EVALUATION OF THE LEUKOTRIENE B4 (LTB4) SIGNALLING PATHWAY LTA4H/LTB4/BLT2 ON DIFFERENT STAGES OF LIVER CANCER DEVELOPMENT

OVIEDO BUSTOS, L; CEBALLOS, MP; COMANZO, CG; FERRETTI, AC; FRATTINI, M; PALMA, NF; VERA, MC; QUIROGA, AD; ALVAREZ, ML

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

LTB4 is generated from arachidonic acid through the sequentialaction of several enzymes, including leukotriene A4 hydrolase(LTA4H). LTB4 is overexpressed in different types of cancers andplays a key role in cancerous cell proliferation. Additionally, recentstudies indicate that the activation of BLT2 (a cell surface receptorfor LTB4 and 12‑hydroxyeicosatetraenoic acid) is necessary for cellproliferation, survival and metastasis; however, its role in hepatocellularcarcinoma (HCC) remains largely unknown. Aim: to assess thestatus of LTA4H/LTB4/BLT2 signalling pathway on different stages ofhepatocarcinogenesis, using animal models. Methods: Early-stageliver cancer (preneoplasia) was evaluated using a two-stage chemicalcarcinogenic model in adult male Wistar rats (initiator: diethynitrosamine(DEN); promotor: 2-acetylaminofluorene). Preneoplasticlesions developed after 6 weeks of treatment. A late stage of hepatocarcinogenesiswas evaluated using a single dose of DEN in14-day-old C57/BL6 mice. HCC developed after 10 months. LTA4Hand BLT2 expressions were tested by western blot assays in ratpreneoplastic livers, mouse HCC tissues and healthy livers. Results:Western blot studies showed a significant increase in the expressionof LTA4H and BLT2 proteins between healthy and preneoplastic livers[LTA4H (arbitrary units, AU): Healthy: 2080± 163, preneoplastic:3258±177*; BLT2 (AU) Healthy: 1664±264, preneoplastic: 3476±427*]. In addition, the expressions of LTA4H and BLT2 were significantlydifferent between healthy and HCC livers [LTA4H (AU):Healthy: 2531±524 HCC: 3812±123*; BLT2 (AU) Healthy: 672±104,HCC: 2196±366]. *p<0.05 vs healthy tissue of each correspondingmodel. Conclusion: The present results, despite being preliminary,indicate that LTA4H/LTB4/BLT2 signalling pathway might be involvedin the different stages of liver cancer development. Targetingthis signalling pathway could establish future strategies for the treatmentof liver cancer.