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Masthoff M, Irle M, Kaldewey D, Rennebaum F, Morgül H, Pöhler GH, Trebicka J, Wildgruber M, Köhler M, Schindler P. Integrating CT Radiomics and Clinical Features to Optimize TACE Technique Decision-Making in Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:893. [PMID: 40075740 PMCID: PMC11899091 DOI: 10.3390/cancers17050893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/28/2025] [Accepted: 03/02/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND/OBJECTIVES To develop a decision framework integrating computed tomography (CT) radiomics and clinical factors to guide the selection of transarterial chemoembolization (TACE) technique for optimizing treatment response in non-resectable hepatocellular carcinoma (HCC). METHODS A retrospective analysis was performed on 151 patients [33 conventional TACE (cTACE), 69 drug-eluting bead TACE (DEB-TACE), 49 degradable starch microsphere TACE (DSM-TACE)] who underwent TACE for HCC at a single tertiary center. Pre-TACE contrast-enhanced CT images were used to extract radiomic features of the TACE-treated liver tumor volume. Patient clinical and laboratory data were combined with radiomics-derived predictors in an elastic net regularized logistic regression model to identify independent factors associated with early response at 4-6 weeks post-TACE. Predicted response probabilities under each TACE technique were compared with the actual techniques performed. RESULTS Elastic net modeling identified three independent predictors of response: radiomic feature "Contrast" (OR = 5.80), BCLC stage B (OR = 0.92), and viral hepatitis etiology (OR = 0.74). Interaction models indicated that the relative benefit of each TACE technique depended on the identified patient-specific predictors. Model-based recommendations differed from the actual treatment selected in 66.2% of cases, suggesting potential for improved patient-technique matching. CONCLUSIONS Integrating CT radiomics with clinical variables may help identify the optimal TACE technique for individual HCC patients. This approach holds promise for a more personalized therapy selection and improved response rates beyond standard clinical decision-making.
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Affiliation(s)
- Max Masthoff
- Clinic for Radiology, University of Münster, 48149 Münster, Germany
| | - Maximilian Irle
- Clinic for Radiology, University of Münster, 48149 Münster, Germany
| | - Daniel Kaldewey
- Clinic for Radiology, University of Münster, 48149 Münster, Germany
| | - Florian Rennebaum
- Department of Internal Medicine B, University of Münster, 48149 Münster, Germany
| | - Haluk Morgül
- Department of General, Visceral and Transplant Surgery, University of Münster, 48149 Münster, Germany
| | | | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, 48149 Münster, Germany
| | | | - Michael Köhler
- Clinic for Radiology, University of Münster, 48149 Münster, Germany
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2
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Rab SO, Roopashree R, Altalbawy FMA, Kumar MR, Chahar M, Singh M, Kubaev A, Alamir HTA, Mohammed F, Kadhim AJ, Alhadrawi M. Phytochemicals and Their Nanoformulations for Targeting Hepatocellular Carcinoma: Exploring Potential and Targeting Strategies. Cell Biochem Funct 2024; 42:e70013. [PMID: 39521962 DOI: 10.1002/cbf.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/18/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Hepatocellular carcinoma (HCC) continues to pose a global health concern, necessitating the exploration of innovative therapeutic approaches. In the recent decade, targeting tumor stroma consisting of extracellular matrix (ECM), immune cells, vascular system, hypoxia, and also suppressive mechanisms in HCC has attracted interest in repressing tumor growth and metastasis. Phytochemicals have attained considerable attention because of their manifold biological effects and high capacity for anticancer activities. These chemical agents have shown the capability to modulate different cells and secretions within the stroma of malignancies. In recent years, the development of nanoformulations has further enhanced the therapeutic potential of phytochemicals by improving their solubility, bioavailability, and targeted delivery to tumor tissues. This review aims to provide an encyclopedic overview of the potential of phytochemicals and their nanoformulations as promising therapeutic strategies for targeting HCC. The review initially highlights the broad array of phytochemicals exhibiting potent anticancer properties, including flavonoids, alkaloids, terpenoids, and phenolic compounds, among others. Then, the nanoformulations and modification of these agents will be reviewed. Finally, we will review the latest experiments that have examined the modulation of HCC using adjuvant phytochemicals and their nanoformulations.
