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

Maojia Zhao, Yixuan Hou, Yan e. Du, Liping Yang, Yilu Qin, Meixi Peng, Shuiqing Liu, Xueying Wan, Yina Qiao, Huan Zeng, Xiaojiang Cui, Yong Teng, Manran Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)8-21
Number of pages14
JournalCancer Letters
Volume478
DOIs
StatePublished - May 28 2020

Keywords

  • Cytoplasmic serine hydroxyl methyltransferase
  • Drosha-independent miRNA
  • Gastric CSC
  • miR-6778–5p
  • One-carbon metabolism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhao, M., Hou, Y., Du, Y. E., Yang, L., Qin, Y., Peng, M., Liu, S., Wan, X., Qiao, Y., Zeng, H., Cui, X., Teng, Y., & Liu, M. (2020). Drosha-independent miR-6778–5p strengthens gastric cancer stem cell stemness via regulation of cytosolic one-carbon folate metabolism. Cancer Letters, 478, 8-21. https://doi.org/10.1016/j.canlet.2020.02.040