Anti-tumour effects of PIM kinase inhibition on progression and chemoresistance of hepatocellular carcinoma
| Autor: | Regina Cheuk-Lam Lo, Carmen Chak-Lui Wong, Wen Juan Dai, Ming Sum Leung, Weiyuan John Kao, Pik Ying Wong, Kwan Yung Au, Terence Kin Wah Lee, Irene Oi-Lin Ng, Kristy Kwan-Shuen Chan, Cheuk Yan Wong |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Carcinoma Hepatocellular Carcinogenesis medicine.medical_treatment Antineoplastic Agents Apoptosis Pathology and Forensic Medicine Targeted therapy 03 medical and health sciences Mice 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 In vivo Cell Movement hemic and lymphatic diseases Medicine Animals Doxorubicin Neoplasm Invasiveness Protein Kinase Inhibitors Cell Proliferation Cisplatin LOXL2 business.industry Cell growth Liver Neoplasms Imidazoles medicine.disease Xenograft Model Antitumor Assays Pyridazines 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Disease Progression business Liver cancer medicine.drug |
| Zdroj: | The Journal of pathologyReferences. 252(1) |
| ISSN: | 1096-9896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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