中期因子是年龄相关变化和乳腺肿瘤发生增加的驱动因素。
Midkine as a driver of age-related changes and increase in mammary tumorigenesis.
发表日期：2024 Sep 26
作者：
Pengze Yan, Ernesto Rojas Jimenez, Zheqi Li, Triet Bui, Marco Seehawer, Jun Nishida, Pierre Foidart, Laura E Stevens, Yingtian Xie, Miguel Munoz Gomez, So Yeon Park, Henry W Long, Kornelia Polyak
来源：
CANCER CELL
摘要：
衰老是癌症的一个关键危险因素，但其潜在机制仍不清楚。在这里，我们通过单细胞多组学探索大鼠乳腺与年龄相关的变化。我们的研究结果包括随着年龄的增长，上皮增殖增加、管腔特性丧失以及初始 B 细胞和 T 细胞减少。我们发现了老年大鼠特有的管腔祖细胞群，其特征反映了癌前变化，并确定中期因子 (Mdk) 是一种随年龄上调的基因，也是与年龄相关的管腔祖细胞的调节因子。中期因子治疗年轻大鼠通过激活 PI3K-AKT-SREBF1 通路模拟与年龄相关的变化，并促进亚硝基-N-甲基脲诱导的乳腺肿瘤发生。人类血液和乳腺上皮中的中期因子水平随着年龄的增长而增加，正常乳腺组织中较高的 MDK 与年轻女性较高的乳腺癌风险相关。我们的研究结果揭示了衰老与肿瘤发生易感性之间的联系，并确定中期因子是乳腺肿瘤发生年龄依赖性增加的介质。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.