PI16 attenuates response to sorafenib and represents a predictive biomarker in hepatocellular carcinoma.
Adult
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Carcinoma, Hepatocellular
/ drug therapy
Carrier Proteins
/ genetics
Caspase 3
/ metabolism
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Databases, Nucleic Acid
Female
Gene Expression Regulation, Neoplastic
Glycoproteins
/ genetics
HEK293 Cells
Hep G2 Cells
Humans
Liver Neoplasms
/ drug therapy
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Protein Kinase Inhibitors
/ pharmacology
Retrospective Studies
Signal Transduction
Sorafenib
/ pharmacology
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases
/ metabolism
apoptosis
p38 MAPK
peptidase inhibitor 16
prognosis
sorafenib
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
11
02
2020
revised:
05
06
2020
accepted:
25
06
2020
pubmed:
12
8
2020
medline:
21
7
2021
entrez:
12
8
2020
Statut:
ppublish
Résumé
Sorafenib has become the only FDA-approved first-line therapy for advanced hepatocellular carcinoma (HCC) for more than 10 years, but there is still no validated predictive or prognostic marker. Peptidase inhibitor 16 (PI16) is a functionally unknown gene in cancer research. This study aimed to determine the exact function of PI16 in HCC and whether it can represent as a biomarker for sorafenib response. We found that PI16 was over expressed in HCC tissues vs paired normal tissues. PI16 knockdown sensitize HCC cells to sorafenib treatment both in vitro and in vivo, whereas ectopic PI16 expression produced the opposite effect. Mechanistically, PI16 could suppress p38 MAPK/caspase-dependent apoptosis in this process, and p38 MAPK inhibitor reversed the sorafenib sensitive phenotype caused by PI16 inhibition. Clinically, immunohistochemistry was used to detect PI16 levels in resected patients with HCC prior to sorafenib treatment. We showed that high PI16 levels represented an independent risk factor for disease progression in patients treated with sorafenib. Patients with low PI16 showed significantly better progression free survival and overall survival after sorafenib therapy. In conclusion, PI16 attenuates response to sorafenib treatment in HCC, and may be a helpful prognostic biomarker of sorafenib treatment.
Identifiants
pubmed: 32779397
doi: 10.1002/cam4.3331
pmc: PMC7541153
doi:
Substances chimiques
Antineoplastic Agents
0
Carrier Proteins
0
Glycoproteins
0
PI16 protein, human
0
Protein Kinase Inhibitors
0
Sorafenib
9ZOQ3TZI87
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
CASP3 protein, human
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6972-6983Informations de copyright
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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