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1
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Sufianov A, Agaverdiev M, Mashkin A, Ilyasova T. Targeting microRNA methylation: Innovative approaches to diagnosing and treating hepatocellular carcinoma. Noncoding RNA Res 2025; 11:150-157. [PMID: 39829957 PMCID: PMC11742574 DOI: 10.1016/j.ncrna.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/15/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer and is frequently linked to underlying chronic liver conditions such as hepatitis B, hepatitis C, and cirrhosis. Despite the progress achieved in the field of oncology, HCC remains a significant clinical challenge, primarily due to its typically late-stage diagnosis and the complex and multifaceted nature of its tumor biology. These factors contribute to the limited effectiveness of current treatment modalities and result in poor patient prognosis. Emerging research has underscored the vital role of microRNAs (miRNAs)-small, non-coding RNA molecules that play a pivotal part in the post-transcriptional regulation of gene expression. These miRNAs are integral to a wide array of cellular functions, including proliferation, apoptosis, and differentiation, and their dysregulation is closely associated with the pathogenesis of various cancers, notably HCC. A major focus in recent studies has been on the epigenetic regulation of miRNAs through methylation, a key mechanism that modulates gene expression. This process, involving the addition of methyl groups to CpG islands in the promoter regions of miRNA genes, can result in either gene silencing or activation, influencing the expression of oncogenes and tumor suppressor genes. Such alterations have profound implications for tumor growth, metastasis, and resistance to treatment. Evidence suggests that aberrant miRNA methylation can serve as a powerful biomarker for early detection and prognosis in HCC and may present novel opportunities for therapeutic intervention. This review aims to provide a comprehensive overview of the current landscape of miRNA methylation in HCC, elucidating its significance in the molecular mechanisms of liver cancer and examining its potential for clinical application. By exploring the diagnostic and therapeutic potential of miRNA methylation, we seek to highlight its value in enhancing personalized treatment strategies and improving patient outcomes.
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Affiliation(s)
- Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Murad Agaverdiev
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| | - Andrey Mashkin
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Tatiana Ilyasova
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
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2
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Zhang X, Li S, Li L, Li D, Zhao H, Gao X, Dang X. circ_0046599 Promotes HCC Progression by Competing with miR-1322 to Enhance NT5DC2 Expression. J Cancer 2025; 16:2275-2288. [PMID: 40302808 PMCID: PMC12036087 DOI: 10.7150/jca.103661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 03/02/2025] [Indexed: 05/02/2025] Open
Abstract
Background: This study aimed to investigate the impact of circ_0046599 on hepatocellular carcinoma (HCC). Methods: Analysis of the GEO dataset identified circ_0046599 as significantly upregulated in HCC, and its impact on cell proliferation, apoptosis, migration, and invasion was assessed. Bioinformatics and dual-luciferase assays identified miR-1322 as a target of circ_0046599, which in turn regulates NT5DC2 expression. In vitro and in vivo experiments confirmed the ceRNA mechanism of circ_0046599 in HCC. Results: circ_0046599 was significantly upregulated in HCC, and predicts a worse survival in HCC patients. Increased expression of circ_0046599 promoted HCC cell proliferation, migration, invasion, and inhibited apoptosis. circ_0046599 bound to miR-1322, which exerted a tumor-suppressive effect in HCC cells. miR-1322 targeted NT5DC2, and circ_0046599 regulated the expression of NT5DC2 by competitively binding to miR-1322. Modulation of NT5DC2 expression affected the oncogenic role of circ_0046599. In in vivo experiments, inhibition of circ_0046599 suppressed the growth of xenograft tumors by upregulating miR-1322 expression and suppressing NT5DC2. Conclusion: circ_0046599 promoted the progression of HCC by competitively binding to miR-1322 and regulating the expression of NT5DC2.
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Affiliation(s)
- Xiaobo Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment in General Surgical (Hepatobiliary and Pancreatic) Diseases of Health Commission of Henan Province, Zhengzhou, China
- Henan Province Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, College of Clinical Medicine of Henan University of Science and Technology, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Suxin Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment in General Surgical (Hepatobiliary and Pancreatic) Diseases of Health Commission of Henan Province, Zhengzhou, China
- Henan Province Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
| | - Luhao Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment in General Surgical (Hepatobiliary and Pancreatic) Diseases of Health Commission of Henan Province, Zhengzhou, China
- Henan Province Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
| | - Dingyang Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment in General Surgical (Hepatobiliary and Pancreatic) Diseases of Health Commission of Henan Province, Zhengzhou, China
- Henan Province Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
| | - Huashan Zhao
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaole Gao
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment in General Surgical (Hepatobiliary and Pancreatic) Diseases of Health Commission of Henan Province, Zhengzhou, China
- Henan Province Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
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3
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Klosowski EM, de Souza BTL, Nanami LF, Bizerra PFV, Mito MS, Esquissato GNM, Constantin RP, Joia BM, Menezes PVMDC, Caetano W, Pereira PCDS, Gonçalves RS, Garcia FP, Bidoia DL, Nakamura TU, Nakamura CV, Ishii-Iwamoto EL, Dos Santos WD, Ferrarese-Filho O, Marchiosi R, Constantin RP. Unraveling the intrinsic and photodynamic effects of aluminum chloride phthalocyanine on bioenergetics and oxidative state in rat liver mitochondria. Toxicol Appl Pharmacol 2025; 494:117157. [PMID: 39551162 DOI: 10.1016/j.taap.2024.117157] [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: 06/03/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
Previous research has revealed that mitochondria are an important target for photodynamic therapy (PDT), which might be employed as a therapeutic approach for several malignancies, including hepatocellular carcinoma (HCC). In this study, we investigated both intrinsic toxicity and photodynamic effects of the photosensitizer (PS) aluminum chloride phthalocyanine (AlClPc) on mitochondrial functions. Several aspects of mitochondrial bioenergetics, structure, and oxidative state were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation. Additionally, experiments were conducted to demonstrate the intrinsic and photodynamic effects of AlClPc on the viability of HepG2 cells. AlClPc interacted with mitochondria regardless of photostimulation; however, at the maximum utilized concentration (40 μM), photostimulation reduced its interaction with mitochondria. Although AlClPc hindered catalase (CAT) and glutathione reductase (GR) activities intrinsically, it had no discernable capacity to generate oxidative stress or impact bioenergetics in mitochondria without photostimulation, as one would anticipate from an ideal PS. When exposed to light, however, AlClPc had a substantially unfavorable influence on mitochondrial function, strengthening its intrinsic inhibitory action on CAT, producing oxidative stress, and jeopardizing mitochondrial bioenergetics. In terms of oxidative stress parameters, AlClPc induced lipid peroxidation and decreased the level of reduced glutathione (GSH) in mitochondria. Regarding bioenergetics, AlClPc promoted oxidative phosphorylation uncoupling and photodynamic inactivation of complex I, complex II, and the FoF1-ATP synthase complex, lowering mitochondrial ATP production. Lastly, AlClPc exhibited a concentration-dependent decrease in the viability of HepG2 cells, regardless of the presence or absence of photostimulation. While the harmful photodynamic effects of AlClPc on mitochondrial bioenergetics hold promise for treating HCC and other malignancies, the inherent toxic impacts on HepG2 cells underscore the need for caution in its application for this purpose.
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Affiliation(s)
- Eduardo Makiyama Klosowski
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Byanca Thais Lima de Souza
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Letícia Fernanda Nanami
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Paulo Francisco Veiga Bizerra
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Márcio Shigueaki Mito
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | | | - Renato Polimeni Constantin
- Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Breno Miguel Joia
- Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | | | - Wilker Caetano
- Department of Chemistry, Research Nucleus in Photodynamic System, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Paulo Cesar de Souza Pereira
- Department of Chemistry, Research Nucleus in Photodynamic System, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Renato Sonchini Gonçalves
- Department of Chemistry, Research Nucleus in Photodynamic System, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Francielle Pelegrin Garcia
- Department of Basic Health Sciences, Laboratory of Technological Innovation in the Development of Pharmaceuticals and Cosmetics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Danielle Lazarin Bidoia
- Department of Basic Health Sciences, Laboratory of Technological Innovation in the Development of Pharmaceuticals and Cosmetics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Tânia Ueda Nakamura
- Department of Basic Health Sciences, Laboratory of Technological Innovation in the Development of Pharmaceuticals and Cosmetics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Celso Vataru Nakamura
- Department of Basic Health Sciences, Laboratory of Technological Innovation in the Development of Pharmaceuticals and Cosmetics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Emy Luiza Ishii-Iwamoto
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Wanderley Dantas Dos Santos
- Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Osvaldo Ferrarese-Filho
- Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Rogério Marchiosi
- Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Rodrigo Polimeni Constantin
- Department of Biochemistry, Laboratory of Biological Oxidations, State University of Maringá, Maringá 87020-900, Paraná, Brazil; Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
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Sahu C, Sahu RK, Roy A. A Review on Nanotechnologically Derived Phytomedicines for the Treatment of Hepatocellular Carcinoma: Recent Advances in Molecular Mechanism and Drug Targeting. Curr Drug Targets 2025; 26:167-187. [PMID: 39385414 DOI: 10.2174/0113894501312571240920070441] [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: 04/09/2024] [Revised: 08/17/2024] [Accepted: 08/30/2024] [Indexed: 10/12/2024]
Abstract
The second largest cause of cancer-related death worldwide, Hepatocellular Carcinoma (HCC) is also the most common primary liver cancer. HCC typically arises in patients with liver cirrhosis. Existing synthetic medicines for treating chronic liver disease are ineffective and come with undesirable side effects. Although herbal remedies have widespread popularity, there is still a long road ahead before they are fully accepted by the scientific community. Secondary metabolites and phytochemicals found in plants are abundant in both the human diet and the non-human environment. Natural plant chemicals have been shown to be beneficial as therapeutic and chemopreventive treatments for a wide variety of chronic disorders. Many diseases, including HCC, can be effectively treated with the help of phytochemicals found in food. Resveratrol, curcumin, urolithin A, silibinin, quercetin, N-trans-feruloyl octopamine, emodin, lycopene, caffeine, and phloretin are all examples. Approximately, 60% of all anticancer medications are determined to be derived from natural substances, according to recent studies. Plant derivatives have played an important role in cancer due to their capacity to scavenge free radicals, limit cell proliferation, and set off apoptosis. The progression of HCC is linked to inflammatory signaling pathways, and this study sought to look at how novel approaches, such as phytomedicines, are being used to fight cancer. Recent advancements in molecular mechanisms and drug targeting for HCC have been discussed in this review.
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Affiliation(s)
| | - Ram Kumar Sahu
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Chauras Campus, Tehri Garhwal-249161, Uttarakhand, India
| | - Amit Roy
- Chhatrapati Shivaji Institute of Pharmacy, Bhilai, Chhattisgarh-491001, India
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5
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WU S, LI Q, ZHU X, ZHANG T. 2-hydroxy-3-methyl anthraquinone promotes apoptosis and inhibits invasion of human hepatocellular carcinoma cells by targeting nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1/cellular tumor antigen p53 signaling pathway. J TRADIT CHIN MED 2024; 44:1104-1110. [PMID: 39617695 PMCID: PMC11589549 DOI: 10.19852/j.cnki.jtcm.20230904.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 04/23/2023] [Indexed: 12/17/2024]
Abstract
OBJECTIVE To investigate the anti-liver cancer effect of 2-hydroxy-3-methyl anthraquinone (HMA) and the specific mechanism based on nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1 (SIRT1)/cellular tumor antigen p53 (p53) pathway. METHODS Cell counting kit-8 method was used to observe the effect of HMA on the activity of human hepatocellular carcinoma cells (HepG2) cells. At 72 h and 80 μL HMA, the apoptosis rate of HepG2 cells in each group was measured by flow cytometry. Transwell was used to assay for cell invasion. The protein expression levels of SIRT1, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-9 (CASP9) and caspase-3 (CASP3) were detected by Western Blot. RESULTS HMA significantly inhibited the proliferation of HepG2 cells, The half inhibiting concentration (IC50) of the HMA at 24, 48 and 72 h were examined and it were 126.3, 98.6, and 80.55 μM, respectively. Compared with the control group, the apoptosis rate of HMA, Selisistat (EX527), and HMA+ EX527 groups enhanced, while the apoptosis rate of SRT1720 diminished, demonstrating that inhibition of SIRT1 can lead to apoptosis of HepG2 cells. HMA+ EX527 group had the highest apoptosis rate, the lowest expression of SIRT1 and Bcl-2, and the highest expression of p53, Bax, CASP9 and CASP3. The number of invasions of HepG2 was significantly reduced after HMA and EX527 intervened. Western blot shows HMA could inhibit SIRT1, promote the expression of p53, and decrease the ratio of Bcl-2/Bax. CONCLUSIONS HMA induced apoptosis in HepG2 cells, while inhibiting proliferation and invasion. The mechanism of HMA against HCC may be related to the SIRT1/p53 pathway.
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Affiliation(s)
- Shuang WU
- 1 Clinical Laboratory, Affiliated Children Hospital of Xi’an Jiaotong University, Xian 710003, China
| | - Qiao LI
- 1 Clinical Laboratory, Affiliated Children Hospital of Xi’an Jiaotong University, Xian 710003, China
| | - Xieying ZHU
- 1 Clinical Laboratory, Affiliated Children Hospital of Xi’an Jiaotong University, Xian 710003, China
| | - Taoyuan ZHANG
- 2 Department of Anesthesiology, Rizhao International Heart Hospital, Rizhao 276800, China
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Dong H, Zhang Z, Ni M, Xu X, Luo Y, Wang Y, Zhang H, Chen J. The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy. Curr Treat Options Oncol 2024; 25:1239-1256. [PMID: 39259476 PMCID: PMC11485193 DOI: 10.1007/s11864-024-01246-9] [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] [Accepted: 07/08/2024] [Indexed: 09/13/2024]
Abstract
OPINION STATEMENT Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.
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Affiliation(s)
- Heng Dong
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Zhengguo Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Mengjie Ni
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Xiaoyun Xu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yifeng Luo
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yaru Wang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Haiyun Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China.
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore.
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Liu X, Gao X, Yang Y, Yang D, Guo Q, Li L, Liu S, Cong W, Lu S, Hou L, Wang B, Li N. EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis. Apoptosis 2024; 29:1161-1184. [PMID: 38743191 DOI: 10.1007/s10495-024-01967-0] [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] [Accepted: 04/08/2024] [Indexed: 05/16/2024]
Abstract
Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Quinolines/pharmacology
- Quinolines/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Phenylurea Compounds/pharmacology
- Phenylurea Compounds/therapeutic use
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Tumor Suppressor Protein p53/metabolism
- Tumor Suppressor Protein p53/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphatidylinositol 3-Kinases/genetics
- Signal Transduction/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Animals
- Cell Line, Tumor
- Mice
- Apoptosis/drug effects
- Cell Proliferation/drug effects
- Mice, Nude
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Gene Expression Regulation, Neoplastic/drug effects
- Male
- Xenograft Model Antitumor Assays
- Mice, Inbred BALB C
- Proto-Oncogene Proteins c-mdm2/metabolism
- Proto-Oncogene Proteins c-mdm2/genetics
- Female
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Affiliation(s)
- Xiaokun Liu
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Xiao Gao
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Yuling Yang
- Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Di Yang
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Qingming Guo
- Clinical Laboratory, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Lianhui Li
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Shunlong Liu
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanxin Cong
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Sen Lu
- Department of Medical Laboratory, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Lin Hou
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Bin Wang
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China
| | - Ning Li
- School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China.
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Bajestani N, Wu G, Hussein A, Makary MS. Examining the Efficacy and Safety of Combined Locoregional Therapy and Immunotherapy in Treating Hepatocellular Carcinoma. Biomedicines 2024; 12:1432. [PMID: 39062006 PMCID: PMC11274263 DOI: 10.3390/biomedicines12071432] [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: 05/28/2024] [Revised: 06/14/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
More than 800,000 people worldwide are diagnosed with HCC (hepatocellular carcinoma) each year, with approximately 700,000 deaths alone occurring in that same year. Treatment of HCC presents complex therapeutic challenges, particularly in intermediate and advanced stages. LRTs such as transarterial chemoembolization (TACE) and ablations have been the mainstay treatment for early to intermediate-stage HCC, and systemic therapies are used to treat intermediate-late-stage HCC. However, novel literature describing combining LRT with systemic therapies has shown promising results. This review explores recent advances in both liver-directed techniques for hepatocellular carcinoma, including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies in conjunction as well as with systemic therapies, with a focus on combination therapies, patient selection, procedural technique, periprocedural management, and outcomes. Our findings suggest that LRT combined with systemic therapies is a viable strategy for improving progression-free survival and time to progression for patients with intermediate-to-late-stage HCC. However, further investigation is required to refine treatment protocols and define patient cohorts that would benefit the most.
