RESUMO
Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
Assuntos
Arginina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Arginina/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismoRESUMO
Colorectal carcinoma (CRC) is one of the most common types of digestive cancer. It has been reported that the ectopic expression of microRNAs (miRs) plays a critical role in the occurrence and progression of CRC. In addition, it has also been suggested that miR151a5p may serve as a useful biomarker for the early detection and treatment of different types of cancer and particularly CRC. However, the specific effects and underlying mechanisms of miR151a5p in CRC remain elusive. The results of the current study demonstrated that miR151a5p was upregulated in CRC cell lines and clinical tissues derived from patients with CRC. Functionally, the results showed that miR151a5p significantly promoted CRC cell proliferation, migration and invasion. Additionally, dual luciferase reporter assays verified that agmatinase (AGMAT) was a direct target of miR151a5p and it was positively associated with miR151a5p expression. Mechanistically, miR151a5p could enhance the epithelialmesenchymal transition of CRC cells. Taken together, the results of the current study revealed a novel molecular mechanism indicating that the miR151a5p/AGMAT axis could serve a crucial role in the regulation of CRC and could therefore be considered as a potential therapeutic strategy for CRC.
Assuntos
Neoplasias Colorretais , MicroRNAs , Ureo-Hidrolases , Humanos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Ureo-Hidrolases/genética , Ureo-Hidrolases/metabolismoRESUMO
Agmatine is an endogenous NMDA (N-methyl-d-aspartate) antagonist which is synthesized from l-Arginine and described as a novel neurotransmitter. Agmatine is considered to play an important role for the development of schizophrenia. The aim of the present study is to explore the role of agmatine and l-arginine metabolism in medication-naive first-episode psychosis (FEP). We conducted a case control study in medication-naive patients with FEP (nâ¯=â¯40). The healthy volunteers with no family history of schizophrenia (nâ¯=â¯35) matched for age, gender and education level were selected as a control group. The patients were recruited to the study and followed up for 10â¯weeks. The plasma l-arginine, l-citrulline, l-ornithine and agmatine levels were measured using modified liquid chromatography/mass spectrometry. The plasma levels of l-arginine, l-citrulline and agmatine (pâ¯<â¯0.0001), but not l-ornithine and agmatinase (pâ¯>â¯0.05), were significantly increased during baseline analysis. After 10â¯weeks of treatment, plasma l-arginine and l-citrulline levels were still significantly increased (pâ¯<â¯0.05) while l-ornithine and agmatinase levels remained unchanged (pâ¯>â¯0.05). Conversely, plasma agmatine levels were significantly decreased after the treatment (pâ¯<â¯0.0001). Positive and negative predictive values of agmatine used for evaluating the diagnostic accuracy were 95.1% and 97.1%, respectively (pâ¯<â¯000.1). This is the first study of arginine metabolism and agmatine in medication-naive first-episode patients and provides evidence of increased levels of an endogenous NMDA antagonist which decreases following antipsychotic treatment.