlated with the levels of the protein, (Figure 1b), suggesting that RKIP expression is downregulated at the RNA level, via changes...

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“…Subsequent studies showed that overexpression of RKIP in prostate and melanoma cell lines suppresses metastasis by decreasing vascular invasion (18,20). Previous studies have described low levels of RKIP in other metastatic tumors, such as breast and colorectal carcinoma (23,45), as well as in many other primary tumors, including GISTs (27), insulinoma (22), hepatocarcinoma (24), ovarian carcinoma (26), merckel cell carcinoma (16) and thyroid carcinoma (15), cutaneous squamous cell carcinoma (46) and nasopharyngeal carcinoma (17).…”

Section: Univariate Analysis Multivariate Analysismentioning

confidence: 99%

“…In cancer, RKIP is considered to be a signal transduction modulator and a metastasis suppressor (14), and down regulated in several human tumors, mainly in highly metastatic carcinomas (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Noteworthy, RKIP has been shown to be a prognostic marker in prostate cancer, colorectal carcinomas, gliomas and GISTs (25,(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Abstract. 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.

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Reduction in Raf Kinase Inhibitor Protein Expression Is Associated with Increased Ras-Extracellular Signal-Regulated Kinase Signaling in Melanoma Cell Lines

Abstract: ABSTRACT

Cited by 166 publications

References 22 publications

Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

Snail is a repressor of RKIP transcription in metastatic prostate cancer cells

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

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