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Role of N-cadherin in epithelial-to-mesenchymal transition and chemosensitivity of colon carcinoma cells

ABSTRACT: Increased N-cadherin expression is a pivotal hallmark and step in epithelial-to-mesenchymal transition (EMT), a trans differentiation process activated by colonic tumor cells to increase their spread and survival in a host organism. Although known to be associated with a considerable tumor aggressiveness and worse patient prognosis, exact mechanism(s) linking N-cadherin expression, EMT and aggressive biological phenotype of tumor cells are not entirely clear. In this study we used and compared two different in vitro cell models with varying N-cadherin expression, i.e. colon cancer cell lines HCT8 and SW480 with artificially upregulated expression of N-cadherin, and colon cancer cells with differing N-cadherin levels obtained from patients. Moreover, we have attempted to investigate the relationship between mesenchymal phenotype of cells (here represented by an increased expression of N-cadherin) and the degree of their chemoresistance. We report that although enforced N-cadherin expression changes select morphological and behavioral characteristics of exposed cells, it fails to successfully reprogram cells to the aggressive, chemoresistant phenotype both in vitro as well as in vivo upon implantation into athymic mice. Conversely, primocultures of patient-colonic cells with naturally high levels of N-cadherin expression show fully aggressive and chemoresistant phenotype pertinent to EMT (in vitro and in vivo), with a potential to develop new mutations and in the presence of dysregulated regulatory pathways as represented by investigated miRNA profiles. These results bring new facts concerning the functional axis of N-cadherin expression and related biological features of colon cancer cells and highlight the colon cancer primocultures as useful models for such studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205027 | GEO | 2022/06/01

REPOSITORIES: GEO

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Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer. Examination of expression of 5-Fluorouracil (5-FU) Panc03.27 cell line resistant clone versus expression of 5-FU sensitive clones (NT) in 4 replicates per cell lines

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Role of N-cadherin in epithelial-to-mesenchymal transition and chemosensitivity of colon carcinoma cells

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