Endodontic Department, Hefei Hospital of Stomatology, 265 Changjiang Middle Road, 230001, Hefei, Anhui, China.
Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 136 Hanzhong Road, 210029, Nanjing, Jiangsu, China.
Exp Mol Med. 2018 Apr 13;50(4):1-14. doi: 10.1038/s12276-018-0048-7.
The putative tumor suppressor microRNA let-7c is extensively associated with the biological properties of cancer cells. However, the potential involvement of let-7c in the differentiation of mesenchymal stem cells has not been fully explored. In this study, we investigated the influence of hsa-let-7c (let-7c) on the proliferation and differentiation of human dental pulp-derived mesenchymal stem cells (DPMSCs) treated with insulin-like growth factor 1 (IGF-1) via flow cytometry, CCK-8 assays, alizarin red staining, real-time RT-PCR, and western blotting. In general, the proliferative capabilities and cell viability of DPMSCs were not significantly affected by the overexpression or deletion of let-7c. However, overexpression of let-7c significantly inhibited the expression of IGF-1 receptor (IGF-1R) and downregulated the osteo/odontogenic differentiation of DPMSCs, as indicated by decreased levels of several osteo/odontogenic markers (osteocalcin, osterix, runt-related transcription factor 2, dentin sialophosphoprotein, dentin sialoprotein, alkaline phosphatase, type 1 collagen, and dentin matrix protein 1) in IGF-1-treated DPMSCs. Inversely, deletion of let-7c resulted in increased IGF-1R levels and enhanced osteo/odontogenic differentiation. Furthermore, the ERK, JNK, and P38 MAPK pathways were significantly inhibited following the overexpression of let-7c in DPMSCs. Deletion of let-7c promoted the activation of the JNK and P38 MAPK pathways. Our cumulative findings indicate that Let-7c can inhibit the osteo/odontogenic differentiation of IGF-1-treated DPMSCs by targeting IGF-1R via the JNK/P38 MAPK signaling pathways.
假定的肿瘤抑制 microRNA let-7c 广泛与癌细胞的生物学特性相关。然而，let-7c 潜在地参与间充质干细胞的分化尚未得到充分探索。在这项研究中，我们通过流式细胞术、CCK-8 测定、茜素红染色、实时 RT-PCR 和 Western blot 研究了 hsa-let-7c（let-7c）对胰岛素样生长因子 1（IGF-1）处理的人牙髓间充质干细胞（DPMSCs）增殖和分化的影响。一般来说，let-7c 的过表达或缺失并未显著影响 DPMSCs 的增殖能力和细胞活力。然而，let-7c 的过表达显著抑制 IGF-1 受体（IGF-1R）的表达，并下调 DPMSCs 的成骨/成牙本质分化，这表现为 IGF-1 处理的 DPMSCs 中几种成骨/成牙本质标志物（骨钙素、osterix、 runt 相关转录因子 2、牙本质涎磷蛋白、牙本质涎蛋白、碱性磷酸酶、I 型胶原和牙本质基质蛋白 1）的水平降低。相反，let-7c 的缺失导致 IGF-1R 水平升高，并增强成骨/成牙本质分化。此外，在 DPMSCs 中过表达 let-7c 后，ERK、JNK 和 P38 MAPK 通路明显受到抑制。let-7c 的缺失促进了 JNK 和 P38 MAPK 通路的激活。我们的综合研究结果表明，Let-7c 可以通过 JNK/P38 MAPK 信号通路靶向 IGF-1R 抑制 IGF-1 处理的 DPMSCs 的成骨/成牙本质分化。
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