Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0019204 (
hepatocellular carcinoma
)
71,386
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
.
...
PMID:Loss of ARF/INK4A Promotes Liver Progenitor Cell Transformation Toward Tumorigenicity Supporting Their Role in Hepatocarcinogenesis. 3231 48
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