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Epithelial-Mesenchymal Transition in Cancer – Relevance of Periostin Splice Variants


Morra, Laura. Epithelial-Mesenchymal Transition in Cancer – Relevance of Periostin Splice Variants. 2011, ETH Zurich.

Abstract

Our study represents a comprehensive analysis of the epithelial-mesenchymal transition (EMT) marker periostin and its splice isoforms in renal cell carcinoma (RCC) and in non-small cell lung cancer (NSCLC). EMT can occur in both RCC and NSCLC, but the molecular mechanisms involved in this complex process are poorly understood. The matrix N-glycoprotein periostin can promote EMT of carcinoma cells and enhance tumor invasion. It shares homology with the insect cell adhesion molecule fasciclin 1 and acts as a ligand for the integrins, promoting the activation of the Akt/PKB and the FAK-mediated signalling pathways. Periostin-activated signaling pathways lead to cellular survival, resistance to hypoxia-induced cell death, angiogenesis and EMT. Periostin is expressed in normal tissues such as placenta, cardiac valves and periosteum, and it is upregulated in several types of cancer such as lung and kidney cancer. There are several isoforms generated by alternative splicing in the C-terminal region of periostin which are thought to modulate the periostin function in the extracellular matrix (ECM). The aim of this thesis was to study the periostin expression and to analyze the periostin isoform pattern in both RCC and NSCLC. For these purposes, we investigated the expression levels of periostin RNA and protein and the expression pattern of its spliced transcripts. We found that periostin was upregulated in RCC as well as in NSCLC at both mRNA and protein levels. For both tumor types, the periostin protein was expressed in epithelial tumor cells as well as in the ECM and in the mesenchymal cells of the tumor stroma. In RCC, periostin mRNA levels were higher in the clear cell than in the papillary subtype (p<0.01). In the clear cell subtype, periostin protein expression in epithelial tumor cells correlated with presence of sarcomatoid differentiation (p<0.001), higher tumor stage (p<0.001), lymph node metastases (p<0.05) and poor overall survival (p=0.009). In NSCLC, periostin mRNA levels correlated with the adenocarcinoma histotype (p<0.05). In epithelial tumor cells, the immunohistochemically detected periostin protein correlated with tumor grade and size (p<0.05), and with tumor histotype (p<0.001). The periostin isoform 16 pattern was characterized at RNA level and, among the several periostin isoforms detected in fetal, cancerous and healthy adult tissues of the kidney and of the lung, five transcripts were newly identified in this study. On the basis of these data, we can conclude that the periostin protein expression in both tumor types may contribute to the EMT and play a role in metastasis. Additionally, the presence of a renal tumor-associated periostin isoform suggests splice-specific regulation in tumor tissue.

Our study represents a comprehensive analysis of the epithelial-mesenchymal transition (EMT) marker periostin and its splice isoforms in renal cell carcinoma (RCC) and in non-small cell lung cancer (NSCLC). EMT can occur in both RCC and NSCLC, but the molecular mechanisms involved in this complex process are poorly understood. The matrix N-glycoprotein periostin can promote EMT of carcinoma cells and enhance tumor invasion. It shares homology with the insect cell adhesion molecule fasciclin 1 and acts as a ligand for the integrins, promoting the activation of the Akt/PKB and the FAK-mediated signalling pathways. Periostin-activated signaling pathways lead to cellular survival, resistance to hypoxia-induced cell death, angiogenesis and EMT. Periostin is expressed in normal tissues such as placenta, cardiac valves and periosteum, and it is upregulated in several types of cancer such as lung and kidney cancer. There are several isoforms generated by alternative splicing in the C-terminal region of periostin which are thought to modulate the periostin function in the extracellular matrix (ECM). The aim of this thesis was to study the periostin expression and to analyze the periostin isoform pattern in both RCC and NSCLC. For these purposes, we investigated the expression levels of periostin RNA and protein and the expression pattern of its spliced transcripts. We found that periostin was upregulated in RCC as well as in NSCLC at both mRNA and protein levels. For both tumor types, the periostin protein was expressed in epithelial tumor cells as well as in the ECM and in the mesenchymal cells of the tumor stroma. In RCC, periostin mRNA levels were higher in the clear cell than in the papillary subtype (p<0.01). In the clear cell subtype, periostin protein expression in epithelial tumor cells correlated with presence of sarcomatoid differentiation (p<0.001), higher tumor stage (p<0.001), lymph node metastases (p<0.05) and poor overall survival (p=0.009). In NSCLC, periostin mRNA levels correlated with the adenocarcinoma histotype (p<0.05). In epithelial tumor cells, the immunohistochemically detected periostin protein correlated with tumor grade and size (p<0.05), and with tumor histotype (p<0.001). The periostin isoform 16 pattern was characterized at RNA level and, among the several periostin isoforms detected in fetal, cancerous and healthy adult tissues of the kidney and of the lung, five transcripts were newly identified in this study. On the basis of these data, we can conclude that the periostin protein expression in both tumor types may contribute to the EMT and play a role in metastasis. Additionally, the presence of a renal tumor-associated periostin isoform suggests splice-specific regulation in tumor tissue.

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Additional indexing

Item Type:Dissertation
Referees:Neri Dario, Moch Holger, Detmar Michael
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:19 Dec 2012 13:05
Last Modified:05 Apr 2016 16:13
Number of Pages:168
Related URLs:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205268/
Permanent URL: https://doi.org/10.5167/uzh-69016

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