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Affiliation(s)
- Nojan Bajestani
- College of Medicine, The Ohio State University, Columbus, OH 43210, USA; (G.W.); (A.H.)
| | - Gavin Wu
- College of Medicine, The Ohio State University, Columbus, OH 43210, USA; (G.W.); (A.H.)
| | - Ahmed Hussein
- College of Medicine, The Ohio State University, Columbus, OH 43210, USA; (G.W.); (A.H.)
| | - Mina S. Makary
- Division of Vascular and Interventional Radiology, Department of Radiology, The Ohio State University Wexner Medical Center, 395 W 12th Avenue, Columbus, OH 43210, USA;
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Sanai FM, Odah HO, Alshammari K, Alzanbagi A, Alsubhi M, Tamim H, Alolayan A, Alshehri A, Alqahtani SA. Nivolumab as Second-Line Therapy Improves Survival in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2196. [PMID: 38927902 PMCID: PMC11202187 DOI: 10.3390/cancers16122196] [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: 03/15/2024] [Revised: 05/03/2024] [Accepted: 05/08/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Limited data exists for the efficacy and outcomes of nivolumab as a second-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of nivolumab in patients with uHCC who experienced disease progression during sorafenib treatment. METHODS In this retrospective, observational, multicenter study, adult Child-Turcotte-Pugh A/7B patients with uHCC who tolerated sorafenib therapy but showed disease progression switched to second-line intravenous nivolumab (n = 42). A similar number of consecutive, unselected patients who were maintained on sorafenib therapy, regardless of tumoral response or progression, served as historical controls (n = 38). The primary endpoint was overall survival (OS, defined as the time from starting sorafenib in either group up to death due to any cause) and analyzed by intention-to-treat. RESULTS The mean age of the overall cohort was 72.4 ± 10.1 years, of whom 87.5% were males and 58.8% had underlying viral etiology. Patients in the two cohorts were similar, except those who received nivolumab had more co-morbidities (70.0% vs. 15.4%), ECOG-2 status (21.4% vs. 15.8%), BCLC stage C (81.0% vs. 47.4%), and extravascular invasion (54.4% vs. 21.8%) (p < 0.05 for all). More patients in the nivolumab arm were Child-Turcotte-Pugh B (35.7% vs. 21.1%, p = 0.15). Median OS was 22.2 months (95% CI: 8.9-49.8) on second-line nivolumab and 11.0 months (95% CI: 3.6-18.4) on sorafenib alone (HR 1.93; 95% CI: 1.1-3.3, p = 0.014). Median OS after starting nivolumab was 10.2 months, and time-to-progression was 4.9 months (95% CI: 3.2-6.3). CONCLUSION Nivolumab is an effective second-line treatment option in patients with uHCC who progress on sorafenib, with significantly improved OS. These early real-life data offer encouraging results, similar to those shown in Phase I/IIa clinical trials. Further investigations are warranted for the use of nivolumab as a monotherapy.
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Affiliation(s)
- Faisal M. Sanai
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Ministry of the National Guard-Health Affairs, Jeddah 21423, Saudi Arabia;
- King Abdullah International Medical Research Center, Jeddah 22384, Saudi Arabia
- King Saud bin Abdulaziz University for Health Sciences, Jeddah 22384, Saudi Arabia
| | - Hassan O. Odah
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Ministry of the National Guard-Health Affairs, Jeddah 21423, Saudi Arabia;
| | - Kanan Alshammari
- Oncology Department, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia (A.A.)
| | - Adnan Alzanbagi
- Gastroenterology and Hepatology Department, King Abdullah Medical City, Makkah 57657, Saudi Arabia;
| | - Murooj Alsubhi
- Department of Medical Imaging, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia;
| | - Hani Tamim
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon
| | - Ashwaq Alolayan
- Oncology Department, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia (A.A.)
| | - Ahmed Alshehri
- Adult Medical Oncology Section, Adult Oncology Department, Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah 22384, Saudi Arabia;
| | - Saleh A. Alqahtani
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh 11564, Saudi Arabia;
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21218, USA
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De Toni EN, Mayerle J, Oehrle B, Seidensticker M, Rimassa L, Philipp A, Roessler D, Khaled NB. Letter: Presence of progression or absence of response? Alternative trial designs for immunotherapy of advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2024; 59:1462-1464. [PMID: 38643505 DOI: 10.1111/apt.17985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 03/24/2024] [Indexed: 04/23/2024]
Abstract
LINKED CONTENTThis article is linked to Jost‐Brinkmann et al papers. To view these articles, visit https://doi.org/10.1111/apt.17441 and https://doi.org/10.1111/apt.18008
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Affiliation(s)
- Enrico N De Toni
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
| | - Bettina Oehrle
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | - Alexander Philipp
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
| | - Daniel Roessler
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine 2, University Hospital, LMU Munich, Munich, Germany
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Xiao C, Gong J, Jie Y, Liang W, Tai Y, Qin W, Lu T, Chong Y, Hei Z, Hu B, Zhang Q. E2F1-mediated Up-regulation of NCAPG Promotes Hepatocellular Carcinoma Development by Inhibiting Pyroptosis. J Clin Transl Hepatol 2024; 12:25-35. [PMID: 38250463 PMCID: PMC10794265 DOI: 10.14218/jcth.2022.00292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 01/30/2023] [Accepted: 02/28/2023] [Indexed: 01/23/2024] Open
Abstract
Background and Aims As a subunit of the condensin complex, NCAPG has an important role in maintaining chromosome condensation, but its biological function and regulatory mechanism in hepatocellular carcinoma (HCC) remains undefined. Methods The prognostic ability of NCAPG in HCC patients was examined by univariate and multivariate Cox regression analysis. ROC curves were plotted to compare the predictive ability of NCAPG and AFP. Double luciferase reporter system, and ChIP were used to investigate transcriptional potential of E2F1 to NCAPG. Pyroptosis was observed by scanning electron microscopy. Protein expression of NCAPG, E2F1, and major proteins constituting NLRP3 inflammasome was determined by western blotting and ELISA. An in vivo tumor formation assay was conducted to verify the in vitro results. Results Up-regulated NCAPG was identified in HCC tissues compared with adjacent tissue and high NCAPG was positively correlated with poor prognosis. Serum NCAPG mRNA level was a prognostic factor in HCC patients and also a diagnostic factor with higher predictive ability compared with AFP [AUROC 0.766 (95% CI: 0.650-0.881) vs. 0.649 (95% CI 0.506-0.793)]. HBx transfection resulted in concomitant up-regulation of E2F1 and NCAPG. E2F1 significantly increased the activity of luciferase reporter fused with NCAPG reporter, and the interaction of E2F1 and NCAPG gene was confirmed by ChIP. Silencing of E2F1 resulted in significant down-regulation of NCAPG. Knockdown of NCAPG promote pyroptosis mediated by NLRP3 inflammasome activation in multiple HCC cell lines and also suppressed tumorigenesis in vitro. Conclusions We identified a novel role of NCAPG in the regulation of NLRP3 inflammasome-mediated pyroptosis, which was regulated by its upstream transactivator, E2F1. The role of E2F1-NCAPG-NLRP3 regulation of pyroptosis network may be a potential target in HCC treatment.
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Affiliation(s)
- Cuicui Xiao
- Biotherapy Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiao Gong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yusheng Jie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Weicheng Liang
- Biotherapy Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Cell-Gene Therapy Translational Medicine Research Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Tai
- Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wei Qin
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tongyu Lu
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yutian Chong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ziqing Hei
- Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qi Zhang
- Biotherapy Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Cell-Gene Therapy Translational Medicine Research Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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12
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Sun SS, Guo XD, Li WD, Chen JL. Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma. World J Clin Cases 2024; 12:285-292. [PMID: 38313649 PMCID: PMC10835699 DOI: 10.12998/wjcc.v12.i2.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/13/2023] [Accepted: 12/27/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Recently, combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma (HCC). However, research on triple therapy [lenvatinib + sintilimab + transarterial chemoembolization (TACE)] as a first-line treatment for advanced HCC is limited. AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC. METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled. All patients were treated with lenvatinib every day and sintilimab once every 3 wk. Moreover, TACE was performed every 4-6 wk if necessary. The primary outcome of the study was overall survival (OS). The secondary outcomes were the objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022. With a median follow-up of 8.5 months, the 3-, 6-, and 12-mo OS rates were 100%, 88.5%, and 22.5%, respectively. The ORR and DCR were 45% and 90%, respectively. The median progressive free survival and median OS were not reached. Common complications were observed in 76% of the patients (grade 3, 15%; grade 4, 2.5%). CONCLUSION Combination therapy comprising lenvatinib, sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.
