E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade

Authors and Affiliations:
Caldeira J ¹*, Figueiredo J ²*, Brás-Pereira C ³, Carneiro P ², Moreira AM ², Pinto MT ², Relvas JB ⁴, Carneiro F ⁵, Barbosa M ⁶, Casares F ⁷, Janody F ³, Seruca R ⁸.
*The authours contributed equally
¹ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Andalusian Centre for Developmental Biology (CABD), Seville, Spain, Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S).
² Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S).
³ Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal.
⁴ Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
⁵ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal, Centro Hospitalar São João, Porto, Portugal and.
⁶ Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS), Porto, Portugal.
⁷ Andalusian Centre for Developmental Biology (CABD), Seville, Spain.
⁸ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal.

Abstract:

Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor-prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focused on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis, nonetheless, at the invasive front, cells ectopically expressed Laminin A and βPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), β1 and β4 integrin, when compared with Ecad-competent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the first evidence that ectopic Laminin expression depends on Ecad loss, and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signaling regulators as molecular targets to impair gastric cancer progression.

Journal: Human Molecular Genetics
 

Link: http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=26246502