Key Laboratory of Laboratory Medical Diagnostics designated by Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing, 400016, China.
Cell Death Differ. 2021 Sep;28(9):2708-2727. doi: 10.1038/s41418-021-00779-y. Epub 2021 Apr 19.
The aberrant classical miRNAs are considered to play significant roles in tumor progression. However, it remains unclear for nonclassical miRNAs, a set of Drosha-independent miRNAs in the process of various biology. Here, we reveal that a nonclassical miR-4646-5p plays a pivotal role in gastric cancer (GC) metastasis. MiR-4646-5p, one of Drosha-independent mirtronic miRNA, is aberrant up-regulated in Drosha-low expressed GC and Drosha-knockdown gastric cancer cells. Mirtronic miR-4646-5p is a specific transcription splicing product of intron 3 of the host gene Abhd16a with the aid of SRSF2. The enhanced miR-4646-5p can stabilize HIF1A by targeting PHD3 to positive feedback regulate Abhd16a and miR-4646-5p itself expressions. ABHD16A, as an emerging phosphatidylserine-specific lipase, involves in lipid metabolism leading to lysophosphatidylserines (lyso-PSs) accumulation, which stimulates RhoA and downstream LIMK/cofilin cascade activity through GPR34/Gi subunit, thus causes metastasis of gastric cancer. In addition, miR-4646-5p/PHD3/HIF1A signaling can also up-regulate RhoA expression and synergistically promote gastric cancer cell invasion and metastasis. Our study provides new insights of nonclassical mirtronic miRNA on tumor progress and may serve as a new diagnostic biomarker for gastric cancer. MiR-4646-5p and its host gene Abhd16a mediated abnormal lipid metabolism may be a new target for clinical treatment of gastric cancer.
异常的经典 miRNA 被认为在肿瘤进展中发挥重要作用。然而，在各种生物学过程中，非经典 miRNA（一组依赖 Drosha 的 miRNA）的作用尚不清楚。在这里，我们揭示了非经典 miR-4646-5p 在胃癌（GC）转移中起着关键作用。miR-4646-5p 是一种非经典的 Drosha 非依赖性 mirtronic miRNA，在 Drosha 低表达的 GC 和 Drosha 敲低的胃癌细胞中异常上调。mirtronic miR-4646-5p 是宿主基因 Abhd16a 内含子 3 的特异性转录剪接产物，在 SRSF2 的帮助下。增强的 miR-4646-5p 可以通过靶向 PHD3 稳定 HIF1A，从而正向反馈调节 Abhd16a 和 miR-4646-5p 自身的表达。ABHD16A 作为一种新兴的磷脂酰丝氨酸特异性脂肪酶，参与脂质代谢导致溶血磷脂酰丝氨酸（lyso-PSs）积累，通过 GPR34/Gi 亚基刺激 RhoA 和下游 LIMK/cofilin 级联活性，从而导致胃癌转移。此外，miR-4646-5p/PHD3/HIF1A 信号还可以上调 RhoA 表达，并协同促进胃癌细胞侵袭和转移。我们的研究为非经典 mirtronic miRNA 在肿瘤进展中的作用提供了新的见解，并可能成为胃癌的新诊断生物标志物。miR-4646-5p 和其宿主基因 Abhd16a 介导的异常脂质代谢可能成为胃癌临床治疗的新靶点。
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