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Anti‐tumour effects of PIM kinase inhibition on progression and chemoresistance of hepatocellular carcinoma
The Journal of pathology, 2020-09, Vol.252 (1), p.65-76
Leung, Ming‐Sum
Chan, Kristy Kwan‐Shuen
Dai, Wen‐Juan
Wong, Cheuk‐Yan
Au, Kwan‐Yung
Wong, Pik‐Ying
Wong, Carmen Chak‐Lui
Lee, Terence Kin‐Wah
Ng, Irene Oi‐Lin
Kao, Weiyuan John
Lo, Regina Cheuk‐Lam
2020
Details
Autor(en) / Beteiligte
Leung, Ming‐Sum
Chan, Kristy Kwan‐Shuen
Dai, Wen‐Juan
Wong, Cheuk‐Yan
Au, Kwan‐Yung
Wong, Pik‐Ying
Wong, Carmen Chak‐Lui
Lee, Terence Kin‐Wah
Ng, Irene Oi‐Lin
Kao, Weiyuan John
Lo, Regina Cheuk‐Lam
Titel
Anti‐tumour effects of PIM kinase inhibition on progression and chemoresistance of hepatocellular carcinoma
Ist Teil von
The Journal of pathology, 2020-09, Vol.252 (1), p.65-76
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
Hepatocellular carcinoma (HCC) is a biologically aggressive cancer. Targeted therapy is in need to tackle challenges in the treatment perspective. A growing body of evidence suggests a promising role of pharmacological inhibition of PIM (proviral integration site for Moloney murine leukaemia virus) kinase in some human haematological and solid cancers. Yet to date, the potential application of PIM inhibitors in HCC is still largely unexplored. In the present study we investigated the pre‐clinical efficacy of PIM inhibition as a therapeutic approach in HCC. Effects of PIM inhibitors on cell proliferation, migration, invasion, chemosensitivity, and self‐renewal were examined in vitro. The effects of PIM inhibitors on tumour growth and chemoresistance in vivo were studied using xenograft mouse models. Potential downstream molecular mechanisms were elucidated by RNA sequencing (RNA‐seq) of tumour tissues harvested from animal models. Our findings demonstrate that PIM inhibitors SGI‐1776 and PIM447 reduced HCC proliferation, metastatic potential, and self‐renewal in vitro. Results from in vivo experiments supported the role of PIM inhibition in suppressing of tumour growth and increasing chemosensitivity of HCC toward cisplatin and doxorubicin, the two commonly used chemotherapeutic agents in trans‐arterial chemoembolisation (TACE) for HCC. RNA‐seq analysis revealed downregulation of the MAPK/ERK pathway upon PIM inhibition in HCC cells. In addition, LOXL2 and ICAM1 were identified as potential downstream effectors. Taken together, PIM inhibitors demonstrated remarkable anti‐tumourigenic effects in HCC in vitro and in vivo. PIM kinase inhibition is a potential approach to be exploited in formulating adjuvant therapy for HCC patients of different disease stages. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.5492
Titel-ID: cdi_proquest_journals_2435122569
Format
–
Schlagworte
Animal models
,
Animals
,
Antineoplastic Agents - pharmacology
,
Antineoplastic Agents - therapeutic use
,
Apoptosis - drug effects
,
Carcinogenesis - drug effects
,
Carcinoma, Hepatocellular - drug therapy
,
Carcinoma, Hepatocellular - pathology
,
Cell migration
,
Cell Movement - drug effects
,
Cell proliferation
,
Cell Proliferation - drug effects
,
Chemoresistance
,
Chemotherapy
,
Cisplatin
,
Disease Progression
,
Doxorubicin
,
Drug Resistance, Neoplasm - drug effects
,
Extracellular signal-regulated kinase
,
Gene therapy
,
Hepatocellular carcinoma
,
hypoxia
,
Imidazoles - pharmacology
,
Imidazoles - therapeutic use
,
inhibitor
,
Intercellular adhesion molecule 1
,
Kinases
,
Leukemia
,
Liver cancer
,
Liver Neoplasms - drug therapy
,
Liver Neoplasms - pathology
,
MAP kinase
,
Metabolic pathways
,
Metastases
,
Mice
,
Molecular modelling
,
Neoplasm Invasiveness - pathology
,
PIM kinase
,
Protein Kinase Inhibitors - pharmacology
,
Protein Kinase Inhibitors - therapeutic use
,
Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors
,
Pyridazines - pharmacology
,
Pyridazines - therapeutic use
,
Ribonucleic acid
,
RNA
,
TACE
,
therapeutics
,
Tumors
,
Xenograft Model Antitumor Assays
,
Xenografts
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