Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 6/2012

01-08-2012 | Research Paper

RAF-kinase inhibitor protein (RKIP) downregulation in esophageal cancer and its metastases

Authors: Peter Birner, Bettina Jesch, Andrea Schultheis, Sebastian F. Schoppmann

Published in: Clinical & Experimental Metastasis | Issue 6/2012

Login to get access

Abstract

Raf kinase inhibitor protein (RKIP) is an inhibitor of Raf-mediated activation of mitogen-activated protein (MAP) kinase (MEK)-MAP kinase and is considered as an important tumor suppressor. RKIP-expression was investigated retrospectively in 321 esophageal cancers [179 adenocarcinomas (ACs), 142 squamous cell carcinomas (SCCs)]. RKIP-expression was further investigated in 41 precursor lesions consisting of 14 cases of non-dysplastic Barrett’s mucosa, 5 low grade dysplasias (LGD), and 12 high grade dysplasias (HGD) as well as, 4 cases with low grade and 6 cases with high-grade squamous cell dysplasia. Corresponding lymph node metastases were investigated in 140 patients, distant metastases in 29, and local recurrences in 12. High RKIP-expression was significantly more common in Barrett’s mucosa without dysplasia and in LGD compared to HGD (p = 0.047, χ2 test) and invasive AC (p < 0.001, χ2 test). In 187 primary esophageal cancers (58.3 %) RKIP was downregulated (AC: 51.4 %; SCC: 66.9 %). RKIP status of primary tumors influenced RKIP expression in corresponding lymph node and distant metastases (p < 0.05, linear regression). Downregulation of RKIP was associated with shorter overall survival (OS) and disease free survival (DFS) in all tumors (p ≤ 0.05, Cox regression). In AC, downregulation of RKIP was an independent prognostic factor for OS and DFS (p ≤ 0.05, Cox regression), while in SCC it reached significance only in univariate analysis (p ≤ 0.05, log-rank test). In conclusion, downregulation of RKIP is associated with shorter survival in esophageal cancers, and RKIP status of tumor cells seems to be preserved at the formation of metastases. Inhibition of RKIP-downregulation might reduce the ability of esophageal cancers to establish disseminated disease.
Literature
1.
Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293(5532):1068–1070PubMedCrossRef
2.
3.
Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5(1):37–50PubMedCrossRef
4.
Yeung K et al (2000) Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol 20(9):3079–3085PubMedCrossRef
5.
Yeung K et al (1999) Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401(6749):173–177PubMedCrossRef
6.
Al-Mulla F et al (2008) Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability. J Clin Pathol 61(4):524–529PubMedCrossRef
7.
Yeung KC et al (2001) Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Mol Cell Biol 21(21):7207–7217PubMedCrossRef
8.
9.
Driessen A et al (2006) Expression of carbonic anhydrase IX (CA IX), a hypoxia-related protein, rather than vascular-endothelial growth factor (VEGF), a pro-angiogenic factor, correlates with an extremely poor prognosis in esophageal and gastric adenocarcinomas. Ann Surg 243(3):334–340PubMedCrossRef
10.
Tanaka N et al (2008) Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer 99(9):1468–1475PubMedCrossRef
11.
Beshir AB et al (2010) Raf kinase inhibitor protein suppresses nuclear factor-kappaB-dependent cancer cell invasion through negative regulation of matrix metalloproteinase expression. Cancer Lett 299(2):137–149PubMedCrossRef
12.
Li TT et al (2009) Beta-arrestin/Ral signaling regulates lysophosphatidic acid-mediated migration and invasion of human breast tumor cells. Mol Cancer Res 7(7):1064–1077PubMedCrossRef
13.
Li HZ et al (2009) Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer. Mol Cancer Res 7(6):832–840PubMedCrossRef
14.
Li HZ et al (2008) Effects of raf kinase inhibitor protein expression on metastasis and progression of human epithelial ovarian cancer. Mol Cancer Res 6(6):917–928PubMedCrossRef
15.
Schuierer MM et al (2004) Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res 64(15):5186–5192PubMedCrossRef
16.
Chatterjee D et al (2004) RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J Biol Chem 279(17):17515–17523PubMedCrossRef
17.
Woods Ignatoski KM et al (2008) Loss of Raf kinase inhibitory protein induces radioresistance in prostate cancer. Int J Radiat Oncol Biol Phys 72(1):153–160PubMedCrossRef
18.
Zaravinos A et al (2009) BRAF and RKIP are significantly decreased in cutaneous squamous cell carcinoma. Cell Cycle 8(9):1402–1408PubMedCrossRef
19.
Paulson TG et al (2009) Chromosomal instability and copy number alterations in Barrett’s esophagus and esophageal adenocarcinoma. Clin Cancer Res 15(10):3305–3314PubMedCrossRef
20.
Ruan L et al (2010) Raf kinase inhibitor protein correlates with sensitivity of nasopharyngeal carcinoma to radiotherapy. J Cell Biochem 110(4):975–981PubMedCrossRef
21.
Zlobec I et al (2008) Two-marker protein profile predicts poor prognosis in patients with early rectal cancer. Br J Cancer 99(10):1712–1717PubMedCrossRef
22.
Minoo P et al (2007) Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. Am J Clin Pathol 127(5):820–827PubMedCrossRef
23.
Hagan S et al (2005) Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res 11(20):7392–7397PubMedCrossRef
24.
Fu Z et al (2006) Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate 66(3):248–256PubMedCrossRef
25.
Chatterjee D et al (2008) Inverse association between Raf Kinase Inhibitory Protein and signal transducers and activators of transcription 3 expression in gastric adenocarcinoma patients: implications for clinical outcome. Clin Cancer Res 14(10):2994–3001PubMedCrossRef
Metadata
Title
RAF-kinase inhibitor protein (RKIP) downregulation in esophageal cancer and its metastases
Authors
Peter Birner
Bettina Jesch
Andrea Schultheis
Sebastian F. Schoppmann
Publication date
01-08-2012
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 6/2012
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-012-9470-8

Other articles of this Issue 6/2012

Clinical & Experimental Metastasis 6/2012 Go to the issue

Research Paper

Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models

Research Paper

CCL27–CCR10 and CXCL12–CXCR4 chemokine ligand-receptor mRNA expression ratio: new predictive factors of tumor progression in cutaneous malignant melanoma

Research Paper

Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer

Research Paper

In vivo imaging of colorectal cancer growth and metastasis by targeting MACC1 with shRNA in xenografted mice

Research Paper

Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Research Paper

The histological growth pattern of colorectal cancer liver metastases has prognostic value
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits