Magana Gomez, Paulyna Gabriela
(2024)
Understanding the roles and impact of Solute Carrier Transporters OCT1, OCTN1, and OCTN2 in lung epithelia.
PhD thesis, University of Nottingham.
Abstract
The organic cation transporters (OCT) 1, 2, and 3, along with the novel organic cation transporters (OCTN) 1 and 2, are members of the Solute Carrier 22 (SLC22) family, these transporters play significant roles in mediating the intracellular movement of endogenous compounds, including neurotransmitters, L-carnitine, and ergothioneine. Furthermore, numerous drugs used in the management of respiratory disorders exhibit cationic properties at physiological pH, making them potential substrates of OCT/Ns. Additionally, the involvement of OCT/Ns in lung diseases, suggests their possible relevance as novel drug targets Moreover, these proteins significantly influence the efficacy of specific anti-cancer drugs, as the transport of these compounds is mediated by OCT/Ns.
This thesis aimed to investigate the expression of OCT1/SLC22A1, OCTN1/SLC22A4, and OCTN2/SLC22A5 in lung epithelia, with a focus on understanding their roles in various lung pathophysiology. Expression profiles of these transporters were analysed in asthma, chronic obstructive pulmonary disease (COPD), lung adenocarcinoma, and lung squamous carcinoma, where OCTN1 and OCTN2 were downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) using datasets from TCGA and GEO. Analysis revealed a downregulation of OCTNs in lung malignancies, whereas OCTN2 was only found differentially expressed in COPD samples.
Functional impact of OCT/OCTNs was explored using CRISPR-Cas9 to target SLC22 genes in HEK293 cells. Migration, proliferation, and adhesion assays on edited cells suggested a role for SLC22 genes in cell development.
Regulatory mechanisms of OCTN1 expression were investigated, suggesting a potential role for RUNX1 transcription factor binding within the promoter region.
Overall, this work sheds light on the expression patterns and functional roles of SLC22A1, SLC22A4, and SLC22A5 in lung epithelia under various pathological conditions. However, further research is necessary to fully elucidate the mechanisms of gene regulation in lung cells and their relationship to lung cancer development.
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