Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
Cancer Immunol Immunother. 2021 Aug;70(8):2247-2259. doi: 10.1007/s00262-021-02862-2. Epub 2021 Jan 25.
Although a number of studies have revealed the important roles of miR-34a in cancer, the regulatory roles of miR-34a in cancer immune response remain largely unknown. Our present study demonstrated a mechanism underlying miR-34a-mediated cancer immune evasion via a SIRT1/NF-κB/B7-H3/TNF-α axis. miR-34a upregulated B7-H3, an important immune checkpoint molecule, through direct inhibition of SIRT1 and consequent acetylation of NF-κB subunit p65 (a-p65), which promoted B7-H3 transcription by direct binding to its promoter. The elevated B7-H3 induced production of pro-inflammatory cytokines including TNF-α. This was further confirmed in the colon of Mir34a-deficient mice, where Sirt1 expression was boosted, and the expressions of a-p65, B7h3, and Tnf were repressed. Consequently, the in vivo inhibitory activity of miR-34a on colorectal cancer (CRC) was eradicated by the reinforced B7-H3 and TNF-α. In conclusion, our study uncovered an etiological mechanism underlying miR-34a-mediated CRC immune evasion through inhibition of SIRT1 and promotion of NF-κB/B7-H3/TNF-α axis.
尽管许多研究揭示了 miR-34a 在癌症中的重要作用，但 miR-34a 在癌症免疫反应中的调节作用在很大程度上仍不清楚。本研究通过 SIRT1/NF-κB/B7-H3/TNF-α 轴阐明了 miR-34a 介导的癌症免疫逃逸的机制。miR-34a 通过直接抑制 SIRT1 并随后乙酰化 NF-κB 亚基 p65(a-p65)，上调了 B7-H3，这是一种重要的免疫检查点分子，从而促进了 B7-H3 的转录，通过直接结合其启动子。升高的 B7-H3 诱导产生了包括 TNF-α 在内的促炎细胞因子。在 Mir34a 缺陷型小鼠的结肠中进一步证实了这一点，其中 Sirt1 表达增强，a-p65、B7h3 和 Tnf 的表达受到抑制。因此，B7-H3 和 TNF-α 的增强消除了 miR-34a 对结直肠癌 (CRC) 的体内抑制活性。总之，本研究揭示了 miR-34a 通过抑制 SIRT1 和促进 NF-κB/B7-H3/TNF-α 轴介导 CRC 免疫逃逸的病因机制。