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Affiliation(s)
- Safia Obaidur Rab
- Central Labs, King Khalid University, AlQura'a, Abha, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, India
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, Rajasthan, India
| | - Manmeet Singh
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Amarah, Maysan, Iraq
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
| | - Merwa Alhadrawi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
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3
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Jiang L, Meng Q, Liu L, Li W. A Comprehensive Review on Molecular Mechanisms, Treatments, and Brief Role of Natural Products in Hepatocellular Cancer. Nat Prod Commun 2024; 19. [DOI: 10.1177/1934578x241284873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Most initial liver cancers are hepatocellular carcinomas (HCC), which make up the vast majority of cases. Hepatitis B or C virus infection as well as alcohol consumption is among the key risk factors. The significance of the most intriguing soluble factors as indicators for early diagnosis and as suggested targets for therapy in light of the increasing challenges in precision medicine. The development of HCC is influenced by a complex combination between pro-inflammatory and anti-inflammatory cytokines and their signalling cascades. Recently,researchers are aims to assess the potential of a number of distinct molecular cascade/cascade including cytokines to function as key players with particular underlying etiologies. Increasing our knowledge of the signaling network that links retro differentiation and inflammationmay help us find novel therapeutic targets and develop combined therapies or treatments that work against tumors with a significant degree of heterogeneity. With nursing processes at its center, comprehensive nursing care is a new nursing paradigm that combines the benefits of primary and group nursin g as well as a perfect synthesis of many nursing metrics like nursing philosophy, nursing plan, and nursing quality evaluation. In order to treat patients with serious liver diseases like cancer, it can conduct nursing interventions item by item in accordance with the unique disease conditions of each patient and combine efficient therapeutic approaches with high-quality nursing modes. Dietary natural products, including fruits, vegetables, and spices, may prevent and treat liver cancer by inhibiting tumor growth, protecting the liver, and enhancing chemotherapy.
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Affiliation(s)
- Linlin Jiang
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Qin Meng
- Department of Nursing, Huaian Hospital of Huaian City, Huaian Jiangsu,China
| | - Lixiu Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Weihang Li
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
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4
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Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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Miura M, Nishino M, Kawaguchi K, Li S, Shimakami T, Tamai T, Nakagawa H, Terashima T, Iida N, Takatori H, Arai K, Sakai Y, Yamashita T, Honda M, Kaneko S, Mizukoshi E, Yamashita T. Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy. PLoS One 2024; 19:e0299424. [PMID: 38781172 PMCID: PMC11115325 DOI: 10.1371/journal.pone.0299424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 02/11/2024] [Indexed: 05/25/2024] Open
Abstract
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
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Affiliation(s)
- Miyabi Miura
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Michiko Nishino
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shihui Li
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Toshikatsu Tamai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hidetoshi Nakagawa
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Information-Based Medicine Development, Kanazawa University Graduate School of Medicine, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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Wang H, Liu L, Gong H, Li H. Upregulation of FAM134B inhibits endoplasmic reticulum stress-related degradation protein expression and promotes hepatocellular carcinogenesis. J Cell Mol Med 2024; 28:e17964. [PMID: 37728036 PMCID: PMC10902567 DOI: 10.1111/jcmm.17964] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Endoplasmic reticulum (ER) stress can stimulate the proliferation and metastasis of hepatocellular carcinoma (HCC) cells while hindering apoptosis and immune system function, but the molecular mechanism of ER stress in HCC has yet to be fully studied. We aim to investigate the molecular mechanism by which FAM134B inhibits autophagy of HCC cells by reducing the expression of ER stress-related degradation proteins. Clinical samples were collected for this study. Normal liver cell lines HL7702 and Hep3B and Huh7 HCC cell lines were cultured. Construction of FAM134B knockdown cell line. Cell proliferation was measured using the CCK-8 assay, while cell migration and invasion capabilities were detected using the plate colony formation assay. Flow cytometry was used to detect the apoptosis rate. Transmission electron microscopy was used to observe the formation of autophagosomes. qRT-PCR and WB detective expression changes related to autophagy proteins. Finally, the expression of the relevant proteins was observed by immunohistochemistry. The expression of FAM134B was significantly increased in human liver cancer tissue and HCC cell lines Hep3B and Huh7. After the lentiviral vector was transfected into Hep3B cells with sh-FAM134B, results showed that sh-FAM134B could effectively inhibit Hep3B cell proliferation and promote HCC cell apoptosis. Meanwhile, sh-FAM134B could effectively induce the autophagy of Hep3B liver cancer cells. Immunohistochemistry results showed that sh-FAM134B could effectively induce ER stress. FAM134B inhibits HCC cell autophagy and promotes the progression of liver cancer by inhibiting the expression of ER stress-related degradation factors such as DERL2, EDEM1, SEL1L and HRD1.
