Verdugo-Sivianes Eva M, Espinosa-Sánchez Asunción, Cases Ildefonso, Rojas Ana M, Otero-Albiol Daniel, Romero Lourdes, Blanco José Ramón, Carnero Amancio
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, 41013, Spain.
CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain.
Cell Death Discov. 2024 Dec 20;10(1):509. doi: 10.1038/s41420-024-02272-0.
Cellular senescence connects aging and cancer. Cellular senescence is a common program activated by cells in response to various types of stress. During this process, cells lose their proliferative capacity and undergo distinct morphological and metabolic changes. Senescence itself constitutes a tumor suppression mechanism and plays a significant role in organismal aging by promoting chronic inflammation. Additionally, age is one of the major risk factors for developing breast cancer. Therefore, while senescence can suppress tumor development early in life, it can also lead to an aging process that drives the development of age-related pathologies, suggesting an antagonistic pleiotropic effect. In this work, we identified Rian/MEG8 as a potential biomarker connecting aging and breast cancer for the first time. We found that Rian/MEG8 expression decreases with age; however, it is high in mice that age prematurely. We also observed decreased MEG8 expression in breast tumors compared to normal tissue. Furthermore, MEG8 overexpression reduced the proliferative and stemness properties of breast cancer cells both in vitro and in vivo by activating apoptosis. MEG8 could exemplify the antagonistic pleiotropic theory, where senescence is beneficial early in life as a tumor suppression mechanism due to increased MEG8, resulting in fewer breast tumors at an early age. Conversely, this effect could be detrimental later in life due to aging and cancer, when MEG8 is reduced and loses its tumor-suppressive role.
细胞衰老将衰老与癌症联系起来。细胞衰老是细胞响应各种应激而激活的一个常见程序。在此过程中，细胞失去增殖能力，并经历明显的形态和代谢变化。衰老本身构成一种肿瘤抑制机制，并通过促进慢性炎症在机体衰老中发挥重要作用。此外，年龄是患乳腺癌的主要风险因素之一。因此，虽然衰老在生命早期可抑制肿瘤发展，但它也可导致驱动与年龄相关病理发展的衰老过程，提示存在拮抗多效性效应。在这项研究中，我们首次鉴定出Rian/MEG8是连接衰老与乳腺癌的一个潜在生物标志物。我们发现Rian/MEG8的表达随年龄增长而降低；然而，在早衰小鼠中其表达较高。我们还观察到与正常组织相比，乳腺肿瘤中MEG8的表达降低。此外，MEG8过表达通过激活细胞凋亡在体外和体内均降低了乳腺癌细胞的增殖和干性特性。MEG8可以例证拮抗多效性理论，即衰老在生命早期作为一种肿瘤抑制机制是有益的，因为MEG8增加，导致早年乳腺肿瘤较少。相反，在生命后期，由于衰老和癌症，当MEG8减少并失去其肿瘤抑制作用时，这种效应可能是有害的。
