Role of Monocarboxylate transporter in lung development and lung cancer

Some studies suggest that lung tumour cell ontogeny is determined by consequences of gene expression that recapitulate important events in embryonic lung development. Hypoxia plays a crucial role either in physiological or pathological conditions such in tumour growth, and in embryonic and fetal development, being one of the most important extracellular factors for lung morphogenesis. In order to adapt to environmental hypoxia, cells rely on anaerobic glycolysis, resulting in increased production of acids, mostly lactic acid. Some studies demonstrated that the control of intracellular pH (pHi) could be carried out by a family of transporters which are H+- monocarboxylate co-transporters, known as monocarboxylate transporters (MCTs). These studies show evidence for the expression of MCTs during early development of human and mouse embryos and in embryo pre-implantation. As in embryonic development, tumour cells take advantage of MCTs to maintain tumour intracellular pH, by promoting the efflux of accumulating acids. There are studies showing the upregulation of MCTs in several solid tumours such as colorectal carcinomas, cervix carcinoma and breast tumours. Regarding lung tumours the results published so far are controversial. MCT family comprises 14 members however only MCT1-MCT4 are proton symporters that exhibit different affinities for lactate, leading to different levels of tissue expression. Ancillary protein, named CD147 is required to maintain the catalytic activity of and the translocation to the plasma membrane of MCT1 and MCT4. Since tumourigenesis and embryogenesis exhibit some common features, such as low oxygen availability, this work aims to study and characterize the role of MCTs both in lung development and lung cancer and thus seek for the metabolic adaptations common to both embryo and tumour development. In lung development, MCT1, MCT4 and CD147 expression was evaluated during human and rat fetal lung development and the effect of MCT inhibition was evaluated on the morphogenesis of rat fetal lung explants. Importantly, MCT1, MCT4 and CD147 were differently expressed during the different phases of lung development suggesting that these molecules are important for lung morphogenesis. Moreover we exposed rat fetal lung explants to the MCT inhibitor CHC and we observed an inhibitory effect on lung branching and viability, in a dose dependent way. Moreover, in lung cancer, MCT1, MCT4 and CD147 were evaluated in a human lung cancer series and in order to understand the influence of MCTs inhibition in lung cancer we disrupted CD147 using the zinc finger technology. The effect the knockout (KO) of CD147 was evaluated using in vitro and in vivo models. Regarding lung cancer, MCT1, MCT4 and CD147 were upregulated in tumour samples when compared with non-tumoural adjacent tissue. With the KO of CD147 we decreased the expression and activity of MCT1 and MCT4. Moreover, the clonal growth of KO cells is inhibited in vitro after oxidative phosphorylation (OXPHOS) inhibition with phenformin and we observed a more pronounced decrease in tumour growth in vivo of KO cells to the treatment with phenformin. To conclude, this study suggests that MCTs are important molecules in the physiology of lung development and provide evidence supporting the exploitation of MCTs/CD147 as therapeutic targets. However, further studies, particularly using specific MCTs/CD147 blockers are urgently needed.

Name thesis:degree_name

Tese de doutoramento em Ciências da Saúde

Year dc:date.issued

2013

Author dc:creator

• Granja, Sara Costa

Advisors dc:contributor.advisor

• Baltazar, Fátima
• Pinto, Jorge Correia

Statement dc:rights

• openAccess

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1822/28874

OAI record oai:identifier

http://repositorium.sdum.uminho.pt/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arepositorium.uminho.pt%3A1822%2F28874