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Affiliation(s)
- Houhong Wang
- Department of General SurgeryThe Affiliated Bozhou Hospital of Anhui Medical UniversityBozhouChina
| | - Lu Liu
- Department of Endocrine DepartmentThe Affiliated Nantong Hospital of Shanghai Jiao Tong UniversityNantongChina
| | - Huihui Gong
- Faculty of Health and Life SciencesOxford Brookes UniversityOxfordEnglandUK
| | - Heng Li
- Department of Comprehensive Surgery, Anhui Provincial Cancer HospitalWest District of The First Affiliated Hospital of USTCHefeiChina
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Luo JX, Zhang Y, Hu XY, Xiang N. Interferon therapy improves survival in patients with hepatitis B virus-related hepatocellular carcinoma after curative surgery: a meta-analysis. Hepatol Int 2024; 18:63-72. [PMID: 38165580 DOI: 10.1007/s12072-023-10618-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 11/16/2023] [Indexed: 01/04/2024]
Abstract
BACKGROUND AND AIM A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. METHODS MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. RESULTS 10 trials with a total of 2062 subjects were screened. Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. CONCLUSIONS Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.
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Affiliation(s)
- Jian-Xing Luo
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yang Zhang
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiao-Yu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Ne Xiang
- Department of TCM, Caojiaxiang Community Health Service Center, Chengdu, Sichuan, China.
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Peng X, Shi Y, Zhang B, Xu C, Lang J. Establishment of nucleic acid sensing pathways-based model in predicting response to immunotherapy and targeted drug in hepatitis virus-related hepatocellular carcinoma. J Med Virol 2023; 95:e29084. [PMID: 37721443 DOI: 10.1002/jmv.29084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/09/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for 80% of liver cancers, while 70%-80% of HCC developed from chronic liver disease with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as the major etiology. Immunotherapy is assuming a role as a pillar of HCC treatment, but the remarkable immune-mediated responses are restricted in a minority of patients. Nucleic acid sensing (NAS) pathways are the central pathway of the innate immune system and antiviral immune response to viral infection, but their role in hepatitis virus-related HCC remains undetermined. In our study, we performed a comprehensive bioinformatics analysis based on transcriptomic data of hepatitis virus related-HCC tissues collected from multiple public data sets. Two subgroups were validated based on NAS-related genes in virus-related HCC patients, which were defined as NAS-activated subgroups and NAS-suppressed subgroups based on the expression of NAS-related genes. On this basis, a NAS-related risk score (NASRS) predictive model was established for risk stratification and prognosis prediction in the hepatitis virus-related HCC (TCGA-LIHC and ICGC cohorts). The predictive values of the NASRS in prognosis and immunotherapy were also verified in multiple data sets. A nomogram was also established to facilitate the clinical use of NASRS and demonstrate its effectiveness through different approaches. Additionally, six potential drugs binding to the core target of the NAS signature were predicted via molecular docking strategy. We subsequently evaluated the cytotoxic capabilities of potential drug in vitro and in vivo. Based on these results, we conclude that the NASRS model could serve as a power prognostic biomarker and predict responses to immunotherapy, which is meaningful in clinical decision-making of hepatitis virus-related HCC patients.
