RESUMEN
Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C (UBE2C) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of UBE2C increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1-mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of UBE2C significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.
Asunto(s)
Metástasis Linfática , Enzimas Ubiquitina-Conjugadoras , Ubiquitinación , Neoplasias de la Vejiga Urinaria , Enzimas Ubiquitina-Conjugadoras/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Animales , Ratones , Línea Celular Tumoral , Linfangiogénesis/genética , Femenino , Masculino , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASCRESUMEN
A field experiment was conducted to study the effects of four cultivation modes (conventional tillage, no-tillage, conventional tillage + stubble-remaining, and no-tillage + stubble-remaining) on the activities of urease, acid phosphatase, protease, and cellulose in different soil layers in a broadcasting rice seedlings paddy field. Under the four cultivation modes, the activities of test enzymes were higher in upper than in deeper soil layers, and had a greater difference between the soil layers under no-tillage + stubble-remaining. In upper soil layers, the activities of test enzymes were higher in the treatments of no-tillage than in the treatments of conventional tillage, being the highest under no-tillage + stubble-remaining and the lowest under conventional tillage. In deeper soil layers, the test enzyme activities were the highest under conventional tillage + stubble-remaining, followed by no-tillage + stubble-remaining, no-tillage, and conventional tillage. During the growth period of rice, soil urease and cellulose activities were lower at tillering stage, increased to the maximum at booting stage, and decreased then, soil acid phosphatase activity was higher at tillering stage but lower at elongating stage, whereas soil protease activity peaked at tillering and heading stages.
Asunto(s)
Agricultura/métodos , Enzimas/metabolismo , Oryza/crecimiento & desarrollo , Tallos de la Planta/química , Suelo/análisis , Fosfatasa Ácida/metabolismo , Celulosa/metabolismo , Oryza/metabolismo , Ureasa/metabolismoRESUMEN
A field experiment was conducted on a paddy field to study the effects of returning straw to soil and different tillage methods (no-tillage + returning straw, no-tillage, tillage + returning straw, and tillage) on the fertility level and microbial quantities of different soil layers. The results showed that in upper soil layer, the organic matter content in treatment 'no-tillage + returning straw' was 5.33, 2.79, and 5.37 g x kg(-1) higher than that in treatments 'no-tillage', 'tillage + returning straw', and 'tillage', respectively, and the contents of total and available N, P and K in treatment 'no-tillage + returning straw' were also the highest, followed by in treatments 'no-tillage' and 'tillage + returning straw', and in treatment 'tillage'. In deeper soil layer, all the fertility indices were higher in treatment 'tillage + returning straw'. Treatments of 'returning straw to soil' had the highest quantities of soil microbes. The quantities of bacteria, fungi, and actinomycetes in upper soil layer were the highest in treatment 'no-tillage + returning straw', and thus, the cellulose decomposition intensity in this treatment at maturity period was 26.44%, 79.01%, and 98. 15% higher than that in treatments 'tillage + returning straw', 'no-tillage', and 'tillage', respectively. In deeper soil layer, the quantities of bacteria, fungi, and actinomycetes were the highest in treatment 'tillage + returning straw'. Treatment 'no-tillage + returning straw' had the features of high fertility and abundant microbes in surface soil layer. The quantities of soil bacteria and actinomycetes and the decomposition intensity of soil cellulose were significantly positively correlated with soil fertility level.