PMID- 30341383
OWN - NLM
STAT- MEDLINE
DCOM- 20191024
LR  - 20191024
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Oct 19
TI  - Synergistic and independent action of endogenous microRNAs 122a and 199a for 
      post-transcriptional liver detargeting of gene vectors.
PG  - 15539
LID - 10.1038/s41598-018-33801-4 [doi]
LID - 15539
AB  - In hepatocellular carcinoma (HCC), which usually develops in a cirrhotic liver, 
      treatments preserving normal liver function and viability are vitally important. 
      Here, we utilise the differential expression of miRNAs 122a and 199a between 
      normal hepatocytes and HCC to generate vectors harbouring their binding sites for 
      hepatocyte detargeting. Using a reporter gene, we observed a synergistic 
      detargeting of cells expressing both miRNAs as well as cells expressing either of 
      the miRNAs; while expression was retained in HCC cells negative for both 
      miRNA122a and miRNA199a. Mimics and inhibitors for individual miRNAs were used to 
      confirm these results. Furthermore, suicide gene therapy with cytosine deaminase 
      (CD)/5-fluorocytosine system resulted in limited killing of cells expressing 
      either of the two miRNAs. Finally, we report feasibility of using adeno 
      associated virus (AAV) based vectors for delivery of this dual regulated gene 
      delivery system. These results present a novel dual targeted system whereby 
      miRNA122a and miRNA199a act either synergistically or independently in regulating 
      transgene expression with vectors harbouring binding sites of both miRNAs and 
      have implications in detargeting vectors from multiple cell types in the liver.
FAU - Dhungel, Bijay
AU  - Dhungel B
AD  - Gallipoli Medical Research Institute, Greenslopes Private Hospital, 102 Newdegate 
      Street, Brisbane, 4120, QLD, Australia.
AD  - Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, 
      Brisbane, 4006, QLD, Australia.
AD  - University of Queensland Diamantina Institute, Translational Research Institute, 
      37 Kent Street, Woolloongabba, 4102, QLD, Australia.
FAU - Ramlogan-Steel, Charmaine A
AU  - Ramlogan-Steel CA
AD  - CQUniversity, Bruce Highway, North Rockhampton, 4702, QLD, Australia.
FAU - Steel, Jason C
AU  - Steel JC
AD  - CQUniversity, Bruce Highway, North Rockhampton, 4702, QLD, Australia. 
      j.steel@cqu.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181019
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (MIRN122 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (mirn199 microRNA, human)
SB  - IM
MH  - Binding Sites
MH  - Carcinoma, Hepatocellular/*therapy
MH  - Cells, Cultured
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Humans
MH  - MicroRNAs/*antagonists & inhibitors/genetics/metabolism
MH  - Models, Biological
MH  - *Nucleic Acid Hybridization
PMC - PMC6195616
COIS- The authors declare no competing interests.
EDAT- 2018/10/21 06:00
MHDA- 2019/10/28 06:00
PMCR- 2018/10/19
CRDT- 2018/10/21 06:00
PHST- 2018/05/29 00:00 [received]
PHST- 2018/10/01 00:00 [accepted]
PHST- 2018/10/21 06:00 [entrez]
PHST- 2018/10/21 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/10/19 00:00 [pmc-release]
AID - 10.1038/s41598-018-33801-4 [pii]
AID - 33801 [pii]
AID - 10.1038/s41598-018-33801-4 [doi]
PST - epublish
SO  - Sci Rep. 2018 Oct 19;8(1):15539. doi: 10.1038/s41598-018-33801-4.