胃癌外泌体环状RNA激活脂肪细胞PRDM16通路促进白色脂肪褐色化的研究

Tumor patients are usually accompanied by cachexia, performing as accelerated energy consumption and emaciation, which leads to poor prognosis and death of patients. Brown adipose tissue can increase heat production and boost metabolism. Primary studies showed that tumor leads to the “browning” of white adipose tissue, however, the mechanism remains unclear. Exosomes are small vesicles that are secreted from cells and mediate signaling transduction between cells. Based on clinical screening, we found a panel of exosome-circRNAs was clearly up-regulated in gastric cancer (GC), and one was named ciRS-133 for its interaction with miR-133, which is closely related to proliferation of adipose tissue. In vitro experiments showed GC exosomes can transport ciRS-133 into pre-adipocytes, and ciRS-133 absorbs miR-133 and activates PRDM16, thus promoting differentiation of pre-adipocytes into brown adipose tissue. This project is designed to demonstrate that GC exosomes promote browning of white adipose tisse and increase metabolic cachexia, and that exosome-ciRS-133 forms a signaling network with miR-133 and PRDM16. We will also try to inhibit browning of WAT and decrease metabolic disorders by targeting ciRS-133. The current study reveals a novel mechanism of tumor metabolic cachexia, and illustrates a new direction in clinical treatment.

肿瘤患者常伴随能量消耗快、消瘦和肌肉萎缩等恶病质，是造成患者预后差和最终死亡的重要原因。褐色脂肪可增加产热，加速代谢。既往研究发现肿瘤会造成白色脂肪褐色化，可能是恶病质的原因之一，但机制不明。外泌体是细胞分泌的微小囊泡，介导细胞间信号传递。预实验结果显示：胃癌外泌体中有一组环状RNA升高显著，其中一种可结合与脂肪分化相关的miR-133，故被称为ciRS-133；并且胃癌外泌体可携带ciRS-133进入脂肪前体细胞, ciRS-133吸附miR-133并激活PRDM16，促进前体细胞分化为褐色脂肪。据此我们假设：胃癌外泌体环状RNA可促进白色脂肪褐色化，加剧恶病质。本课题拟从临床分析ciRS-133与恶病质相关性；体内和体外实验证明外泌体ciRS-133调控脂肪细胞的关键通路；并尝试靶向ciRS-133，抑制脂肪的褐色化，减轻代谢紊乱。本研究将揭示肿瘤恶病质的新机制，并提供临床治疗新方向。

癌症相关恶病质是一种代谢综合征，以脂肪和骨骼肌的消耗失调为特征，伴有体重减轻和全身炎症。癌症恶病质的治疗选择是有限的，分子机制仍然不清楚。环状rna (circRNAs)是一种新的内源性非编码rna家族，已被提出调控哺乳动物基因表达。外泌体是来自细胞的小泡，最近的研究表明环状rna在外泌体中是稳定的。然而，关于外泌体中环状rna的生物学作用知之甚少。在我们的研究中，我们发现血浆外泌体中的环状rna在胃癌(GC)中具有特定的表达特征，并且ciRS-133与胃癌患者白色脂肪组织(WAT)的褐变有关。来自GC细胞的外泌体将ciRS-133传递到前脂肪细胞，通过激活PRDM16和抑制miR-133促进前脂肪细胞向棕色样细胞的分化。此外，敲除ciRS-133可以减少植入肿瘤小鼠的癌症恶病质，减少氧消耗和热产生。因此，外泌体递送的环状rna参与WAT的褐变，并在癌症相关的恶病质中发挥关键作用。