Researchers from IPATIMUP identified a molecule that can influence gastric cancer progression

Gastric cancer is one of the most prevalent and fatal in the world, especially due to its invasive nature, and the capacity to metastasize at distance, frequently without symptoms. E-cadherin is one of the most important structural molecules in the stomach, and its expression in the gastric epithelia suppresses cancer development. Carriers of mutations in the gene encoding E-cadherin have high probability of developing hereditary diffuse gastric cancer. Strategies aiming to prevent the loss of E-cadherin expression enclose high therapeutic potential for gastric cancer.

In this work, published in Human Molecular Genetics, researchers from the Cancer Genetics group of IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto) have identified DNAJB4 as a new molecular regulator of E-cadherin. It influences E-cadherin expression in gastric cell models, and is able to distinguish the mutant forms associated to hereditary cancer. DNAJB4 belongs to the family of molecular chaperones, which major function is to modulate the structure of other proteins. The results demonstrate that DNAJB4 influences E-cadherin stability, determines the lifetime of its mutant forms in the cell, and consequently influences cell adhesion. The anti-invasive role of DNAJB4 was demonstrated using an animal model, and its loss of expression in gastric cancer suggests that DNAJB4 acts as a tumor suppressor in the stomach.

The study was coordinated by Joana Simões Correia and centred in IPATIMUP, but gathered researchers from other institutions, such as INEB - Instituto de Engenharia Biomédica and IBILI – Instituto de Imagem Biomédica e Ciências da Vida, using a multidisciplinary approach. The elucidation of this new molecular mechanism of E-cadherin regulation might support the development of new therapeutic strategies for gastric cancer.

Authors and affiliations:

Joana Simões-Correia1,2, Diana I. Silva1,3, Soraia Melo1, Joana Figueiredo1, Joana Caldeira1,4, Marta T Pinto1, Henrique Girão2, Paulo Pereira2, Raquel Seruca1,5

1.IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal;

2.IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;

3.ICBAS – Institute of Biomedical Sciences Abel Salazar, University of Porto, 4099-001 Porto, Portugal

4.INEB - Instituto de Engenharia Biomédica, University of Porto, 4150-180 Porto, Portugal;

5.Medical Faculty of the University of Porto, 4200-319 Porto, Portugal;

Abstract:

E-cadherin (Ecad) is a well-known invasion suppressor and its loss of expression is common in invasive carcinomas. Germline Ecad mutations are the only known genetic cause of Hereditary Diffuse Gastric Cancer (HDGC), demonstrating the causative role of Ecad impairment in gastric cancer. HDGC-associated Ecad missense mutations can lead to folding defects and premature proteasome-dependent Endoplasmic Reticulum Associated Degradation (ERAD), but the molecular determinants for this fate were unidentified. Using a Drosophila-based genetic screen, we found that Drosophila DnaJ-1 interacts with WT (Wild Type) and mutant human Ecad in vivo. DNAJB4, the human homolog of DnaJ-1, influences Ecad localization and stability even in the absence of Ecad endogenous promoter, suggesting a post-transcriptional level of regulation. Increased expression of DNAJB4 leads to stabilization of WT Ecad in the plasma membrane, while it induces premature degradation of unfolded HDGC mutants in the proteasome. The interaction between DNAJB4 and Ecad is direct, and is increased in the context of the unfolded mutant E757K, especially when proteasome degradation is inhibited, suggesting that DNAJB4 is a molecular mediator of ERAD. Post-translational regulation of native Ecad by DNAJB4 molecular chaperone is sufficient to influence cell adhesion in vitro. Using a chick embryo chorioallantoic membrane (CAM) assay with gastric cancer derived cells, we demonstrate that DNAJB4 stimulates the anti-invasive function of WT Ecad in vivo. Additionally, the expression of DNAJB4 and Ecad is concomitantly decreased in human gastric carcinomas. Altogether, we demonstrate that DNAJB4 is a sensor of Ecad structural features that might contribute to gastric cancer progression.

Journal:

Human Molecular Genetics

Link:

http://hmg.oxfordjournals.org/content/early/2013/12/13/hmg.ddt602