Bustamante-Marin Ximena, Devlin Kaylyn L, McDonell Shannon B, Dave Om, Merlino Jenna L, Grindstaff Emma J, Ho Alyssa N, Rezeli Erika T, Coleman Michael F, Hursting Stephen D
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA.
Cancers (Basel). 2023 Aug 29;15(17):4320. doi: 10.3390/cancers15174320.
Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.
在几种临床前模型中，热量限制（CR）与胰岛素样生长因子1（IGF1）信号传导降低相关，可抑制三阴性乳腺癌（TNBC）进展。为了研究CR对靶向IGF1/IGF1R途径的微小RNA（miR）的影响，我们使用了TNBC的自发小鼠模型C3(1)/SV40 T抗原（C3-TAg）。在C3-TAg小鼠中，CR降低了体重、IGF1水平和TNBC进展。我们评估了10种miR的肿瘤表达。CR增加了miR-199a-3p、miR-199a-5p、miR-486和miR-15b的表达。然而，只有miR-15b的表达与TNBC进展的M28、M6和M6C C3-TAg细胞系中的肿瘤发生相关。过表达miR-15b可降低小鼠（M6）和人（MDA-MB-231）细胞系的增殖。单独的血清限制或与低水平重组IGF1联合使用可显著上调M6细胞中miR-15b的表达并降低其增殖。用BMS754807对IGFR进行药理学抑制可逆转这些作用。使用miR网络工具进行的计算机分析预测，miR-15b靶向与IGF1/mTOR途径和细胞周期相关的基因。我们的研究结果表明，CR与降低的IGF1水平相关，可能上调miR-15b以下调其增殖，并有助于CR的抗癌作用。因此，miR-15b可能是模拟CR对TNBC有益作用的治疗靶点。
