PMID- 32317048
OWN - NLM
STAT- MEDLINE
DCOM- 20210412
LR  - 20210412
IS  - 1555-3884 (Electronic)
IS  - 1052-2166 (Print)
IS  - 1052-2166 (Linking)
VI  - 20
IP  - 1
DP  - 2020 Jun 12
TI  - Loss of ARF/INK4A Promotes Liver Progenitor Cell Transformation Toward 
      Tumorigenicity Supporting Their Role in Hepatocarcinogenesis.
PG  - 39-52
LID - 10.3727/105221620X15874935364268 [doi]
AB  - Liver progenitor cells (LPCs) contribute to liver regeneration during chronic 
      damage and are implicated as cells of origin for liver cancers including 
      hepatocellular carcinoma (HCC). The CDKN2A locus, which encodes the tumor 
      suppressors alternate reading frame protein (ARF) and INK4A, was identified as 
      one of the most frequently altered genes in HCC. This study demonstrates that 
      inactivation of CDKN2A enhances tumorigenic transformation of LPCs. The level of 
      ARF and INK4A expression was determined in a panel of transformed and 
      nontransformed wild-type LPC lines. Moreover, the transforming potential of LPCs 
      with inactivated CDKN2A was shown to be enhanced in LPCs derived from Arf(-/-) 
      and CDKN2A(fl/fl) mice and in wild-type LPCs following CRISPR-Cas9 suppression of 
      CDKN2A. ARF and INK4A abundance is consistently reduced or ablated following LPC 
      transformation. Arf(-/-) and CDKN2A(-/-) LPCs displayed hallmarks of 
      transformation such as anchorage-independent and more rapid growth than control 
      LPC lines with unaltered CDKN2A. Transformation was not immediate, suggesting 
      that the loss of CDKN2A alone is insufficient. Further analysis revealed 
      decreased p21 expression as well as reduced epithelial markers and increased 
      mesenchymal markers, indicative of epithelial-to-mesenchymal transition, 
      following inactivation of the CDKN2A gene were required for tumorigenic 
      transformation. Loss of ARF and INK4A enhances the propensity of LPCs to undergo 
      a tumorigenic transformation. As LPCs represent a cancer stem cell candidate, 
      identifying CDKN2A as a driver of LPC transformation highlights ARF and INK4A as 
      viable prognostic markers and therapeutic targets for HCC.
FAU - Strauss, Robyn P
AU  - Strauss RP
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
FAU - Audsley, Katherine M
AU  - Audsley KM
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
FAU - Passman, Adam M
AU  - Passman AM
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
FAU - van Vuuren, Joanne H
AU  - van Vuuren JH
AD  - Centre for Medical Research, Harry Perkins Institute of Medical ResearchNedlands, 
      WAAustralia.
FAU - Finch-Edmondson, Megan L
AU  - Finch-Edmondson ML
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
FAU - Callus, Bernard A
AU  - Callus BA
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
FAU - Yeoh, George C
AU  - Yeoh GC
AD  - School of Molecular Sciences, The University of Western AustraliaCrawley, 
      WAAustralia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200421
PL  - United States
TA  - Gene Expr
JT  - Gene expression
JID - 9200651
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Snai2 protein, mouse)
RN  - 0 (Snail Family Transcription Factors)
RN  - 0 (Vim protein, mouse)
RN  - 0 (Vimentin)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Animals
MH  - Azacitidine/pharmacology
MH  - CRISPR-Cas Systems
MH  - Cell Line, Transformed
MH  - Cell Transformation, Neoplastic/*genetics
MH  - Cyclin-Dependent Kinase Inhibitor p16/biosynthesis/deficiency/*physiology
MH  - DNA Methylation/drug effects
MH  - Epithelial-Mesenchymal Transition
MH  - Gene Deletion
MH  - Gene Expression Regulation, Neoplastic/genetics
MH  - Gene Knockout Techniques
MH  - Genes, p16
MH  - Liver/cytology/embryology
MH  - Liver Neoplasms, Experimental/*genetics
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasm Proteins/biosynthesis/genetics/physiology
MH  - Phenotype
MH  - Snail Family Transcription Factors/biosynthesis/genetics
MH  - Stem Cells/*pathology
MH  - Tumor Stem Cell Assay
MH  - Vimentin/biosynthesis/genetics
PMC - PMC7284103
COIS- The authors declare no conflicts of interest.
EDAT- 2020/04/23 06:00
MHDA- 2021/04/13 06:00
PMCR- 2020/06/12
CRDT- 2020/04/23 06:00
PHST- 2020/04/23 06:00 [pubmed]
PHST- 2021/04/13 06:00 [medline]
PHST- 2020/04/23 06:00 [entrez]
PHST- 2020/06/12 00:00 [pmc-release]
AID - GE412 [pii]
AID - 10.3727/105221620X15874935364268 [doi]
PST - ppublish
SO  - Gene Expr. 2020 Jun 12;20(1):39-52. doi: 10.3727/105221620X15874935364268. Epub 
      2020 Apr 21.