PMID- 35400173
OWN - NLM
STAT- MEDLINE
DCOM- 20221221
LR  - 20221222
IS  - 2379-5077 (Print)
IS  - 2379-5077 (Electronic)
IS  - 2379-5077 (Linking)
VI  - 7
IP  - 2
DP  - 2022 Apr 26
TI  - Antitumor Activities of tRNA-Derived Fragments and tRNA Halves from 
      Non-pathogenic Escherichia coli Strains on Colorectal Cancer and Their 
      Structure-Activity Relationship.
PG  - e0016422
LID - 10.1128/msystems.00164-22 [doi]
LID - e00164-22
AB  - tRNAs purified from non-pathogenic Escherichia coli strains (NPECSs) possess 
      cytotoxic properties on colorectal cancer cells. In the present study, the 
      bioactivity of tRNA halves and tRNA fragments (tRFs) derived from NPECSs are 
      investigated for their anticancer potential. Both the tRNA halves and tRF mimics 
      studied exhibited significant cytotoxicity on colorectal cancer cells, with the 
      latter being more effective, suggesting that tRFs may be important contributors 
      to the bioactivities of tRNAs derived from the gut microbiota. Through 
      high-throughput screening, the EC83 mimic, a double-strand RNA with a 
      22-nucleotide (nt) 5'-tRF derived from tRNA-Leu(CAA) as an antisense chain, was 
      identified as the one with the highest potency (50% inhibitory concentration 
      [IC(50)] = 52 nM). Structure-activity investigations revealed that 
      2'-O-methylation of the ribose of guanosine (Gm) may enhance the cytotoxic 
      effects of the EC83 mimic via increasing the stability of its tertiary structure, 
      which is consistent with the results of in vivo investigations showing that the 
      EC83-M2 mimic (Gm modified) exhibited stronger antitumor activity against both 
      HCT-8 and LoVo xenografts. Consistently, 4-thiouridine modification does not. 
      This provides the first evidence that the bioactivity of tRF mimics would be 
      impacted by chemical modifications. Furthermore, the present study provides the 
      first evidence to suggest that novel tRNA fragments derived from the gut 
      microbiota may possess anticancer properties and have the potential to be potent 
      and selective therapeutic molecules. IMPORTANCE While the gut microbiota has been 
      increasingly recognized to be of vital importance for human health and disease, 
      the current literature shows that there is a lack of attention given to 
      non-pathogenic Escherichia coli strains. Moreover, the biological activities of 
      tRNA fragments (tRFs) derived from bacteria have rarely been investigated. The 
      findings from this study revealed tRFs as a new class of bioactive constituents 
      derived from gut microorganisms, suggesting that studies on biological functional 
      molecules in the intestinal microbiota should not neglect tRFs. Research on tRFs 
      would play an important role in the biological research of gut microorganisms, 
      including bacterium-bacterium interactions, the gut-brain axis, and the gut-liver 
      axis, etc. Furthermore, the guidance on the rational design of tRF therapeutics 
      provided in this study indicates that further investigations should pay more 
      attention to these therapeutics from probiotics. The innovative drug research of 
      tRFs as potent druggable RNA molecules derived from intestinal microorganisms 
      would open a new area in biomedical sciences.
FAU - Cao, Kai-Yue
AU  - Cao KY
AD  - State Key Laboratory of Quality Research in Chinese Medicine, Macau University of 
      Science and Technology, Taipa, Macau SAR, China.
FAU - Pan, Yu
AU  - Pan Y
AD  - State Key Laboratory of Quality Research in Chinese Medicine, Macau University of 
      Science and Technology, Taipa, Macau SAR, China.
FAU - Yan, Tong-Meng
AU  - Yan TM
AD  - State Key Laboratory of Quality Research in Chinese Medicine, Macau University of 
      Science and Technology, Taipa, Macau SAR, China.
FAU - Tao, Peng
AU  - Tao P
AD  - School of Physics, Huazhong University of Science and Technology, Wuhan, China.
AD  - Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Xiao, Yi
AU  - Xiao Y
AD  - School of Physics, Huazhong University of Science and Technology, Wuhan, China.
AD  - Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Jiang, Zhi-Hong
AU  - Jiang ZH
AD  - State Key Laboratory of Quality Research in Chinese Medicine, Macau University of 
      Science and Technology, Taipa, Macau SAR, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220411
PL  - United States
TA  - mSystems
JT  - mSystems
JID - 101680636
RN  - 9014-25-9 (RNA, Transfer)
MH  - Humans
MH  - *RNA, Transfer/chemistry
MH  - Escherichia coli/genetics
MH  - Structure-Activity Relationship
MH  - *Colorectal Neoplasms
PMC - PMC9040620
OTO - NOTNLM
OT  - antitumor activity
OT  - chemical modifications
OT  - gut microbiota
OT  - tRF
COIS- The authors declare no conflict of interest.
EDAT- 2022/04/12 06:00
MHDA- 2022/04/12 06:01
PMCR- 2022/04/11
CRDT- 2022/04/11 05:23
PHST- 2022/04/12 06:00 [pubmed]
PHST- 2022/04/12 06:01 [medline]
PHST- 2022/04/11 05:23 [entrez]
PHST- 2022/04/11 00:00 [pmc-release]
AID - 00164-22 [pii]
AID - msystems.00164-22 [pii]
AID - 10.1128/msystems.00164-22 [doi]
PST - ppublish
SO  - mSystems. 2022 Apr 26;7(2):e0016422. doi: 10.1128/msystems.00164-22. Epub 2022 
      Apr 11.