|
1
|
Wang P, Laster K, Jia X, Dong Z, Liu K. Targeting CRAF kinase in anti-cancer therapy: progress and opportunities. Mol Cancer 2023; 22:208. [PMID: 38111008 PMCID: PMC10726672 DOI: 10.1186/s12943-023-01903-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023] Open
Abstract
The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.
Collapse
Affiliation(s)
- Penglei Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Kyle Laster
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
- Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450000, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
| |
Collapse
|
|
2
|
Tian N, Wu D, Tang M, Sun H, Ji Y, Huang C, Chen L, Chen G, Zeng M. RAF1 Expression is Correlated with HAF, a Parameter of Liver Computed Tomographic Perfusion, and may Predict the Early Therapeutic Response to Sorafenib in Advanced Hepatocellular Carcinoma Patients. Open Med (Wars) 2020; 15:167-174. [PMID: 32190741 PMCID: PMC7065427 DOI: 10.1515/med-2020-0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 02/12/2019] [Indexed: 12/14/2022] Open
Abstract
Objectives Monitoring the early treatment effect of sorafenib in advanced hepatocellular carcinoma (HCC) patients is a diagnostic challenge. In a previous study, we reported the potential role of liver computed tomography perfusion (CTP) in the assessment of the response to sorafenib therapy in HCC. The present study aims to investigate whether sorafenib-targeted genes is correlated with CTP parameter, and investigate the potential of sorafenib-targeted genes in early prediction of therapeutic response to sorafenib in advanced HCC. Methods A total of 21 HCC patients were enrolled. Sorafenib was administered orally at a dose of 400 mg twice daily continuously. Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) criteria. CTP scanning was performed before and after two weeks of sorafenib treatment using a 320-detector row CT scanner. The perfusion parameters of portal vein flow (PVF), hepatic artery flow (HAF), and perfusion index (PI) were acquired by CTP. The expression levels of several sorafenib-targeted genes were assayed using real-time quantitative PCR and western blot analysis. Logistic regression was performed to analyze the relationship between HAF values and RAF1 expression levels. Results According to mRECIST, the disease control rate (CR+PR+SD) of treatment group was 70.5% after two months of treatment. Compared to background controls, tumor tissues exhibited higher HAF. A sorafenib-targeted gene, RAF1 expression, was increased in tumor tissues especially in the sorafenib-resistant group. The sorafenib-resistant group exhibited a significantly higher RAF1 expression and HAF than the sensitive group. Moreover, the RAF1 expression is positively correlated with the HAF value. Conclusion RAF1 expression might predict therapeutic effects of sorafenib in advanced HCC, where RAF1 could potentially serve as a molecular marker for monitoring early therapeutic effects after sorafenib treatment.
Collapse
Affiliation(s)
- Ninzi Tian
- Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032, China.,Shanghai Institute of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dong Wu
- Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032, China.,Shanghai Institute of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ming Tang
- Shanghai Institute of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032, China
| | - Huichuan Sun
- Department of Liver Surgery, Zhongshan hospital of Fudan University, Shanghai 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan hospital of Fudan University, Shanghai 200032, China
| | - Cheng Huang
- Department of Liver Surgery, Zhongshan hospital of Fudan University, Shanghai 200032, China
| | - Lingli Chen
- Department of Pathology, Zhongshan hospital of Fudan University, Shanghai 200032, China
| | - Gang Chen
- Shanghai Institute of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032, China
| | - Mengsu Zeng
- Shanghai Institute of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032, China
| |
Collapse
|
|
3
|
Ghosh A, Ghosh S, Dasgupta D, Ghosh A, Datta S, Sikdar N, Datta S, Chowdhury A, Banerjee S. Hepatitis B Virus X Protein Upregulates hELG1/ ATAD5 Expression through E2F1 in Hepatocellular Carcinoma. Int J Biol Sci 2016; 12:30-41. [PMID: 26722215 PMCID: PMC4679396 DOI: 10.7150/ijbs.12310] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 10/04/2015] [Indexed: 01/04/2023] Open
Abstract
The precise mechanism by which HBx protein of hepatitis B virus (HBV) impacts on hepato-carcinogenesis remain largely elusive despite strong evidences for its' involvement in the process. Here, we have investigated the role of HBx on expression of a novel gene hELG1/ATAD5, which is required for genome maintenance and its' importance in hepatocarcinogenesis. This study has for the first time showed that the expression of this gene was significantly higher in human cancer such as HBV-associated hepatocellular carcinoma (HCC) and in different HCC cell lines compared to normal liver. In addition, a significant elevation in ATAD5 expression was also found in HBx transfected HCC cell lines implicating HBx mediated transcriptional regulation on ATAD5. Using different deletion mutant constructs of putative promoter, the active promoter region was first identified here and subsequently the regulatory region of HBx was mapped by promoter-luciferase assay. But ChIP assay with anti-HBx antibody revealed that HBx was not physically present in ATAD5 transcription machinery whereas anti-E2F1 antibody showed the presence of E2F1 in the complex. Luciferase assay with E2F1 binding site mutant had further confirmed it. Moreover, both loss-and gain-of-function studies of ATAD5 showed that ATAD5 could enhance HBV production in transfected cells whereas knock down of ATAD5 increased the sensitivity of HCC cell line to chemotherapeutics 5-fluorouracil. Overall, this data suggests that a positive feedback loop regulation between ATAD5 and HBV contributed to both viral replication and chemo-resistance of HCC cells.
