Cancer Biomarkers - Volume 12, issue 2

Authors: Mackinder, Mary Anne | Evans, Caroline Akrill | Chowdry, Joanna | Staton, Carolyn Ann | Corfe, Bernard Michael

Article Type: Research Article

Abstract: Background: In breast cancer the development of metastasis is a major turning point in the treatment and outcome of the disease. Throughout tumour development, and especially in the development of metastasis, epithelial mesenchymal transition takes place. During this transformation into a mesenchymal phenotype, the tumour cells undergo a series of structural changes. The loss of structural integrity and adoption of mesenchymal filaments enables cells to detach from the epithelial cell layer and metastasise. Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells. During cancer progression the intermediate filaments are reorganised, and dramatic changes are seen …in their protein components. Keratins K8, K18, K19 and vimentin are intermediate filament proteins with altered expression profiles during tumour development. Method: We have used in vivo and in vitro models to analyse changes in intermediate filament proteins. Antibody-based methods were used to study K8 levels and proteomic analysis to profile the protein content of metastatic breast cancer cell variants. Results: K8 expression declines as human breast tumours progress into an invasive phenotype. Analysis of IF proteins indicated altered expression profiles of K8, K18, K19 and vimentin, with K8, K18, K19 expressed in high levels in the T47D and MCF-7 cell lines, whereas the highly metastatic cell lines expressed lower levels of K8 and K18 and no detectable K19. Vimentin showed reverse expression profile with T47D and MCF-7 cells having no detectable vimentin expression whereas the highly metastatic MDA-MB-231 and MDA-MB-436 showed high levels. Analysis of acetylation status using specific antibodies suggested acetylation occurred within the central coiled domain in the MCF-7 and T47D cells. Inhibition of tumour growth by tissue factor (TF) shRNA resulted in a dramatic re-elevation of expression of K8 in xenographs of the highly metastatic MDA-MB-436 line. Conclusion: Intermediate filament expression alters during epithelial mesenchymal transition. Identified post translational modifications may play a role in alterations seen in the organisation, solubility and stability of these filaments. Epithelial mesenchymal transition can be reversed and an epithelial phenotype re-established. Show more

Keywords: Epithelial mesenchymal transition, intermediate filaments, keratins, breast cancer

DOI: 10.3233/CBM-120293

Citation: Cancer Biomarkers, vol. 12, no. 2, pp. 49-64, 2013

Authors: Catarino, R. | Coelho, A. | Nogueira, A. | Araújo, A. | Gomes, M. | Lopes, C. | Medeiros, R.

Article Type: Research Article

Abstract: Cyclin D1 (CCND1) is a key regulatory protein of the cell cycle. The purpose of our study was to assess the role of CCND1 genetic variants influencing the genetic susceptibility of non-small cell lung cancer (NSCLC). We conducted a study of 1234 individuals, including 892 controls and 342 cases. Individuals carrying two G-alleles have a 2-fold increased risk for the development of NSCLC and the waiting time for onset of NSCLC in these patients was 2 years earlier in comparison with other individuals. Our results may be important in contributing to the knowledge of the mechanisms involved in lung carcinogenesis.

Keywords: Cyclin D1, genetic polymorphism, NSCLC

DOI: 10.3233/CBM-130294

Citation: Cancer Biomarkers, vol. 12, no. 2, pp. 65-72, 2013

Authors: Na, Yeonkyung | Lee, Su Man | Kim, Dong Sun | Park, Jae Yong

Article Type: Research Article

Abstract: Dickkopf-1 (DKK1) is known as a negative regulator of the Wnt signaling pathway, which plays a crucial role in carcinogenesis. However, aberrant expression and the role of DKK1 in human cancers remain controversial. To estimate the role of DKK1 and its prognostic potential in lung cancer, promoter methylation of DKK1 was evaluated in 139 primary non-small cell lung cancers (NSCLCs) by methylation-specific PCR and its association with clinical and prognostic parameters. DKK1 hypermethylation was detected in 48.9% of neoplastic lung tissues and was significantly more frequent in stage I than the more advanced stages II-IIIA (P=0.04). Additionally, patients with DKK1 …methylation had a better overall survival than those with no methylation under univariate analysis. When stratified by clinicopathologic features, DKK1 methylation was significantly associated with a favorable survival in a subset of patients. The current findings suggested that DKK1 promoter methylation may be a tumor-associated event in the early stage of NSCLC and could also be useful prognostic indicator for NSCLC. Further work may clarify the molecular basis of DKK1 action in progression of NSCLC. Show more

Keywords: Hypermethylation, NSCLC, DKK1, MSP, prognosis

DOI: 10.3233/CBM-2012-00295

Citation: Cancer Biomarkers, vol. 12, no. 2, pp. 73-79, 2013

Authors: Rucksaken, Rucksak | Khoontawad, Jarinya | Roytrakul, Sittiruk | Pinlaor, Porntip | Hiraku, Yusuke | Wongkham, Chaisiri | Pairojkul, Chawalit | Boonmars, Thidarut | Pinlaor, Somchai

Article Type: Research Article

Abstract: Proteomic analysis was performed to search for the diagnostic biomarkers of the early stage of cholangiocarcinoma (CCA). For this purpose, CCA was experimentally induced in hamsters by the combination of N-nitrosodimethylamine (NDMA) treatment and Opisthorchis viverrini (OV) infection. Pooled plasma of normal control, NDMA-treated, OV-infected and OV + NDMA (ON) treated group was separated by 1-D PAGE, and the trypsin-digested bands were analyzed with LC-MS/MS. Among 82 overexpressed proteins, the study focused on 26 proteins overexpressed in ON group because CCA development was almost exclusively found in this group. A further selection was made based on the protein overexpression on …day 21, the precancerous stage. Orosomucoid 2 (Orm2) was overexpressed in OV and ON groups and kinesin 18A (KIF18A) was overexpressed in the ON group. The overexpression levels were verified by real-time RT-PCR and western blotting in the liver and plasma. The transcription and translation levels of these two candidate molecules increased significantly at 21 days post-treatment before tumor development. Immunohistochemistry revealed KIF18A was expressed in the epithelial cells of newly formed small bile ducts, some inflammatory cells and hepatocytes. These results suggest that Orm2 and KIF18A could be the potential biomarkers for early diagnosis of CCA. Show more

Keywords: Opisthorchis viverrini, cholangiocarcinoma, orosomucoid 2, kinesin 18A, plasma proteome

DOI: 10.3233/CBM-130296

Citation: Cancer Biomarkers, vol. 12, no. 2, pp. 81-95, 2013

Authors: Canis, Martin | Lechner, Axel | Mack, Brigitte | Zengel, Pamela | Laubender, Rüdiger Paul | Koehler, Udo | Heissmeyer, Vigo | Gires, Olivier

Article Type: Research Article

Abstract: Background: The pentaspan protein CD133 (Prominin-1) is a predictive marker and part of the signature of tumour-initiating cells (TICs) for various cancer entities. Methods: The correlation of CD133 expression with clinical parameters was assessed in primary samples of head and neck squamous cell carcinomas (n=98) and normal mucosas (n=24). Results: A gradual and inversely proportional correlation between CD133 expression in primary tumours and decreased overall survival was observed, along with a positive correlation with the presence of lymph node metastases. Conclusions: CD133 has the potential of being a novel clinically relevant prognostic marker for …head and neck malignancies, which is possibly involved in regulation of tumourigenicity. Show more

Keywords: CD133, HNSCCs, overall survival

DOI: 10.3233/CBM-130297

Citation: Cancer Biomarkers, vol. 12, no. 2, pp. 97-105, 2013