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Chen LC, Lin HY, Hung SK, Chiou WY, Lee MS. Role of modern radiotherapy in managing patients with hepatocellular carcinoma. World J Gastroenterol 2021; 27:2434-2457. [PMID: 34092968 PMCID: PMC8160620 DOI: 10.3748/wjg.v27.i20.2434] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/16/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement (e.g., stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated.
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Affiliation(s)
- Liang-Cheng Chen
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi 62247, Taiwan
| | - Hon-Yi Lin
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi 62247, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien 970, Taiwan
- Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi 62102, Taiwan
| | - Shih-Kai Hung
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi 62247, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien 970, Taiwan
| | - Wen-Yen Chiou
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi 62247, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien 970, Taiwan
| | - Moon-Sing Lee
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi 62247, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien 970, Taiwan
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Shao QP, Wei C, Yang J, Zhang WZ. miR-3609 Decelerates the Clearance of Sorafenib in Hepatocellular Carcinoma Cells by Targeting EPAS-1 and Reducing the Activation of the Pregnane X Receptor Pathway. Onco Targets Ther 2020; 13:7213-7227. [PMID: 32801751 PMCID: PMC7394586 DOI: 10.2147/ott.s246471] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
Background The pregnane X receptor (PXR) not only plays an important role in cellular metabolism processes but also induces the resistance of hepatocellular carcinoma (HCC) cells to molecularly targeted drugs by mediating their metabolism and clearance by these cells. Endothelial PAS domain-containing protein 1 (EPAS-1) acts as a coactivator to regulate the transcription factor activity of PXR. In the present study, a microRNA that potentially targets EPAS-1, namely miR-3609, was identified using the miRDB tool. Methods The expression of miR-3609 and EPAS-1 was examined by qPCR. Lentiviral particles containing the full-length sequences of miR-3609 (pri-miR-3609) were prepared. The antitumor effect of antitumor agents was examined by the in vitro and in vivo assays. Results The expression of miR-3609 was negatively correlated with that of EPAS-1 in both HCC clinical specimens and paired non-tumor specimens, and the effect of miR-3609 on the expression of EPAS-1 was confirmed by Western blot experiments. Overexpression of miR-3609 decreased the expression of EPAS-1 and, in turn, repressed the activation of the PXR pathway. miR-3609 decreased the transcription factor activation of PXR, repressed its recruitment to its target gene promoter regions, and decreased the expression of its target genes CYP3A4 and P-GP. In addition, miR-3609 decelerated the metabolism and clearance of sorafenib in HCC cells and enhanced the antitumor effect of sorafenib in HCC cells. Conclusion Therefore, the results indicate that miR-3609 decreases the expression of EPAS-1 and enhances the sensitivity of HCC cells to sorafenib.
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Affiliation(s)
- Qing-Ping Shao
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province 450008, People's Republic of China
| | - Chen Wei
- Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People's Republic of China
| | - Jie Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People's Republic of China
| | - Wen-Zhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province 450008, People's Republic of China
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Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, Martinelli E, Ciardiello F, Morgillo F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol 2017; 23:4330-4340. [PMID: 28706416 PMCID: PMC5487497 DOI: 10.3748/wjg.v23.i24.4330] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/13/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma (HCC) is poor because there are few treatment options. Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis, proliferation and progression of HCC. Among all of the pathways that are involved in the development of HCC, Hedgehog (HH) signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression. HH plays a physiological role in embryogenesis, through the induction of the differentiation of hepatocytes from endodermal progenitors. The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development. HH activation sustains the sub-population of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC, and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells. High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome. In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth, metastasis and a mesenchymal phenotype.
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Ikeda M, Shimizu S, Sato T, Morimoto M, Kojima Y, Inaba Y, Hagihara A, Kudo M, Nakamori S, Kaneko S, Sugimoto R, Tahara T, Ohmura T, Yasui K, Sato K, Ishii H, Furuse J, Okusaka T. Reply to the Letter to the editor 'Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus Sorafenib for advanced hepatocellular carcinoma: randomized phase II trial' by Fornaro et al. Ann Oncol 2017; 28:903-904. [PMID: 28137738 DOI: 10.1093/annonc/mdx013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Indexed: 11/12/2022] Open
Affiliation(s)
- M Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - S Shimizu
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - T Sato
- Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan
| | - M Morimoto
- Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Y Kojima
- Department of Gastroenterology, National Center for Global Health and Medicine Center Hospital, Tokyo, Japan
| | - Y Inaba
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - A Hagihara
- Department of Hepatology, Osaka City University Hospital, Osaka, Japan
| | - M Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan
| | - S Nakamori
- Department of Hepatobiliary and Pancreatic Surgery, Osaka National Hospital, Osaka, Japan
| | - S Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - R Sugimoto
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - T Tahara
- Department of Gastroenterology, Saiseikai Utsunomiya Hospital, Tochigi, Japan
| | - T Ohmura
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - K Yasui
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - K Sato
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - H Ishii
- Clinical Research Center, Shikoku Cancer Center, Matsuyama, Japan
| | - J Furuse
- Department of Medical Oncology, Kyorin University, Tokyo, Japan
| | - T Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
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