Background: Breast cancer (BC) is highly heterogeneous, with varying molecular characteristics, such as reliance on autophagy. Autophagy is a critical cellular degradation process that helps cells survive under stress, but its regulation can be influenced by altered microRNA (miRNA) expression. Studying miRNA changes during starvation-induced autophagy in both mammary epithelial cells and BC cells could reveal potential molecular therapy targets.Methods: Rat mammary gland healthy epithelial and cancer cells were subjected to starvation, and differences in proliferation, migration, invasion, autophagy, and expression of autophagy-associated miRNAs were determined. Afterward, we assessed the effects of miR-218-5p modulation on the aforementioned processes.Results: Starvation-induced autophagy reduced the proliferation of all cells and increased the invasive and migratory capacity of cancer cells (p≤ 0.05). We identified a miRNA signature related to starvation, comprising twenty-seven miRNAs. One miRNA had a significantly elevated baseline expression, while another six, including miR-218-5p, had a significantly lower basal expression in cancer cells compared to healthy cells (p≤ 0.05). However, starvation caused significant miRNA expression changes, with miR-218-5p being upregulated specifically in cancer cells (p= 0.20–0.01). Functional studies on the role of miR-218-5p show that its inhibition decreases migration and leads to autophagosome accumulation. The study of miR-218-5p molecular targets has shown that its inhibition of sorting nexin 18 (SNX18) may act as an important regulator of the starvation-induced response in cancer cells.Conclusions: The baseline expression of miRNA related to starvation and autophagy differs between rat mammary gland cancer and healthy cells. The response to starvation also varies between cancer cells and normal cells. Starvation induces BC-specific miRNA dysregulation, affecting particularly miR-218-5p, which acts via SNX18, promoting the cancer cells’ survival.
背景：乳腺癌具有高度异质性，其分子特征存在差异，例如对自噬的依赖性。自噬是一种关键的细胞降解过程，有助于细胞在应激状态下存活，但其调控可能受微小RNA表达变化的影响。研究乳腺上皮细胞和乳腺癌细胞在饥饿诱导自噬过程中的miRNA变化，可能揭示潜在的分子治疗靶点。 方法：对大鼠乳腺健康上皮细胞和癌细胞进行饥饿处理，测定其增殖、迁移、侵袭、自噬及自噬相关miRNA表达的差异。随后评估miR-218-5p调控对上述过程的影响。 结果：饥饿诱导的自噬降低了所有细胞的增殖能力，同时增强了癌细胞的侵袭和迁移能力（p≤0.05）。我们鉴定出27个与饥饿相关的miRNA特征谱。其中1个miRNA在癌细胞中的基础表达显著升高，另有6个（包括miR-218-5p）的基础表达显著低于健康细胞（p≤0.05）。然而，饥饿导致miRNA表达发生显著变化，其中miR-218-5p在癌细胞中特异性上调（p=0.20–0.01）。对miR-218-5p功能的研究表明，抑制该miRNA可降低细胞迁移能力并导致自噬体积累。对其分子靶标的研究显示，miR-218-5p通过抑制分选连接蛋白18（SNX18），可能在癌细胞饥饿诱导反应中发挥重要调控作用。 结论：与饥饿和自噬相关的miRNA在大鼠乳腺癌细胞与健康细胞中存在基础表达差异。癌细胞与正常细胞对饥饿的反应亦不相同。饥饿诱导乳腺癌特异性miRNA失调，尤其影响通过SNX18通路发挥作用的miR-218-5p，从而促进癌细胞存活。
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