肠内酯联合m6A阅读蛋白IGF2BP3可抑制卵巢癌的恶性血管生成和疾病进展。
Enterolactone combined with m6A Reader IGF2BP3 inhibits malignant angiogenesis and disease progression in ovarian cancer.
作者信息
Xu Mengzhi, Guo Yi, Wang Fengge, Lin Caiji, Cao Danli, Yan Yu, Chai Shuhui, Zhao Yufan, Deng Shimenghui, Wei Jiayu, Kang Xin, Liu Yuhan, Zhang Yinuo, Luo Lingjie, Liu Shu-Lin, Liu Huidi
机构信息
Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China.
College of Life Science, Northeast Forestry University, Harbin, Heilongjiang, 150040, PR China.
出版信息
Phytomedicine. 2025 Jan;136:156343. doi: 10.1016/j.phymed.2024.156343. Epub 2024 Dec 21.
BACKGROUND
Among all gynecological cancers, ovarian cancer is the leading cause of death. Epithelial ovarian cancer (EOC) accounts for over 85 % of ovarian cancer cases and is characterized by insidious onset, early metastasis, and a high recurrence rate. Alterations in gut microbiota, often as a consequence of chemotherapy, can promote cancer development and exacerbate the disease. The m6A reader IGF2BP3 is a regulator in the occurrence and progression of various tumors and is associated with angiogenesis. Enterolactone (ENL) has demonstrated significant anti-tumor activity against various human cancers, including EOC. However, whether ENL could interact with IGF2BP3 to suppress EOC remains unclear.
PURPOSE
This study aims to investigate suppressive effects of ENL upon combining with IGF2BP3 on EOC and elucidates the underlying mechanism.
METHODS
The Cell Counting Kit-8 and crystal violet assays were used to assess tumor cell proliferation. Scratch and Transwell assays were employed to evaluate tumor cell migration, while tube formation assays were utilized to examine angiogenesis. Western blotting was used to measure the expression levels of IGF2BP3, VEGF, PI3K, AKT1, p-PI3K, and p-AKT1. An in vivo xenograft nude mouse model was established, fecal samples were collected, and 16S rDNA sequencing was performed to analyze gut microbiota in association with the suppressive effects of ENL and its interactions with IGF2BP3.
RESULTS
IGF2BP3 is highly expressed in EOC and is positively correlated with poor survival in EOC patients. ENL reduces IGF2BP3 expression in EOC, thereby inhibiting the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and suppressing the proliferation, migration, invasion, and angiogenesis of EOC. Additionally, ENL ameliorates gut microbiome, especially in conjunction with shIGF2BP3.
CONCLUSION
ENL interacts with IGF2BP3 and suppresses its expression in EOC, leading to the deactivation of the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and the subsequent inhibition of angiogenesis. The combination of ENL and shIGF2BP3 demonstrates a synergistic effect on EOC. ENL also ameliorates the gut microbiome, especially in conjunction with shIGF2BP3, to suppress EOC.
背景
在所有妇科癌症中，卵巢癌是主要的死亡原因。上皮性卵巢癌（EOC）占卵巢癌病例的85%以上，其特点是发病隐匿、早期转移且复发率高。肠道微生物群的改变，通常是化疗的结果，可促进癌症发展并使疾病恶化。m6A阅读蛋白IGF2BP3是各种肿瘤发生和进展的调节因子，与血管生成有关。肠内酯（ENL）已显示出对包括EOC在内的各种人类癌症具有显著的抗肿瘤活性。然而，ENL是否能与IGF2BP3相互作用以抑制EOC仍不清楚。
目的
本研究旨在探讨ENL与IGF2BP3联合对EOC的抑制作用，并阐明其潜在机制。
方法
采用细胞计数试剂盒-8和结晶紫试验评估肿瘤细胞增殖。划痕试验和Transwell试验用于评估肿瘤细胞迁移，而管形成试验用于检测血管生成。蛋白质印迹法用于检测IGF2BP3、VEGF、PI3K、AKT1、p-PI3K和p-AKT1的表达水平。建立体内异种移植裸鼠模型，收集粪便样本，并进行16S rDNA测序，以分析与ENL的抑制作用及其与IGF2BP3相互作用相关的肠道微生物群。
结果
IGF2BP3在EOC中高表达，且与EOC患者的不良生存呈正相关。ENL降低EOC中IGF2BP3的表达，从而抑制IGF2BP3介导的VEGF/PI3K/AKT信号通路，并抑制EOC的增殖、迁移、侵袭和血管生成。此外，ENL改善肠道微生物群，特别是与shIGF2BP3联合使用时。
结论
ENL与IGF2BP3相互作用并抑制其在EOC中的表达，导致IGF2BP3介导的VEGF/PI3K/AKT信号通路失活，随后抑制血管生成。ENL和shIGF2BP3联合对EOC具有协同作用。ENL还改善肠道微生物群，特别是与shIGF2BP3联合使用时，以抑制EOC。
Zotero 插件