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Mirtronic miR-4646-5p promotes gastric cancer metastasis by regulating ABHD16A and metabolite lysophosphatidylserines

Authors
  • Yang, Liping1
  • Hou, Yixuan1
  • Du, Yan-e2
  • Li, Qiao1
  • Zhou, Fanlin3
  • Li, Yu3
  • Zeng, Huan1
  • Jin, Ting1
  • Wan, Xueying1
  • Guan, Shengdong1
  • Wang, Rui1
  • Liu, Manran1
  • 1 Chongqing Medical University, Chongqing, 400016, China , Chongqing (China)
  • 2 Chongqing Medical University, Chongqing, 400010, China , Chongqing (China)
  • 3 Chongqing University Cancer Hospital, Chongqing, 400030, China , Chongqing (China)
Type
Published Article
Journal
Cell Death & Differentiation
Publisher
Nature Publishing Group UK
Publication Date
Apr 19, 2021
Volume
28
Issue
9
Pages
2708–2727
Identifiers
DOI: 10.1038/s41418-021-00779-y
Source
Springer Nature
Disciplines
  • article
License
Green

Abstract

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.

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