背景:癌周围脂肪组织的富集是结直肠癌(CRC)的一个独特特征,加速疾病进展和恶化预后。肿瘤细胞与邻近脂肪细胞之间的通讯在CRC进展中起着至关重要的作用。然而,精确的调节机制在很大程度上是未知的。本研究旨在探讨迁移侵袭抑制蛋白(MIIP)下调在肿瘤细胞-脂肪细胞通讯重塑中的作用机制及其在促进CRC中的作用。
结果:发现在CRC组织中MIIP表达降低,并且与邻近脂肪细胞褐变密切相关。在体外共培养模型中,用MIIP下调的肿瘤上清液处理的脂肪细胞显示出加重的褐变和脂解。在与脂肪细胞和MIIP下调的鼠CRC细胞共同注射的皮下同种异体移植小鼠中进一步证实了这一发现。机械上,MIIP与关键脂质动员因子AZGP1相互作用,并通过干扰其与STT3A的关联来调节AZGP1的糖基化状态。MIIP下调促进肿瘤细胞中AZGP1的N-糖基化和过度分泌。随后,AZGP1通过cAMP-PKA途径诱导脂肪细胞褐变和脂解,将游离脂肪酸(FFA)释放到微环境中。这些FFA作为主要能源,促进CRC细胞增殖,入侵,和凋亡抗性,伴随着代谢重编程。在荷瘤小鼠模型中,抑制β-肾上腺素受体或FFA摄取,联合奥沙利铂,显著改善MIIP表达异常的CRC的治疗效果。
结论:我们的数据表明,MIIP通过调节AZGP1的N-糖基化和分泌在CRC与邻近脂肪组织之间的通讯中起调节作用。MIIP减少导致AZGP1过度分泌,导致脂肪褐变诱导的CRC快速进展和不良预后。抑制β-肾上腺素受体或FFA摄取,联合奥沙利铂,可能代表了具有异常MIIP表达的CRC的有希望的治疗策略。
BACKGROUND: The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (
MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC.
RESULTS: MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with
MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically,
MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1\'s glycosylation status by interfering with its association with STT3A.
MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression.
CONCLUSIONS: Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.