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Affiliation(s)
- Sha-Sha Sun
- Department of Oncology, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing 100015, China
| | - Xiao-Di Guo
- Department of Oncology, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing 100015, China
| | - Wen-Dong Li
- Department of Oncology, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing 100015, China
| | - Jing-Long Chen
- Department of Oncology, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing 100015, China
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13
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Luo T, Chen X, Pan W, Zhang S, Huang J. The sorafenib resistance-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma. Cell Cycle 2024; 23:150-168. [PMID: 38444181 PMCID: PMC11037289 DOI: 10.1080/15384101.2024.2309020] [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: 01/07/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 03/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Most patients with advanced HCC acquire sorafenib resistance. Drug resistance reflects the heterogeneity of tumors and is the main cause of tumor recurrence and death.We identified and validated sorafenib resistance related-genes (SRGs) as prognostic biomarkers for HCC. We obtained SRGs from the Gene Expression Omnibus and selected four key SRGs using the least absolute shrinkage and selection operator, random forest, and Support Vector Machine-Recursive feature elimination machine learning algorithms. Samples from the The Cancer Genome Atlas (TCGA)-HCC were segregated into two groups by consensus clustering. Following difference analysis, 19 SRGs were obtained through univariate Cox regression analysis, and a sorafenib resistance model was constructed for risk stratification and prognosis prediction. In multivariate Cox regression analysis, the risk score was an independent predictor of overall survival (OS). Patients classified as high-risk were more sensitive to other chemotherapy drugs and showed a higher expression of the common immune checkpoints. Additionally, the expression of drug-resistance genes was verified in the International Cancer Genome Consortium cohort. A nomogram model with a risk score was established, and its prediction performance was verified by calibration chart analysis of the TCGA-HCC cohort. We conclude that there is a significant correlation between sorafenib resistance and the tumor immune microenvironment in HCC. The risk score could be used to identify a reliable prognostic biomarker to optimize the therapeutic benefits of chemotherapy and immunotherapy, which can be helpful in the clinical decision-making for HCC patients.
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Affiliation(s)
- Tianxin Luo
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Xiaomei Chen
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Wei Pan
- Prenatal Diagnosis Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Shu Zhang
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
- Center for Clinical Laboratories, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jian Huang
- Center for Clinical Laboratories, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
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14
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Wang Z, Zhou C, Zhang Y, Tian X, Wang H, Wu J, Jiang S. From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma. Biomed Pharmacother 2024; 170:116074. [PMID: 38147732 DOI: 10.1016/j.biopha.2023.116074] [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: 11/04/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.
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Affiliation(s)
- Zijian Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunyang Zhou
- Department of Radiation Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Haochen Wang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
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Gao X, Yang C, Li H, Shao L, Wang M, Su R. EMT-related gene risk model establishment for prognosis and drug treatment efficiency prediction in hepatocellular carcinoma. Sci Rep 2023; 13:20380. [PMID: 37990105 PMCID: PMC10663558 DOI: 10.1038/s41598-023-47886-z] [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: 09/13/2023] [Accepted: 11/20/2023] [Indexed: 11/23/2023] Open
Abstract
This study was designed to evaluate the prognosis and pharmacological therapy sensitivity of epithelial mesenchymal transition-related genes (EMTRGs) that obtained from the EMTome database in hepatocellular carcinoma (HCC) using bioinformatical method. The expression status of EMTRGs were also investigated using the clinical information of HCC patients supported by TCGA database and the ICGC database to establish the TCGA cohort as the training set and the ICGC cohort as the validation set. Analyze the EMTRGs between HCC tissue and liver tissue in the TCGA cohort in the order of univariate COX regression, LASSO regression, and multivariate COX regression, and construct a risk model for EMTRGs. In addition, enrichment pathways, gene mutation status, immune infiltration, and response to drugs were also analyzed in the high-risk and low-risk groups of the TCGA cohort, and the protein expression status of EMTRGs was verified. The results showed a total of 286 differentially expressed EMTRGs in the TCGA cohort, and EZH2, S100A9, TNFRSF11B, SPINK5, and CCL21 were used for modeling. The TCGA cohort was found to have a worse outcome in the high-risk group of HCC patients, and the ICGC cohort confirmed this finding. In addition, EMTRGs risk score was shown to be an independent prognostic factor in both cohorts by univariate and multivariate COX regression. The results of GSEA analysis showed that most of the enriched pathways in the high-risk group were associated with tumor, and the pathways enriched in the low-risk group were mainly associated with metabolism. Patients in various risk groups had varying immunological conditions, and the high-risk group might benefit more from targeted treatments. To sum up, the EMTRGs risk model was developed to forecast the prognosis for HCC patients, and the model might be useful in assisting in the choice of treatment drugs for HCC patients.
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Affiliation(s)
- Xiaqing Gao
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
| | - Chunting Yang
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Department of Geriatrics, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province and Gansu Provincial Traditional Chinese Medicine New Product Innovation Engineering Laboratory, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
| | - Hailong Li
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China.
- Department of Geriatrics, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China.
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province and Gansu Provincial Traditional Chinese Medicine New Product Innovation Engineering Laboratory, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China.
- Key Laboratory of Dunhuang Medicine and Transformation, Ministry of Education, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China.
| | - Lihua Shao
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Department of Geriatrics, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Key Laboratory of Dunhuang Medicine and Transformation, Ministry of Education, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
| | - Meng Wang
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Department of Geriatrics, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province and Gansu Provincial Traditional Chinese Medicine New Product Innovation Engineering Laboratory, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
| | - Rong Su
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, People's Republic of China
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Zhang Y, Shen H, Zheng R, Sun Y, Xie X, Lu MD, Liu B, Huang G. Development and Assessment of Nomogram Based on AFP Response for Patients with Unresectable Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors. Cancers (Basel) 2023; 15:5131. [PMID: 37958306 PMCID: PMC10647527 DOI: 10.3390/cancers15215131] [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: 08/09/2023] [Revised: 10/15/2023] [Accepted: 10/20/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have been increasingly used to treat hepatocellular carcinoma (HCC). Prognostic biomarkers are an unmet need. We aimed to develop a prognostic nomogram for patients with unresectable HCC receiving ICIs therapy. METHODS A total of 120 patients with unresectable HCC receiving ICIs treatment were enrolled in this study. Patients were randomly divided into a training set (n = 84) and a validation set (n = 36) in a 7:3 ratio. Clinical characteristics were retrospectively analyzed. Serum α-fetoprotein protein (AFP) response was defined as a decline of ≥20% in AFP levels within the initial eight weeks of treatment. Univariable and multivariable Cox analyses were used to select relevant variables and construct the nomogram. The areas under the receiver operating characteristic curves (AUCs) were used to determine the performance of the model. Kaplan-Meier analysis with the log-rank test was used to compare different risk groups. RESULTS The median progression-free survival (PFS) was 7.7 months. In the multivariate Cox analysis, the presence of extrahepatic metastasis (hazard ratio [HR] = 2.08, 95% confidence interval [CI]: 1.02-4.27, p < 0.05), white blood cell count (HR = 3.48, 95% CI: 1.02-11.88, p < 0.05) and AFP response (HR = 0.41, 95% CI: 0.18-0.95, p < 0.05) independently predicted PFS. A nomogram for PFS was established with AUCs of 0.79 and 0.70 in the training and validation sets, respectively. The median PFS of the high- and low-risk subgroups was 3.5 and 11.7 months, respectively (p < 0.05). CONCLUSION The nomogram could predict PFS in patients with unresectable HCC receiving ICIs treatment and further help decision making in daily clinical practice.
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Affiliation(s)
- Yi Zhang
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Hui Shen
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Ruiying Zheng
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Yueting Sun
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Xiaoyan Xie
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Ming-De Lu
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China
| | - Baoxian Liu
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
| | - Guangliang Huang
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou 510080, China; (Y.Z.); (H.S.); (M.-D.L.)