Collapse
Affiliation(s)
- Alip Ghosh
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Suchandrima Ghosh
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Debanjali Dasgupta
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Amit Ghosh
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Somenath Datta
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | | | - Simanti Datta
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Abhijit Chowdhury
- 3. Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- 1. Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| |
Collapse
|
|
4
|
Lu ZP, Xiao ZL, Yang Z, Li J, Feng GX, Chen FQ, Li YH, Feng JY, Gao YE, Ye LH, Zhang XD. Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2α and sphingosine kinase 1. Acta Pharmacol Sin 2015; 36:1228-36. [PMID: 26073327 DOI: 10.1038/aps.2015.38] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 03/30/2015] [Indexed: 12/17/2022]
Abstract
AIM Sphingosine kinase 1 (SPHK1) is involved in various cellular functions, including cell growth, migration, apoptosis, cytoskeleton architecture and calcium homoeostasis, etc. As an oncogenic kinase, SPHK1 is associated with the development and progression of cancers. The aim of this study was to investigate whether SPHK1 was involved in hepatocarcinogenesis induced by the hepatitis B virus X protein (HBx). METHODS The expression of SPHK1 in hepatocellular carcinoma (HCC) tissue and hepatoma cells were measured using qRT-PCR and Western blot analysis. HBx expression levels in hepatoma cells were modulated by transiently transfected with HBx or psi-HBx plasmids. The SPHK1 promoter activity was measured using luciferase reporter gene assay, and the interaction of the transcription factor AP2α with the SPHK1 promoter was studied with chromatin immunoprecipitation assay. The growth of hepatoma cells was evaluated in vitro using MTT and colony formation assays, and in a tumor xenograft model. RESULTS A positive correlation was found between the mRNA levels of SPHK1 and HBx in 38 clinical HCC samples (r=+0.727, P<0.01). Moreover, the expression of SPHK1 was markedly increased in the liver cancer tissue of HBx-transgenic mice. Overexpressing HBx in normal liver cells LO2 and hepatoma cells HepG2 dose-dependently increased the expression of SPHK1, whereas silencing HBx in HBx-expressing hepatoma cells HepG2-X and HepG2.2.15 suppressed SPHK1 expression. Furthermore, overexpressing HBx in HepG2 cells dose-dependently increased the SPHK1 promoter activity, whereas silencing HBx in HepG2-X cells suppressed this activity. In HepG2-X cells, AP2α was found to directly interact with the SPHK1 promoter, and silencing AP2α suppressed the SPHK1 promoter activity and SPHK1 expression. Silencing HBx in HepG2-X cells abolished the HBx-enhanced proliferation and colony formation in vitro, and tumor growth in vivo. CONCLUSION HBx upregulates SPHK1 through the transcription factor AP2α, which promotes the growth of human hepatoma cells.
Collapse
|
|
5
|
Zhou HB, Hu JY, Hu HP. Hepatitis B virus infection and intrahepatic cholangiocarcinoma. World J Gastroenterol 2014; 20:5721-5729. [PMID: 24914333 PMCID: PMC4024782 DOI: 10.3748/wjg.v20.i19.5721] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a devastating malignant tumor arising from the peripheral intrahepatic bile duct epithelium. The incidence and mortality of ICC is markedly increasing over the past two decades worldwide, though the cause for this rise in incidence is unclear, thus intensifying the search for alternative etiological agents and pathogenetic mechanisms. Hepatolithiasis, primary sclerosing cholangitis, parasitic infection (Opisthorchis viverrini or Clonorchis sinensis), fibropolycystic liver disease, and chemical carcinogen exposure are thought to be the risk factors for ICC. Nevertheless, the majority of ICC patients do not have any of these risk factors, and none of the established risk factors can explain the recent increasing trend of ICC. Therefore, identifying other risk factors may lead to the prevention and early detection of ICC. Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in HBV-endemic areas. This review discusses the evidence implicating chronic HBV infection as a likely etiology of ICC and the pathogenetic mechanisms that might be involved.
Collapse
|