Division of GYN/ONC, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Oncogene. 2024 Nov;43(49):3586-3597. doi: 10.1038/s41388-024-03182-2. Epub 2024 Oct 16.
Endometrial cancer (EC) is the leading gynecologic malignancy in the United States with obesity implicated in 57% of cases. This research investigates the molecular complexities of extracellular vesicles (EV) secretion as carriers of oncogenic protein and their involvement in obesity-mediated EC. An understanding of these mechanisms is pivotal for unraveling pathways relevant to obesity-associated EC, thereby guiding the development of innovative prevention and treatment strategies. Our exploration revealed a significant increase in EV secretion carrying oncogenic proteins (TMEM205, STAT5, and FAS) in adipose and uterine tissues/serum samples from obese EC patients compared to control (without cancer). We identified alterations in EV-regulating proteins (Rab7, Rab11, and Rab27a) in obesity-mediated EC patients, adipose/uterine tissues, and serum samples. Through a 24-week analysis of the effects of a 45% kcal high-fat diet (HFD) on mice, we observed increased body weight, increased adipose tissue, enlarged uterine horns, and increased inflammation in the HFD group. This correlated with elevated levels of EV secretion and increased expression of oncogenic proteins TMEM205, FAS, and STAT5 and downregulation of the tumor suppressor gene PIAS3 in adipose and uterine tissues. Furthermore, our study confirmed that adipocyte derived EV increased EC cell proliferation, migration and xenograft tumor growth. Additionally, we identified that the small molecule inhibitors (HO-3867) or Metformin inhibited EV secretion in vitro and in vivo, demonstrating significant inhibition of high glucose or adipocyte-mediated EC cell proliferation and a reduction in body weight and adipose tissue accumulation when administered to HFD mice. Moreover, HO-3867 or Metformin treatment inhibited HFD induced hyperplasia (precursor of EC) by altering the expression of EV-regulated proteins and decreasing oncogenic protein expression levels. This study provides critical insights into the mechanisms underpinning obesity-mediated EV secretion with oncogenic protein expression, shedding light on their role in EC pathogenesis. Additionally, it offers pre-clinical evidence supporting the initiation of novel studies for EV-targeted therapies aimed at preventing obesity-mediated EC.
子宫内膜癌（EC）是美国主要的妇科恶性肿瘤，肥胖症在其中 57%的病例中起作用。本研究探讨了细胞外囊泡（EV）作为致癌蛋白载体分泌的分子复杂性及其在肥胖介导的 EC 中的作用。这些机制的理解对于揭示与肥胖相关的 EC 相关途径至关重要，从而为开发创新的预防和治疗策略提供指导。我们的研究发现，与对照组（无癌症）相比，肥胖的 EC 患者的脂肪组织和子宫组织/血清样本中携带致癌蛋白（TMEM205、STAT5 和 FAS）的 EV 分泌显著增加。我们在肥胖介导的 EC 患者、脂肪/子宫组织和血清样本中发现了 EV 调节蛋白（Rab7、Rab11 和 Rab27a）的改变。通过对 45%卡路里高脂肪饮食（HFD）对小鼠的 24 周影响分析，我们观察到 HFD 组体重增加、脂肪组织增加、子宫角增大和炎症增加。这与 EV 分泌增加以及致癌蛋白 TMEM205、FAS 和 STAT5 的表达增加以及肿瘤抑制基因 PIAS3 在脂肪和子宫组织中的表达下调相关。此外，我们的研究证实脂肪细胞衍生的 EV 增加了 EC 细胞的增殖、迁移和异种移植肿瘤生长。此外，我们发现小分子抑制剂（HO-3867）或二甲双胍可抑制体外和体内的 EV 分泌，当给予 HFD 小鼠时，可显著抑制高葡萄糖或脂肪细胞介导的 EC 细胞增殖，并减轻体重和脂肪组织积累。此外，HO-3867 或二甲双胍治疗通过改变 EV 调节蛋白的表达和降低致癌蛋白表达水平，抑制 HFD 诱导的过度增生（EC 的前体）。这项研究提供了关于肥胖介导的 EV 分泌与致癌蛋白表达的机制的重要见解，揭示了它们在 EC 发病机制中的作用。此外，它提供了支持针对 EV 靶向治疗的新研究的临床前证据，旨在预防肥胖介导的 EC。