- Department of Medical Ultrasonics, Guangxi Hospital Division, The First Affiliated Hospital of Sun Yat-sen University, Nanning 530022, China
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17
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Üremiş MM, Üremiş N, Türköz Y. Cucurbitacin E shows synergistic effect with sorafenib by inducing apoptosis in hepatocellular carcinoma cells and regulates Jak/Stat3, ERK/MAPK, PI3K/Akt/mTOR signaling pathways. Steroids 2023; 198:109261. [PMID: 37355001 DOI: 10.1016/j.steroids.2023.109261] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/16/2023] [Accepted: 06/16/2023] [Indexed: 06/26/2023]
Abstract
OBJECTIVE Cucurbitacin E (CuE), a natural compound found in medicinal plants such as Ecballium Elaterium, has demonstrated antiproliferative and apoptotic effects in various cancer cell types due to its tetracyclic triterpenoid structure. Sorafenib, a multi-tyrosine kinase inhibitor, is commonly used in hepatocellular carcinoma (HCC) treatment. This study aimed to investigate the anticancer effect of CuE alone and in combination with sorafenib on HepG2 cells. METHODS CuE was extracted from Ecballium Elaterium fruit juice and quantitatively evaluated using HPLC. The effect of sorafenib and CuE on cell growth inhibition was determined using the MTT test. Cell cycle progression and apoptosis were assessed using flow cytometry. Mitochondrial damage was evaluated with ΔΨm, and DNA damage was assessed using the comet assay. The expression of Jak2/Stat3, PI3K/Akt/mTOR, MAPK, and Bcl-2 family-related genes and proteins were analyzed using western blot and qRT-PCR, respectively. RESULTS Both CuE (0.1-5 µM) and sorafenib (0.5-10 µM) exhibited dose- and time-dependent antiproliferative and cytotoxic effects against the HepG2 cell line. Both compounds induced apoptosis in HepG2 cells and halted the cell cycle in the G2/M phase while causing mitochondrial and DNA damage. Both compounds down-regulated Jak2/Stat3, PI3K/Akt/mTOR, MAPK signaling pathway proteins, and Bcl-xL levels, while up-regulated Caspase-9 and Bax protein levels. CONCLUSION Based on the results of this study, it can be concluded that CuE alone or in combination with sorafenib has the potential to be an effective therapeutic option for the treatment of HCC by inducing apoptosis and regulating multiple signaling pathways.
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Affiliation(s)
- Muhammed Mehdi Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey.
| | - Nuray Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Yusuf Türköz
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
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Motomura K, Kuwano A, Tanaka K, Koga Y, Masumoto A, Yada M. Potential Predictive Biomarkers of Systemic Drug Therapy for Hepatocellular Carcinoma: Anticipated Usefulness in Clinical Practice. Cancers (Basel) 2023; 15:4345. [PMID: 37686621 PMCID: PMC10486942 DOI: 10.3390/cancers15174345] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation.
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Affiliation(s)
- Kenta Motomura
- Department of Hepatology, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505, Japan; (A.K.); (K.T.); (Y.K.); (A.M.); (M.Y.)
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Bodard S, Liu Y, Guinebert S, Yousra K, Asselah T. Prognostic value of genotyping in hepatocellular carcinoma: A systematic review. J Viral Hepat 2023; 30:582-587. [PMID: 36922710 DOI: 10.1111/jvh.13833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/20/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023]
Abstract
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death. Advances in sequencing technology are opening genomics to widespread application for diagnosis and research. The poor prognosis of advanced HCC warrants a personalized approach. The objective was to assess the value of genotyping for risk stratification and prognostication of HCC. We performed a systematic review of manuscripts published on MEDLINE from 1 January 2009 to 1 January 2022, addressing the value of genotyping for HCC risk stratification and prognostication. Publication information for each has been collected using a standardized data extraction form. Twenty-five articles were analysed. This study showed that various genomics approaches (i.e., NGS, SNP, CASP or polymorphisms in circadian genes' association) provided predictive and prognostic information, such as disease control rate, median progression-free survival, and shorter median overall survival. Genotyping, which advances in understanding the molecular origin, could be a solution to predict prognosis or treatment response in patients with HCC.
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Affiliation(s)
- Sylvain Bodard
- AP-HP-centre, Service d'Imagerie Adulte, Hôpital Necker Enfants Malades, Paris, F-75015, France
- Université de Paris Cité, Paris, F-75006, France
- Sorbonne Université, CNRS UMR, INSERM, Laboratoire d'Imagerie Biomédicale (LIB), Paris, F-75006, France
| | - Yan Liu
- Faculty of Life Science and Medicine, King's College London, London, UK
- Median Technologies, 1800 Route des Crêtes, Valbonne, F-06560, France
| | - Sylvain Guinebert
- AP-HP-centre, Service d'Imagerie Adulte, Hôpital Necker Enfants Malades, Paris, F-75015, France
- Université de Paris Cité, Paris, F-75006, France
| | | | - Tarik Asselah
- Université de Paris Cité, Paris, F-75006, France
- APHP.Nord, Service d'hépatologie, INSERM, Hôpital Beaujon, Clichy, F-92110, France
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20
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Wang G, Zhang W, Luan X, Wang Z, Liu J, Xu X, Zhang J, Xu B, Lu S, Wang R, Ma G. The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy. Front Immunol 2023; 14:1151967. [PMID: 37215117 PMCID: PMC10196479 DOI: 10.3389/fimmu.2023.1151967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
Purpose To investigate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), as an imaging biomarker, for predicting pathological response and prognosis of unresectable hepatocellular carcinoma (HCC) patients treated with Lenvatinib and programmed cell death protein 1 (PD-1) inhibitors as a conversion therapy. Methods A total of 28 unresectable HCC patients with BCLC stage B or C were treated with Lenvatinib and PD-1 inhibitors before surgery. The 18F-FDG PET/CT scans were acquired before pre- (scan-1) and post-conversion therapy (scan-2). The maximum standardized uptake value (SUVmax), TLR (tumor-to-normal liver standardized uptake value ratio), and the percentages of post-treatment changes in metabolic parameters (ΔSUVmax [%] and ΔTLR [%]) were calculated. Major pathological response (MPR) was identified based on the residual viable tumor in the resected primary tumor specimen (≤10%). Differences in the progression-free survival (PFS) and overall survival (OS) stratified by ΔTLR were examined by the Kaplan-Meier method. Results 11 (11/28, 39.3%) patients were considered as MPR responders and 17 (17/28, 60.7%) patients as non-MPR responders after conversion therapy. ΔSUVmax (-70.0 [-78.8, -48.8] vs. -21.7 [-38.8, 5.7], respectively; P<0.001) and ΔTLR (-67.6 [-78.1, -56.8] vs. -18.6 [-27.9, 4.0], respectively; P<0.001) were reduced in the responder group than those in the non-responder group. According to the results of the receiver operating characteristic curve analysis, ΔTLR showed an excellent predictive value for the MPR of primary HCC lesions (area under curve=0.989, with the optimal diagnostic threshold of -46.15). When using ΔTLR of -21.36% as a threshold, patients with ΔTLR-based metabolic response had superior PFS (log-rank test, P=0.001) and OS (log-rank test, P=0.016) compared with those without ΔTLR-based metabolic response. Conclusion 18F-FDG PET is a valuable tool for predicting pathological response and prognosis of unresectable HCC patients treated by Lenvatinib combined with PD-1 as a conversion therapy.
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Affiliation(s)
- Guanyun Wang
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Nuclear Medicine Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wenwen Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital/Institute of Hepatobiliary Surgery of Chinese People's Liberation Army/Key Laboratory of Digital Hepetobiliary Surgery, People's Liberation Army, Beijing, China
| | - Xiaohui Luan
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China
| | - Zhanbo Wang
- Department of Pathology, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jiajin Liu
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiaodan Xu
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jinming Zhang
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Baixuan Xu
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital/Institute of Hepatobiliary Surgery of Chinese People's Liberation Army/Key Laboratory of Digital Hepetobiliary Surgery, People's Liberation Army, Beijing, China
| | - Ruimin Wang
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Guangyu Ma
- Department of Nuclear Medicine, The First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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21
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Lan SY, Ding Y, Wang C, Fang J, Ren C, Liu JL, Kang H, Chang Y. High Level of Ubiquitin Conjugate Enzyme E2O Indicates Poor Prognosis of Patients with Hepatocellular Carcinoma. Curr Med Sci 2023; 43:93-103. [PMID: 36269535 DOI: 10.1007/s11596-022-2609-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/14/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Ubiquitin conjugate enzyme E2O (UBE2O) is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis. This study investigated the role of UBE2O in hepatocellular carcinoma (HCC). METHODS The expression of UBE2O was detected using qRT-PCR, Western blotting, and immunohistochemical staining. Cell proliferation and Transwell assays were used to detect proliferation, migration, and invasion of HCC cells, respectively. Bioinformatic analysis was performed to analyze the relationship between UBE2O and the clinical features, prognosis, and immune cell infiltration of HCC. RESULTS UBE2O was significantly over-expressed in HCC tissues. High expression of UBE2O was associated with poor tumor grade and poor prognosis. Functional experiments showed that down-regulation of UBE2O inhibited HCC cell proliferation, migration, and invasion. Co-expression gene analysis and gene set enrichment analysis showed that UBE2O was associated with protein hydrolysis, cell cycle, and cancer-related pathways in HCC. The results of immune analysis revealed that the expression of UBE2O was positively correlated with the immune infiltration and expression of immune-related chemokines of HCC. CONCLUSIONS UBE2O is significantly correlated with the prognosis of HCC and may be a valuable prognostic biomarker for HCC.