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Affiliation(s)
- Xinhao Peng
- Department of Biomedical Engineering, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Oncology, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China
| | - Ying Shi
- Department of Biomedical Engineering, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Biqin Zhang
- Department of Biomedical Engineering, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Chuan Xu
- Department of Biomedical Engineering, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jinyi Lang
- Department of Biomedical Engineering, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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9
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Brown ZJ, Ruff SM, Pawlik TM. The effect of liver disease on hepatic microenvironment and implications for immune therapy. Front Pharmacol 2023; 14:1225821. [PMID: 37608898 PMCID: PMC10441240 DOI: 10.3389/fphar.2023.1225821] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related death worldwide. HCC often occurs in the setting of chronic liver disease or cirrhosis. Recent evidence has highlighted the importance of the immune microenvironment in the development and progression of HCC, as well as its role in the potential response to therapy. Liver disease such as viral hepatitis, alcohol induced liver disease, and non-alcoholic fatty liver disease is a major risk factor for the development of HCC and has been demonstrated to alter the immune microenvironment. Alterations in the immune microenvironment may markedly influence the response to different therapeutic strategies. As such, research has focused on understanding the complex relationship among tumor cells, immune cells, and the surrounding liver parenchyma to treat HCC more effectively. We herein review the immune microenvironment, as well as the relative effect of liver disease on the immune microenvironment. In addition, we review how changes in the immune microenvironment can lead to therapeutic resistance, as well as highlight future strategies aimed at developing the next-generation of therapies for HCC.
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Affiliation(s)
- Zachary J. Brown
- Department of Surgery, New York University Long Island School of Medicine, Mineola, NY, United States
| | - Samantha M. Ruff
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Timothy M. Pawlik
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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10
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Lin C, Tsai SCS, Huang JY, Lin FCF. HPV infection and breast cancer risk: insights from a nationwide population study in Taiwan. Front Oncol 2023; 13:1210381. [PMID: 37519781 PMCID: PMC10379647 DOI: 10.3389/fonc.2023.1210381] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 06/29/2023] [Indexed: 08/01/2023] Open
Abstract
Background The prevalence of cancer, specifically breast cancer, has raised globally. The etiology of breast cancer has been attributed to age, genetic mutations, reproductive history, hormone therapy, lifestyle factors, and viral infections. The human papillomavirus (HPV) has been one of the most widespread sexually transmitted infection in the United States. The role of HPV in breast oncogenesis was hypothesized before, yet the association remained unclear. Methods In this study, we employed a nationwide population study using centralized patient data managed by the Ministry of Health and Welfare in Taiwan and the Taiwan Cancer Registry database. The breast cancer incidence rates of the 467,454 HPV patients were compared to twice as many non-HPV patients with matching sex and age. Cumulative breast cancer incidence rates were presented by a Kaplan-Meier curve, and the relative risk of breast cancer for HPV and non-HPV patients were calculated using Cox-regression model. Results Our results indicated a crude hazard ratio (HR) and an adjusted hazard ratio (aHR) of 2.336 and 2.271, respectively, when comparing the risk of breast cancer in the HPV and non-HPV group. The risk of breast cancer was comparable or higher than those of head and neck cancer (aHR=1.595) and cervical cancer (aHR=2.225), which both were found to have causal relationships with HPV. The Kaplan-Meier curve further illustrated a higher cumulative risk across 84 months for HPV patients (p<.0001). Besides HPV, age (p<.0001), insurance providers (p<.001), and comorbidities such as abnormal liver function (aHR=1.191, p=.0069) and hyperlipidemia (aHR=1.218, p=.0002) were found to be correlated with higher risks of breast cancer. Conclusion A correlation between HPV and breast cancer can be inferred using national health databases. More molecular studies are required to understand the mechanism of the virus-induced oncogenesis of the breast.
