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Drosha-independent miR-6778-5p strengthens gastric cancer stem cell stemness via regulation of cytosolic one-carbon folate metabolism.

Authors
  • Zhao, Maojia1
  • Hou, Yixuan2
  • Du, Yan-E3
  • Yang, Liping1
  • Qin, Yilu1
  • Peng, Meixi1
  • Liu, Shuiqing1
  • Wan, Xueying1
  • Qiao, Yina1
  • Zeng, Huan1
  • Cui, Xiaojiang4
  • Teng, Yong5
  • Liu, Manran6
  • 1 Key Laboratory of Laboratory Medical Diagnostics Designated By Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. , (China)
  • 2 Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing, 400016, China. , (China)
  • 3 Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. , (China)
  • 4 Department of Surgery, Department of Obstetrics and Gynecology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center. Los Angeles, CA, 91006, USA.
  • 5 Department of Oral Biology, Dental College of Georgia, Georgia Cancer Center, Augusta University, Augusta, GA, USA. , (Georgia)
  • 6 Key Laboratory of Laboratory Medical Diagnostics Designated By Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Cancer letters
Publication Date
May 28, 2020
Volume
478
Pages
8–21
Identifiers
DOI: 10.1016/j.canlet.2020.02.040
PMID: 32142918
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Drosha-dependent canonical microRNAs (miRNAs) play a crucial role in the biological functions and development of cancer. However, the effects of Drosha-independent non-canonical miRNAs remain poorly understood. In our previous work, we found a set of aberrant miRNAs, including some upregulated miRNAs, called Drosha-independent noncanonical miRNAs, in Drosha-knockdown gastric cancer (GC) cells. Surprisingly, Drosha-silenced GC cells still retained strong malignant properties (e.g., proliferation ability and cancer stem cell (CSC) characteristics), indicating that aberrantly upregulated non-canonical miRNAs may play an important role in the maintenance of the malignant properties in GC cells that express low Drosha levels. Here, we report that miR-6778-5p, a noncanonical miRNA, acts as a crucial regulator for maintenance of CSC stemness in Drosha-silenced GC cells. MiR-6778-5p belongs to the 5'-tail mirtron type of non-canonical miRNAs and is transcript splice-derived from intron 5 of SHMT1 (coding cytoplasmic serine hydroxymethyltransferase). It positively regulates expression of its host gene, SHMT1, via targeting YWHAE in Drosha-knockdown GC cells. Similar to its family member SHMT2, SHMT1 plays a crucial role in folate-dependent serine/glycine inter-conversion in one-carbon metabolism. In Drosha wild type GC cells, SHMT2 mediates a mitochondrial-carbon metabolic pathway, which is a major pathway of one-carbon metabolism in normal cells and most cancer cells. However, in Drosha-silenced or Drosha low-expressing GC cells, miR-6778-5p positively regulates SHMT1, instead of SHMT2, thus mediating a compensatory activation of cytoplasmic carbon metabolism that plays an essential role in the maintenance of CSCs in gastric cancer (GCSCs). Drosha wild type GCSCs with SHMT2 are sensitive to 5-fluorouracil; however, Drosha low-expressing GCSCs with SHMT1 are 5-FU-resistant. The loss of miR-6778-5p or SHMT1 notably mitigates GCSC sphere formation and increases sensitivity to 5-fluorouracil in Drosha-knockdown gastric cancer cells. Thus, our study reveals a novel function of Drosha-independent noncanonical miRNAs in maintaining the stemness of GCSCs. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

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