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Affiliation(s)
- Si-Yu Lan
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Yang Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Chun Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Jun Fang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Chao Ren
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Jia-Liang Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Hui Kang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China.
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22
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Bodard S, Liu Y, Guinebert S, Kherabi Y, Asselah T. Performance of Radiomics in Microvascular Invasion Risk Stratification and Prognostic Assessment in Hepatocellular Carcinoma: A Meta-Analysis. Cancers (Basel) 2023; 15:cancers15030743. [PMID: 36765701 PMCID: PMC9913680 DOI: 10.3390/cancers15030743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death. Advances in phenomenal imaging are paving the way for application in diagnosis and research. The poor prognosis of advanced HCC warrants a personalized approach. The objective was to assess the value of imaging phenomics for risk stratification and prognostication of HCC. METHODS We performed a meta-analysis of manuscripts published to January 2023 on MEDLINE addressing the value of imaging phenomics for HCC risk stratification and prognostication. Publication information for each were collected using a standardized data extraction form. RESULTS Twenty-seven articles were analyzed. Our study shows the importance of imaging phenomics in HCC MVI prediction. When the training and validation datasets were analyzed separately by the random-effects model, in the training datasets, radiomics had good MVI prediction (AUC of 0.81 (95% CI 0.76-0.86)). Similar results were found in the validation datasets (AUC of 0.79 (95% CI 0.72-0.85)). Using the fixed effects model, the mean AUC of all datasets was 0.80 (95% CI 0.76-0.84). CONCLUSIONS Imaging phenomics is an effective solution to predict microvascular invasion risk, prognosis, and treatment response in patients with HCC.
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Affiliation(s)
- Sylvain Bodard
- Service de Radiologie Adulte, Hôpital Universitaire Necker-Enfants Malades, AP-HP Centre, 75015 Paris, France
- Faculté de Médecine, Université Paris Cité, 75007 Paris, France
- CNRS, INSERM, UMR 7371, Laboratoire d’Imagerie Biomédicale, Sorbonne Université, 75006 Paris, France
- Correspondence: ; Tel.: +33-6-18-81-62-10
| | - Yan Liu
- Faculty of Life Science and Medicine, King’s College London, London WC2R 2LS, UK
- Median Technologies, 1800 Route des Crêtes, 06560 Valbonne, France
| | - Sylvain Guinebert
- Service de Radiologie Adulte, Hôpital Universitaire Necker-Enfants Malades, AP-HP Centre, 75015 Paris, France
- Faculté de Médecine, Université Paris Cité, 75007 Paris, France
| | - Yousra Kherabi
- Faculté de Médecine, Université Paris Cité, 75007 Paris, France
| | - Tarik Asselah
- Faculté de Médecine, Université Paris Cité, 75007 Paris, France
- Service d’Hépatologie, INSERM, UMR1149, Hôpital Beaujon, AP-HP.Nord, 92110 Clichy, France
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Li X, Sun X, Wang B, Li Y, Tong J. Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions. Asian J Pharm Sci 2023; 18:100771. [PMID: 36896445 PMCID: PMC9989663 DOI: 10.1016/j.ajps.2022.100771] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/24/2022] [Accepted: 12/04/2022] [Indexed: 12/30/2022] Open
Abstract
Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.
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Affiliation(s)
- Xinguo Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaonan Sun
- The 4th People's Hospital of Shenyang, Shenyang 110031, China
| | - Bingyuan Wang
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Yiling Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Jing Tong
- The First Hospital of China Medical University, Shenyang 110001, China
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24
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Wei Y, Wei L, Han T, Ding S. miR-3154 promotes hepatocellular carcinoma progression via suppressing HNF4α. Carcinogenesis 2022; 43:1002-1014. [PMID: 35917569 DOI: 10.1093/carcin/bgac067] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/02/2022] [Accepted: 07/28/2022] [Indexed: 01/13/2023] Open
Abstract
MicroRNAs (miRNAs) play an important role in cancer proliferation, metastasis, drug resistance and apoptosis by targeting oncogenes or tumor suppressor genes. miR-3154 has been reported to be up-regulated in cervical cancer and leukemia, but its role in hepatocellular carcinoma (HCC) remains unclear. Here, we for the first time demonstrated that miR-3154 was elevated in HCC and liver cancer stem cells (CSCs). Up-regulated miR-3154 was associated with overall survival and disease-free survival of HCC patients. MiR-3154 knockdown inhibits HCC cells self-renewal, proliferation, metastasis, and tumorigenesis. Mechanistically, miR-3154 target directly to HNF4α. MiR-3154 knockdown upregulated HNF4α mRNA and protein expression. HNF4α interference abolish the differences of self-renewal, proliferation, metastasis, and tumorigenesis between miR-3154 knockdown cells and control hepatoma cells. Furthermore, miR-3154 expression was negatively correlated with HNF4α in HCC tissues. The combined HHC panels exhibited a better disease-free survival prognostic value for HCC patients than any of these components alone. More importantly, miR-3154 determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort and patient-derived xenografts (PDXs) further suggest that miR-3154 might predict lenvatinib clinical benefit in HCC patients. In conclusion, we reveal the crucial role of miR-3514 in HCC progression and lenvatinib response, suggesting potential therapeutic targets for HCC.
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Affiliation(s)
- Yuan Wei
- Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Lai Wei
- Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Tao Han
- Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Shuang Ding
- Department of Rheumatology & Immunology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
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25
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Zhang L, Xu J, Chu X, Zhang H, Yao X, Zhang J, Guo Y. Identification of the cuproptosis-related molecular subtypes and an immunotherapy prognostic model in hepatocellular carcinoma. BMC Bioinformatics 2022; 23:485. [PMID: 36384423 PMCID: PMC9667659 DOI: 10.1186/s12859-022-04997-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/20/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Cuproptosis, a newly discovered mode of cell death, has been less studied in hepatocellular carcinoma (HCC). Exploring the molecular characteristics of different subtypes of HCC based on cuproptosis-related genes (CRGs) is meaningful to HCC. In addition, immunotherapy plays a pivotal role in treating HCC. Exploring the sensitivity of immunotherapy and building predictive models are critical for HCC. METHODS The 357 HCC samples from the TCGA database were classified into three subtypes, Cluster 1, Cluster 2, and Cluster 3, based on the expression levels of ten CRGs genes using consensus clustering. Six machine learning algorithms were used to build models that identified the three subtypes. The molecular features of the three subtypes were analyzed and compared from some perspectives. Moreover, based on the differentially expressed genes (DEGs) between Cluster 1 and Cluster 3, a prognostic scoring model was constructed using LASSO regression and Cox regression, and the scoring model was used to predict the efficacy of immunotherapy in the IMvigor210 cohort. RESULTS Cluster 3 had the worst overall survival compared to Cluster 1 and Cluster 2 (P = 0.0048). The AUC of the Catboost model used to identify Cluster 3 was 0.959. Cluster 3 was significantly different from the other two subtypes in gene mutation, tumor mutation burden, tumor microenvironment, the expression of immune checkpoint inhibitor genes and N6-methyladenosine regulatory genes, and the sensitivity to sorafenib. We believe Cluster 3 is more sensitive to immunotherapy from the above analysis results. Therefore, based on the DEGs between Cluster 1 and Cluster 3, we obtained a 7-gene scoring prognostic model, which achieved meaningful results in predicting immunotherapy efficacy in the IMvigor210 cohort (P = 0.013). CONCLUSIONS Our study provides new ideas for molecular characterization and immunotherapy of HCC from machine learning and bioinformatics. Moreover, we successfully constructed a prognostic model of immunotherapy.
