Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, China.
Department of Cancer Center, The First Hospital of Jilin University, Changchun 130024, China.
Pharmacol Res. 2022 May;179:106196. doi: 10.1016/j.phrs.2022.106196. Epub 2022 Mar 28.
Cancer stemness, chemoresistance, and metastasis are related biological events. However, whether they have common molecular mechanisms remains to be determined. Here, we report that imiquimod (IMQ) facilitates the acquisition of stem-cell-like properties and chemoresistance via the upregulation of matrix metalloproteinase 1 (MMP1) and downregulation of microRNA-145 (miR-145). MiR-145-5p was found to suppress MMP1 expression through direct binding, and miR-145-mediated downregulation of MMP1 reversed the effects of IMQ. In addition, IMQ downregulated miR-145 by promoting DNA methylation at its promoter. DNA methyltransferase inhibitors limited IMQ-induced MMP1 expression, stemness, and chemoresistance. Collectively, our results highlight the miR-145-MMP1 axis as a potential coordinator of cancer stemness and chemoresistance. Given the role of MMP1 in the initiation of metastasis, the miR-145-MMP1 axis serves as a promising therapeutic target for improved cancer treatment.
癌症干性、化疗耐药和转移是相关的生物学事件。然而，它们是否具有共同的分子机制仍有待确定。在这里，我们报告咪喹莫特（IMQ）通过上调基质金属蛋白酶 1（MMP1）和下调 microRNA-145（miR-145）促进获得干性和化疗耐药性。发现 miR-145-5p 通过直接结合抑制 MMP1 的表达，而 miR-145 介导的 MMP1 下调逆转了 IMQ 的作用。此外，IMQ 通过促进其启动子的 DNA 甲基化来下调 miR-145。DNA 甲基转移酶抑制剂限制了 IMQ 诱导的 MMP1 表达、干性和化疗耐药性。总之，我们的结果强调了 miR-145-MMP1 轴作为癌症干性和化疗耐药性的潜在协调者。鉴于 MMP1 在转移起始中的作用，miR-145-MMP1 轴是改善癌症治疗的有前途的治疗靶点。