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Affiliation(s)
- Chuck Lin
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
| | - Stella Chin-Shaw Tsai
- Superintendents’ Office, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Jing-Yang Huang
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Frank Cheau-Feng Lin
- Department of Thoracic Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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11
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Scholte LL, Bethony JM, Xian RR. Diagnosis and monitoring of virus-associated cancer using cell-free DNA. Curr Opin Virol 2023; 60:101331. [PMID: 37187125 PMCID: PMC11411455 DOI: 10.1016/j.coviro.2023.101331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/14/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023]
Abstract
Viral-associated cancers are a distinct group of malignancies with a unique pathogenesis and epidemiology. Liquid biopsy is a minimally invasive way to identify tumor-associated abnormalities in blood derivatives, such as plasma, to guide the diagnosis, prognosis, and treatment of patients with cancer. Liquid biopsy encompasses a multitude of circulating analytes with the most extensively studied being cell-free DNA (cfDNA). In recent decades, substantial advances have been made toward the study of circulating tumor DNA in nonviral-associated cancers. Many of these observations have been translated to the clinic to improve the outcomes of patients with cancer. The study of cfDNA in viral-associated cancers is rapidly evolving and reveals tremendous potential for clinical applications. This review provides an overview of the pathogenesis of viral-associated malignancies, the current state of cfDNA analysis in oncology, the current state of cfDNA analysis in viral-associated cancers, and perspectives for the future of liquid biopsies in viral-associated cancers.
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Affiliation(s)
- Larissa Ls Scholte
- Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington DC, United States
| | - Jeffrey M Bethony
- Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington DC, United States
| | - Rena R Xian
- Department of Pathology and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, United States; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States.
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12
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Guven DC, Erul E, Sahin TK, Dizdar O, Yalcin S, Sahin IH. The benefit of immunotherapy in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Future Oncol 2022; 18:4119-4136. [PMID: 36533987 DOI: 10.2217/fon-2022-0642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: A systemic review of the survival benefit of immune checkpoint inhibitors (ICIs) in phase III hepatocellular carcinoma (HCC) trials was conducted. Methods: Meta-analyses were performed with the generic inverse-variance method with a fixed-effects model. Results: In 10 trials encompassing 6123 patients, ICI-based therapy (monotherapy/combination) improved overall survival (OS) compared with the control arm (hazard ratio [HR]: 0.77; 95% CI: 0.70-0.84; p < 0.001). The survival benefit was consistent across variable treatment lines, Eastern Cooperative Oncology Group performance status and AFP levels. While the OS benefit was more pronounced in hepatitis B-related HCC (HR: 0.70; 95% CI: 0.63-0.77; p < 0.001), OS was improved in hepatitis C-related (HR: 0.83; 95% CI: 0.71-0.98) and nonviral HCC (HR: 0.86; 95% CI: 0.77-0.97). Conclusion: ICI-based therapies should be the standard for all patients with advanced HCC.
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Affiliation(s)
- Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Enes Erul
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey
| | - Taha Koray Sahin
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey
| | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Ibrahim Halil Sahin
- Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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13
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Xie Y, Yan F, Wang X, Yu L, Yan H, Pu Q, Li W, Yang Z. Mechanisms and network pharmacological analysis of Yangyin Fuzheng Jiedu prescription in the treatment of hepatocellular carcinoma. Cancer Med 2022; 12:3237-3259. [PMID: 36043445 PMCID: PMC9939140 DOI: 10.1002/cam4.5064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/22/2022] [Accepted: 07/03/2022] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. METHODS The H22 tumor-bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor-infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The proportion of CD8+ T cells and the expression of programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC-related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component-target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein-protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene-gene inner and component-target-pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor-bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. RESULTS Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor-bearing mice. FZP increased the immune organ index and the levels of CD8+ and CD3+ T cells in the spleen and peripheral blood of H22 tumor-bearing mice. FZP also reduced the expression of PD-1, TIGIT, and TIM3 in CD8+ T cells and the production of IL-10, IL-4, IL-6, and IL-1β. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC-related signaling pathways, including the PIK3-Akt signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. CONCLUSION FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC-related targets, pathways, and biological processes.