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Affiliation(s)
- Li Zhang
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingwei Xu
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiufeng Chu
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongqiao Zhang
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xueyuan Yao
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian Zhang
- grid.460069.dDepartment of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanwei Guo
- Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Peng TR, Wu CC, Chang SY, Chen YC, Wu TW, Hsu CS. Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma. Int Immunopharmacol 2022; 112:109223. [PMID: 36084538 DOI: 10.1016/j.intimp.2022.109223] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Immune checkpoint inhibitor therapy is the backbone of numerous combination regimens for improving the therapeutic response of patients with hepatocellular carcinoma (HCC). We aimed to investigate the therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable HCC. METHODS Patients with unresectable HCC who received sorafenib and followed at Taipei Tzu Chi Hospital from January 2016 to May 2022 were selected for this study, and those treated with nivolumab plus sorafenib and those with sorafenib alone were propensity score matched. The primary outcome was overall survival (OS) presented as a hazard ratio calculated using Cox proportional hazards regression models. RESULTS In the analysis, 36 patients receiving nivolumab plus sorafenib and 36 receiving sorafenib alone were propensity score matched. The median OS for those receiving nivolumab plus sorafenib and sorafenib alone were 3.6 years and 1.2 years, respectively (p = 0.031). The hazard ratio of OS for nivolumab plus sorafenib compared to sorafenib alone was 0.36 (95 %CI, 0.19-0.70; p = 0.003). Furthermore, patients receiving nivolumab plus sorafenib with a baseline α-fetoprotein(AFP) < 10 ng/mL and early reduction in AFP had a 100 % objective response rate and disease control rate. CONCLUSION In patients with unresectable HCC, nivolumab plus sorafenib resulted in better OS outcomes than sorafenib.
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Affiliation(s)
- Tzu-Rong Peng
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chao-Chuan Wu
- Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Sou-Yi Chang
- Division of Hematology & Oncology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, Taiwan
| | - Yen-Chih Chen
- Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Ta-Wei Wu
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan; Liver Disease Prevention and Treatment Center, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan; School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.
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Bai J, Tang R, Zhou K, Chang J, Wang H, Zhang Q, Shi J, Sun C. An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma. BMC Med Genomics 2022; 15:222. [PMID: 36284275 PMCID: PMC9594908 DOI: 10.1186/s12920-022-01380-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/20/2022] [Indexed: 11/28/2022] Open
Abstract
Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method.
Results HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01380-z.
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Affiliation(s)
- Jianguo Bai
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ruifeng Tang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Keyu Zhou
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jialei Chang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongyue Wang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qixin Zhang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jiahui Shi
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chao Sun
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
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Samadaei M, Senfter D, Madlener S, Uranowska K, Hafner C, Trauner M, Rohr‐Udilova N, Pinter M. Targeting DNA repair to enhance the efficacy of sorafenib in hepatocellular carcinoma. J Cell Biochem 2022; 123:1663-1673. [PMID: 36271841 PMCID: PMC9828257 DOI: 10.1002/jcb.30340] [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: 12/20/2021] [Revised: 09/23/2022] [Accepted: 10/07/2022] [Indexed: 01/12/2023]
Abstract
The multityrosine kinase inhibitor sorafenib remains an important systemic treatment option for hepatocellular carcinoma (HCC). Signaling pathways, which are targeted by sorafenib, are involved in checkpoint and DNA repair response, RAD51 being a candidate protein. Here, we aim to evaluate the effect of the human RAD51 inhibitor B02 in combination with sorafenib in human HCC cells. Impact of RAD51 expression on HCC patient survival was evaluated by an in silico approach using Human Protein Atlas dataset. Cell viability of HUH7, AKH12, AKH13, and 3P was assessed by neutral red assay. To measure the cytotoxicity, we quantified loss of membrane integrity by lactate dehydrogenase release. We also employed colony formation assay and hanging drop method to assess clonogenic and invasive ability of HCC cell lines upon sorafenib and B02 treatment. Cell cycle distribution and characterization of apoptosis was evaluated by flow cytometry. In silico approach revealed that HCC patients with higher expression of RAD51 messenger RNA had a significantly shorter overall survival. The RAD51 inhibitor B02 alone and in combination with sorafenib significantly reduced viability, colony formation ability, and invasion capacity of HCC cells. Cell cycle analysis revealed that the combination of both agents reduces the proportion of cells in the G2/M phase while leading to an accumulating in the subG1 phase. The RAD51 inhibitor B02 seems to be a promising agent for HCC treatment and enhances the antitumor effects of sorafenib in vitro.
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Affiliation(s)
- Mahzeiar Samadaei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Liver Cancer (HCC) Study Group ViennaDepartment of Internal Medicine III, Medical University of ViennaViennaAustria
| | - Daniel Senfter
- Department of Pediatrics and Adolescent MedicineMolecular Neuro‐Oncology, Medical University of ViennaViennaAustria
| | - Sibylle Madlener
- Department of Pediatrics and Adolescent MedicineMolecular Neuro‐Oncology, Medical University of ViennaViennaAustria
| | - Karolina Uranowska
- Department of Dermatology, University Hospital St. PoeltenKarl Landsteiner University of Health SciencesSt. PoeltenAustria,Center for Pathophysiology, Infectiology and Immunology, Institute of Pathophysiology and Allergy ResearchMedical University of ViennaViennaAustria
| | - Christine Hafner
- Department of Dermatology, University Hospital St. PoeltenKarl Landsteiner University of Health SciencesSt. PoeltenAustria,Karl Landsteiner Institute of Dermatological ResearchKarl Landsteiner GesellschaftSt. PoeltenAustria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Nataliya Rohr‐Udilova
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Liver Cancer (HCC) Study Group ViennaDepartment of Internal Medicine III, Medical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Liver Cancer (HCC) Study Group ViennaDepartment of Internal Medicine III, Medical University of ViennaViennaAustria
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Association between Adverse Events and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab: A Multicenter Retrospective Study. Cancers (Basel) 2022; 14:cancers14174284. [PMID: 36077816 PMCID: PMC9454839 DOI: 10.3390/cancers14174284] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin–bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.
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Xiao J, Liu Z, Wang J, Zhang S, Zhang Y. Identification of cuprotosis-mediated subtypes, the development of a prognosis model, and influence immune microenvironment in hepatocellular carcinoma. Front Oncol 2022; 12:941211. [PMID: 36110946 PMCID: PMC9468823 DOI: 10.3389/fonc.2022.941211] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/05/2022] [Indexed: 12/25/2022] Open
Abstract
Purpose Cuprotosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by copper-dependent and associated with mitochondrial respiration. However, the prognostic significance and function of cuprotosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are unknown. This study aims to develop cuprotosis-mediated patterns-related gene (CMPRG) prediction models for the prognosis of patients with HCC, exploring the functional underlying the CRGs on the influence of tumor microenvironment (TME) features. Experimental design This study obtained transcriptome profiling and the corresponding clinical information from the TCGA and GEO databases. Besides, the Cox regression model with LASSO was implemented to build a multi-gene signature, which was then validated in an internal validation set and two external validation sets through Kaplan-Meier, DCA, and ROC analyses. Results According to the LASSO analysis, we screened out a cuprotosis-mediated pattern 5-gene combination (including PBK; MMP1; GNAZ; GPC1 and AKR1D1). A nomogram was constructed for the presentation of the final model. The ROC curve assessed the model’s predictive ability, which resulted in an area under the curve (AUC) values ranging from 0.604 to 0.787 underwent internal and two external validation sets. Meanwhile, the risk score divided the patients into two groups of high and low risk, and the survival rate of high-risk patients was significantly lower than that of low-risk patients (P<0.01). The risk score could be an independent prognostic factor in the multifactorial Cox regression analysis (P<0.01). Functional analysis revealed that immune status, mutational loads, and drug sensitivity differed between the two risk groups. Conclusions In summary, we identified three cuprotosis-mediated patterns in HCC. And CMPRGs are a promising candidate biomarker for HCC early detection, owing to their strong performance in predicting HCC prognosis and therapy. Quantifying cuprotosis-mediated patterns in individual samples may help improve the understanding of multiomic characteristics and guide the development of targeted therapy for HCC.
