National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
Int J Mol Sci. 2022 Feb 26;23(5):2608. doi: 10.3390/ijms23052608.
Semaphorins (SEMAs) are axon guidance factors that participate in axonal connections and nerve system development. However, the functional roles of SEMAs in tumorigenesis are still largely uncovered. By using in silico data analysis, we found that SEMA6C was downregulated in pancreatic cancer, and its reduction was correlated with worse survival rates. RNA sequencing revealed that cell cycle-related genes, especially cyclin D1, were significantly altered after blockage of SEMA6C by neutralizing antibodies or ectopic expressions of SEMA6C. Mechanistic investigation demonstrated that SEMA6C acts as a tumor suppressor in pancreatic cancer by inhibiting the AKT/GSK3 signaling axis, resulting in a decrease in cyclin D1 expression and cellular proliferation. The enhancement of cyclin D1 expression and cyclin-dependent kinase activation in SEMA6C-low cancer created a druggable target of CDK4/6 inhibitors. We also elucidated the mechanism underlying SEMA6C downregulation in pancreatic cancer and demonstrated a novel regulatory role of miR-124-3p in suppressing SEMA6C. This study provides new insights of SEMA6C-mediated anti-cancer action and suggests the treatment of SEMA6C-downregulated cancer by CDK4/6 inhibitors.
信号素（SEMA）是轴突导向因子，参与轴突连接和神经系统发育。然而，SEMA 在肿瘤发生中的功能作用在很大程度上仍未被揭示。通过使用计算机数据分析，我们发现信号素 6C（SEMA6C）在胰腺癌中下调，其减少与生存率降低相关。RNA 测序显示，阻断 SEMA6C 后，细胞周期相关基因，尤其是细胞周期蛋白 D1，明显改变。机制研究表明，SEMA6C 通过抑制 AKT/GSK3 信号轴在胰腺癌中发挥肿瘤抑制作用，导致细胞周期蛋白 D1 表达和细胞增殖减少。在 SEMA6C 低表达的癌症中，细胞周期蛋白 D1 表达和细胞周期依赖性激酶激活的增强为 CDK4/6 抑制剂提供了一个可靶向的目标。我们还阐明了 SEMA6C 在胰腺癌中下调的机制，并证明了 miR-124-3p 在抑制 SEMA6C 中的新的调节作用。这项研究为 SEMA6C 介导的抗癌作用提供了新的见解，并提示通过 CDK4/6 抑制剂治疗 SEMA6C 下调的癌症。
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