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Affiliation(s)
- Yuqing Xie
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Qing Pu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Weihong Li
- School of Traditional Chinese MedicineBeijing University of Chinese MedicineBeijingP.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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15
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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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16
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Parafibromin Is Highly Expressed in Hepatocellular Carcinoma and Its Expression Correlates with Poor Prognosis. J Clin Med 2022; 11:jcm11071773. [PMID: 35407381 PMCID: PMC9000084 DOI: 10.3390/jcm11071773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/19/2022] [Accepted: 03/21/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Much progress has been made regarding the understanding of hepatocarcinogenesis, yet the long-term survival rate of HCC patients remains poor. Recent efforts have shown parafibromin has a pathologic role in many human cancers, but little is known about the effects of parafibromin in HCC. This study aimed to investigate the pattern of parafibromin expression and its clinicopathologic significance in human HCC. Immunohistochemical analysis of HCC and matched non-tumor liver tissues from 50 HCC patients showed that the nuclear expression of parafibromin was higher in HCC tissues (50/50 cases) than in non-tumor liver tissues (17/50 cases). Moreover, elevated parafibromin expression was found to be significantly correlated with the presence of microvascular invasion (p = 0.017), hepatitis virus infection-induced occurrence (p = 0.005), and poorer tumor differentiation (Edmondson-Steiner grade; p = 0.000). Kaplan-Meier analysis showed that HCC patients with elevated parafibromin expression had poorer recurrence-free (p = 0.014, log-rank test = 6.079) and overall survival (p = 0.036, log-rank test = 4.414). These findings indicate parafibromin may be related to the pathogenesis of HCC and a potential prognostic marker for HCC patients after hepatectomy.
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17
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Wang Y, Wang Z, Sun J, Qian Y. Identification of HCC Subtypes With Different Prognosis and Metabolic Patterns Based on Mitophagy. Front Cell Dev Biol 2022; 9:799507. [PMID: 34977039 PMCID: PMC8716756 DOI: 10.3389/fcell.2021.799507] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 11/30/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Mitophagy is correlated with tumor initiation and development of malignancy. However, HCC heterogeneity with reference to mitophagy has yet not been systematically explored. Materials and Methods: Mitophagy-related, glycolysis-related, and cholesterol biosynthesis-related gene sets were obtained from the Reactome database. Mitophagy-related and metabolism-related subtypes were identified using the ConsensusClusterPlus algorithm. Univariate Cox regression was analysis was performed to identify prognosis-related mitophagy regulators. Principal component analysis (PCA) was used to create composite measures of the prognosis-related mitophagy regulators (mitophagyscore). Individuals with a mitophagyscore higher or lower than the median value were classified in high- or low-risk groups. Kaplan-Meier survival and ROC curve analyses were utilized to evaluate the prognostic value of the mitophagyscore. The nomogram and calibration curves were plotted using the“rms” R package. The package “limma” was used for differential gene expression analysis. Differentially expressed genes (DEGs) between high- and low-risk groups were used as queries in the CMap database. R package “pRRophetic” and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to determine the sensitivity of 21 previously reported anti-HCC drugs. Results: Three distinct HCC subtypes with different mitophagic accumulation (low, high, and intermediate mitophagy subtypes) were identified. High mitophagy subtype had the worst outcome and highest glycolysis level. The lowest degree of hypoxia and highest cholesterol biosynthesis was observed in the low mitophagy subtype; oncogenic dedifferentiation level in the intermediate mitophagy subtype was the lowest. Mitophagyscore could serve as a novel prognostic indicator for HCC.High-risk patients had a poorer prognosis (log-rank test, p < 0.001). The area under the ROC curve for mitophagyscore in 1-year survival was 0.77 in the TCGA cohort and 0.75 in the ICGC cohort. Nine candidate small molecules which were potential drugs for HCC treatment were identified from the CMap database. A decline in the sensitivity towards 21 anti-HCC drugs was observed in low-risk patients by GDSC database. We also identified a novel key gene, SPP1, which was highly associated with different mitophagic subtypes. Conclusion: Based on bioinformatic analyses, we systematically examined the HCC heterogeneity with reference to mitophagy and observed three distinct HCC subtypes having different prognoses and metabolic patterns.
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Affiliation(s)
- Yao Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhen Wang
- Department of General Surgery, Feixi County People's Hospital, Hefei, China
| | - Jingjing Sun
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yeben Qian
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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18
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Ezzat R, Eltabbakh M, El Kassas M. Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures. World J Gastrointest Oncol 2021; 13:1919-1938. [PMID: 35070033 PMCID: PMC8713321 DOI: 10.4251/wjgo.v13.i12.1919] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/17/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.
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Affiliation(s)
- Reem Ezzat
- Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Cairo, Egypt
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