miR-3155b is a Senomorphic MicroRNA, Reducing Senescent Cell Inflammatory Signaling
Senescent cells accumulate with age to drive the onset and progression of age-related disease and loss of function. Over the past decade, a broad range of research and development efforts have emerged to attempt to address this cause of aging. Senostatic therapies reduce the pace at which senescent cells are created. Senolytic therapies selectively destroy senescent cells. Senomorphic therapies suppress aspects of the harmful behavior of senescent cells, principally the pro-inflammatory signaling that contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Researchers here describe the discovery of a senomorphic microRNA in the context of an attempt to reduce the burden of senescent cells generated by cancer therapy. Many forms of cancer treatment leave the patient with increased numbers of senescent cells, and this greater burden of dysfunction is thought to be an important contributing cause of increased mortality and disease risk in cancer survivors.
Senomorphic microRNAs (miRNAs) are a class of small regulatory RNAs that selectively suppress the senescence-associated secretory phenotype (SASP) without eliminating senescent cells, thereby offering a targeted approach to counteract the pro-tumorigenic consequences of therapy-induced senescence (TIS). Despite their therapeutic potential, senomorphic miRNAs in luminal breast cancer remain poorly characterized. Here, we performed small RNA sequencing to profile miRNA expression changes in a doxorubicin-induced TIS model using the luminal breast cancer line MCF7. We identified miR-3155b as a previously uncharacterized miRNA significantly downregulated during TIS.
Functional studies revealed that miR-3155b overexpression suppressed the mRNA and protein levels of multiple SASP factors, including IL6, IL8 (CXCL8), MMP13, TNF, IL1B, and IFNB1, whereas its knockdown enhanced their expression. Critically, these effects occurred without affecting core senescence phenotypes such as proliferation arrest, SA-β-gal activity, or DNA damage foci formation. This senomorphic function was further confirmed in an ionizing radiation (IR)-induced TIS model and in T47D luminal breast cancer cells. miR-3155b was confirmed to target the CXCL8 mRNA by luciferase reporter assays, and RNA pull-down assays indicated that miR-3155b physically associates with IFNB1, IL6, TNF, and MMP13 mRNAs.
Collectively, our findings identify miR-3155b as a senomorphic miRNA in Luminal A breast cancer TIS and provide a potential target for optimizing chemoradiotherapy strategies aimed at mitigating SASP-driven adverse effects.