Alterations in gene expression induced by oxaliplatin-based chemotherapy in colorectal cáncer

  1. Deborah Rotoli
Supervised by:
  1. Pablo Martín Vasallo Director
  2. Julio Tomás Ávila Marrero Director
  3. Manuel Morales Director

Defence university: Universidad de La Laguna

Year of defence: 2017

Department:
  1. Bioquímica, Microbiología, Biología Celular y Genética

Type: Thesis

Abstract

We analized the expression of the scaffold proteins IQGAP1, FKBP51 and AmotL2 and the Na,K-ATPase α and β subunits in colorectal cancer and liver metastases after the administration of oxaliplatin-based chemotherapy. Double immuno-fluorescence protein localization, along with specific cell markers, on human cancer tissue specimens, showed that the expression levels and the subcellular redistribution of IQGAP1, FKBP51 and AmotL2 proteins in CRC cells, as well as the altered pattern of protein expression detected in tumour affected areas of CRC and related metastases, are indicative of the involvement of this scaffold proteins in CRC tumorigenesis and progression, as well as in the EMT process. The co-localization of the three proteins with CD34 and/or CD31 in several cell vessels, including expression in pericytes and/or telocytes, suggests their involvement in tumour angiogenesis and/or in vascular invasion. Due to the key role that these scaffold proteins exert in the dynamics of tumor cells, they represent an attractive group of interacting proteins that could be used as biomarkers for diagnostic staging and as targets for therapy. The expression pattern and localization of the α and β subunits of the Na,K-ATPase is also affected in CRC, in metastases and in metastasized liver tissue. The α1, α3 and β1 isoforms are the most highly expressed in tumour cells and metastases. The high levels of perinuclear and cytoplasmic α3 isoform detected in malignant liver tissues, suggests moonlighting functions for this isoform, besides ion transport. Based on the data collected in this study, the possible predominant isozymes present in tumour and metastatic cells are α1β1 and α3β1, which exhibit the highest and lowest sodium ion affinity respectively, and the highest potassium ion affinity. These isozymes are likely to favor optimal conditions for the function of nuclear enzymes involved in mitosis. Double immunofluorescent labelling of α3 and β1 subunits in liver metastases tissue samples, confirms the co-localization of both isoforms in malignant cells, and suggests the possible role for this isozyme as a novel biomarker for CRC metastatic cells in liver