TY - JOUR
T1 - Drosha-independent miR-6778–5p strengthens gastric cancer stem cell stemness via regulation of cytosolic one-carbon folate metabolism
AU - Zhao, Maojia
AU - Hou, Yixuan
AU - Du, Yan e.
AU - Yang, Liping
AU - Qin, Yilu
AU - Peng, Meixi
AU - Liu, Shuiqing
AU - Wan, Xueying
AU - Qiao, Yina
AU - Zeng, Huan
AU - Cui, Xiaojiang
AU - Teng, Yong
AU - Liu, Manran
N1 - Funding Information:
This work was supported in part by National Natural Science Foundation of China (NSFC 31671481 , NSFC 81472476 and NSFC 81172296 ); and National Natural Science Foundation of China (NSFC 81802447 ) for Yan-e Du; And also supported in part by the outstanding Postgraduate Fund of Chongqing Medical University (2017) and Chongqing Graduate Research and Innovation Project of the Chongqing Education Committee (2017) ( CYS17162 ) for Maojia Zhao.
Publisher Copyright:
© 2020 The Authors
PY - 2020/5/28
Y1 - 2020/5/28
N2 - 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.
AB - 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.
KW - Cytoplasmic serine hydroxyl methyltransferase
KW - Drosha-independent miRNA
KW - Gastric CSC
KW - One-carbon metabolism
KW - miR-6778–5p
UR - http://www.scopus.com/inward/record.url?scp=85081677208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081677208&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2020.02.040
DO - 10.1016/j.canlet.2020.02.040
M3 - Article
C2 - 32142918
AN - SCOPUS:85081677208
SN - 0304-3835
VL - 478
SP - 8
EP - 21
JO - Cancer Letters
JF - Cancer Letters
ER -
