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AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization

Batur, Tugce ; Argundogan, Ayse ; Keles, Umur LU ; Mutlu, Zeynep ; Alotaibi, Hani ; Senturk, Serif and Ozturk, Mehmet (2021) In International Journal of Molecular Sciences 22(24). p.1-17
Abstract

AXL, a member of the TAM family, is a promising therapeutic target due to its elevated expression in advanced hepatocellular carcinoma (HCC), particularly in association with acquired drug resistance. Previously, RNA interference was used to study its role in cancer, and several phenotypic changes, including attenuated cell proliferation and decreased migration and invasion, have been reported. The mechanism of action of AXL in HCC is elusive. We first studied the AXL expression in HCC cell lines by real-time PCR and western blot and showed its stringent association with a mesenchymal phenotype. We then explored the role of AXL in mesenchymal SNU475 cells by CRISPR-Cas9 mediated gene knock-out. AXL-depleted HCC cells displayed drastic... (More)

AXL, a member of the TAM family, is a promising therapeutic target due to its elevated expression in advanced hepatocellular carcinoma (HCC), particularly in association with acquired drug resistance. Previously, RNA interference was used to study its role in cancer, and several phenotypic changes, including attenuated cell proliferation and decreased migration and invasion, have been reported. The mechanism of action of AXL in HCC is elusive. We first studied the AXL expression in HCC cell lines by real-time PCR and western blot and showed its stringent association with a mesenchymal phenotype. We then explored the role of AXL in mesenchymal SNU475 cells by CRISPR-Cas9 mediated gene knock-out. AXL-depleted HCC cells displayed drastic phenotypic changes, including increased DNA damage response, prolongation of doubling time, G2 arrest, and polyploidization in vitro and loss of tumorigenicity in vivo. Pharmacological inhibition of AXL by R428 recapitulated G2 arrest and polyploidy phenotype. These observations strongly suggest that acute loss of AXL in some mesenchymal HCC cells is lethal and points out that its inhibition may represent a druggable vulnerability in AXL-high HCC patients.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Benzocycloheptenes, CRISPR-Cas Systems, Carcinoma, Hepatocellular/genetics, Cell Line, Tumor, Cell Movement, Cell Proliferation, G2 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Liver Neoplasms/genetics, Male, Mice, Neoplasm Transplantation, Phenotype, Proto-Oncogene Proteins/genetics, Receptor Protein-Tyrosine Kinases/genetics, Triazoles, Up-Regulation, Axl Receptor Tyrosine Kinase
in
International Journal of Molecular Sciences
volume
22
issue
24
article number
13247
pages
1 - 17
publisher
MDPI AG
external identifiers
  • scopus:85120803176
  • pmid:34948046
ISSN
1422-0067
DOI
10.3390/ijms222413247
language
English
LU publication?
no
id
8ce1a172-9c5f-4d1e-9a1c-f6d8f715f41a
date added to LUP
2022-12-28 10:08:30
date last changed
2025-04-18 19:44:57
@article{8ce1a172-9c5f-4d1e-9a1c-f6d8f715f41a,
  abstract     = {{<p>AXL, a member of the TAM family, is a promising therapeutic target due to its elevated expression in advanced hepatocellular carcinoma (HCC), particularly in association with acquired drug resistance. Previously, RNA interference was used to study its role in cancer, and several phenotypic changes, including attenuated cell proliferation and decreased migration and invasion, have been reported. The mechanism of action of AXL in HCC is elusive. We first studied the AXL expression in HCC cell lines by real-time PCR and western blot and showed its stringent association with a mesenchymal phenotype. We then explored the role of AXL in mesenchymal SNU475 cells by CRISPR-Cas9 mediated gene knock-out. AXL-depleted HCC cells displayed drastic phenotypic changes, including increased DNA damage response, prolongation of doubling time, G2 arrest, and polyploidization in vitro and loss of tumorigenicity in vivo. Pharmacological inhibition of AXL by R428 recapitulated G2 arrest and polyploidy phenotype. These observations strongly suggest that acute loss of AXL in some mesenchymal HCC cells is lethal and points out that its inhibition may represent a druggable vulnerability in AXL-high HCC patients.</p>}},
  author       = {{Batur, Tugce and Argundogan, Ayse and Keles, Umur and Mutlu, Zeynep and Alotaibi, Hani and Senturk, Serif and Ozturk, Mehmet}},
  issn         = {{1422-0067}},
  keywords     = {{Animals; Benzocycloheptenes; CRISPR-Cas Systems; Carcinoma, Hepatocellular/genetics; Cell Line, Tumor; Cell Movement; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Humans; Liver Neoplasms/genetics; Male; Mice; Neoplasm Transplantation; Phenotype; Proto-Oncogene Proteins/genetics; Receptor Protein-Tyrosine Kinases/genetics; Triazoles; Up-Regulation; Axl Receptor Tyrosine Kinase}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  pages        = {{1--17}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization}},
  url          = {{http://dx.doi.org/10.3390/ijms222413247}},
  doi          = {{10.3390/ijms222413247}},
  volume       = {{22}},
  year         = {{2021}},
}