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Affiliation(s)
- Jingjing Xiao
- Department of Hepatobiliary Surgery, Guizhou Provincial People’s Hospital, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Zhenhua Liu
- Department of Hepatobiliary Surgery, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Jinlong Wang
- Department of Critical Care Medicine, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Shuaimin Zhang
- Department of Hepatobiliary Surgery, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yi Zhang
- Department of Hepatobiliary Surgery, Guizhou Provincial People’s Hospital, Guiyang, China
- *Correspondence: Yi Zhang,
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Liu R, Sun Y, Chen S, Hong Y, Lu Z. FOXD3 and GAB2 as a pair of rivals antagonistically control hepatocellular carcinogenesis. FEBS J 2022; 289:4536-4548. [DOI: 10.1111/febs.16403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 09/05/2021] [Accepted: 02/15/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Ruimin Liu
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Yan Sun
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Shuai Chen
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Yun Hong
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Zhongxian Lu
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research School of Pharmaceutical Sciences Xiamen China
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Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Liver Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:3968303. [PMID: 35855852 PMCID: PMC9288334 DOI: 10.1155/2022/3968303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 06/09/2022] [Accepted: 06/27/2022] [Indexed: 12/24/2022]
Abstract
Background Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC. Methods The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method. Results A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis. Conclusion In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes (ALDH2, EZH2, NDRG2, and PGAM5) for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively.
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Mechanism of a Herbal Formula Associated with Prognosis and Immune Infiltration in LIHC: Transcriptomics Analysis and Molecular Dynamics Simulations. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6084321. [PMID: 35754689 PMCID: PMC9217603 DOI: 10.1155/2022/6084321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/08/2022] [Accepted: 05/19/2022] [Indexed: 11/26/2022]
Abstract
Background The aim of this study is to explore the interactions between effective monomers of herbal formulas and their therapeutic targets using systems biology approaches which may be a promising approach to unraveling their underlying mechanisms. Shentao Ruangan decoction (STRGD), which has been experimentally, clinically demonstrated to be effective in treating liver hepatocellular carcinoma (LIHC), was selected. Methods Bioactive ingredients and drug targets of STRGD were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform and BATMAN-TCM databases. LIHC-related differentially expressed genes (DEGs) and key modules were identified by a weighted gene coexpression network analysis using The Cancer Genome Atlas data. The Kaplan–Meier analysis was used to investigate the relationship between STRGD tumor targets and patients survival. The CIBERSORT deconvolution algorithm was used to analyze the correlation between STRGD tumor targets and infiltrating immune cells. Enrichment analysis was used to analyze biological functions. Interactions between STRGD compounds and LIHC-immune-related genes were investigated using molecular docking and MDS. Results We identified 24 STRGD tumor targets, which were found to be correlated with survival and the level of immune cell infiltration in LIHC patients. Immune infiltration, gene set enrichment, and Kyoto Encyclopedia of Genes and Genomes analyses highlighted the roles of T and B cell subsets, which were both related to activator protein 1 (AP1), in STRGD action. Docking studies and HPLC indicated that tanshinone IIA is the main compound of STRGD in LIHC treatment, and MDS showed that the potential LIHC-immune-related targets 1FOS and 1JUN firmly bind to tanshinone IIA. Conclusions The mechanisms of STRGD in improving the immune and survival status of LIHC patients include interactions between STRGD compounds and LIHC-immune-related targets. The findings of this study can guide research studies on the potential usefulness of tanshinone IIA in the development of drugs targeting 1JUN and 1FOS for the treatment of LIHC.
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Hucke F, Pinter M, Hucke M, Bota S, Bolf D, Hackl M, Peck-Radosavljevic M. Changing Epidemiological Trends of Hepatobiliary Carcinomas in Austria 2010–2018. Cancers (Basel) 2022; 14:cancers14133093. [PMID: 35804861 PMCID: PMC9264900 DOI: 10.3390/cancers14133093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Primary liver cancer is currently the sixth most common cancer and the third common cause of cancer-related mortality worldwide. Incidences have increased in recent year, especially in high-income countries. The epidemiology of predisposing risk factors for hepatobiliary carcinomas have changed significantly, while treatment and therapeutic options have markedly improved. Here, we provide an update of incidence, mortality, and survival trends in recent years, in Austria. While age-adjusted incidence rates remained stable in almost all hepatobiliary carcinoma subtypes—except for gall-bladder cancer—the overall survival improved significantly. Abstract Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990–1999 and 2000–2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma (n = 7146), intrahepatic cholangiocarcinoma (n = 1858), extrahepatic cholangiocarcinoma (n = 1649), gallbladder carcinoma (n = 1365), and ampullary carcinoma (n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010–2018 as compared with over the periods of 2000–2009 and 1990–1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990–2009.
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Affiliation(s)
- Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria; (M.H.); (S.B.); (D.B.); (M.P.-R.)
- Correspondence:
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, 1090 Vienna, Austria;
| | - Miriam Hucke
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria; (M.H.); (S.B.); (D.B.); (M.P.-R.)
| | - Simona Bota
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria; (M.H.); (S.B.); (D.B.); (M.P.-R.)
| | - Dajana Bolf
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria; (M.H.); (S.B.); (D.B.); (M.P.-R.)
| | - Monika Hackl
- Austrian National Cancer Registry, Statistics Austria, 1110 Vienna, Austria;
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria; (M.H.); (S.B.); (D.B.); (M.P.-R.)
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The Impact of VR-CALM Intervention Based on VR on Psychological Distress and Symptom Management in Breast Cancer Survivors. JOURNAL OF ONCOLOGY 2022; 2022:1012813. [PMID: 35712124 PMCID: PMC9197609 DOI: 10.1155/2022/1012813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/06/2022] [Accepted: 05/20/2022] [Indexed: 01/02/2023]
Abstract
Objective To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully based on VR (VR-CALM), which is used to manage expected symptoms of cancer itself, relieve psychological distress, and improve quality of life (QOL) in the Chinese breast cancer survivors (BCs). Methods Ninety-eight patients with breast cancer were recruited in this study. These patients were randomly assigned to the VR-CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy-Breast cancer patient (FACT-B), Distress Thermometer (DT), Concerns About Recurrence Scale (CARS), Piper Fatigue Scale (PFS), Pittsburgh Sleep Quality Index (PSQI), The Self-Rating Anxiety Scale (SAS), and The Self-Rating Depression Scale (SDS) before and after VR-CALM or CAU application to BCs. We compared the differences in all these scores between the VR-CALM group and the control group. Results Patients in the VR-CALM group showed a significant decrease in levels of distress, anxiety, depression, sleep disorders, and fatigue (t = −6.829, t = −5.819, t = −2.094, t = −3.031, t = −10.082, P ≤ 0.001, 0.001, 0.05, 0.01, 0.001, respectively) and had higher level of quality of life (t = 8.216, P ≤ 0.001) compared with the CAU group after intervention. And postintervention patients in VR-CALM group compared with preintervention showed lower level of distress and remarkable improvement of QOL (t = 11.521, t = −10.379, P ≤ 0.001, 0.001). The preintervention questionnaire revealed no significant between-group differences regarding distress, anxiety, depression, sleep disorders, fatigue, and quality of life. Conclusion VR-CALM is a psychotherapy tailored to the needs of patients with breast cancer. This research innovatively used VR-based CALM intervention to improve psychological and chronic symptoms in BCs. The results of the present study indicate that VR-CALM has salutary effects on the improvement of QOL and relieves psychological distress, anxiety, depression, sleep disorders, and fatigue in BCs.
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Circ_0001955 Acts as a miR-646 Sponge to Promote the Proliferation, Metastasis and Angiogenesis of Hepatocellular Carcinoma. Dig Dis Sci 2022; 67:2257-2268. [PMID: 34021822 DOI: 10.1007/s10620-021-07053-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 05/11/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Circular RNA (circRNA) exerts a crucial role in the progression of many cancers, including hepatocellular carcinoma (HCC). However, the function of circ_0001955 in HCC progression has been poorly studied. AIMS Elucidating the role and molecular mechanism of circ_0001955 in HCC progression. METHODS Quantitative real-time PCR was employed to detect the expression of circ_0001955 and miR-646. Cell counting kit 8 assay, Ethynyl-2-deoxyuridine assay, flow cytometry, transwell assay, and tube formation assay were conducted to measure cell proliferation, metastasis, angiogenesis and apoptosis. Dual-luciferase reporter assay and biotin-labeled RNA pull-down assay were performed to analyze the interactions among circ_0001955, miR-646 and frizzled class receptor 4 (FZD4). Moreover, animal experiments were performed to examine the influence of circ_0001955 on HCC tumor growth in vivo. RESULTS Circ_0001955 was a highly expressed circRNA in HCC tissues and cells. Circ_0001955 knockdown inhibited the proliferation, metastasis, angiogenesis, and enhanced the apoptosis of HCC cells. Meanwhile, miR-646 could be sponged by circ_0001955, and its inhibitor could reverse the negative regulation of circ_0001955 knockdown on HCC progression. Further, FZD4 was a target of miR-646, and its overexpression could invert the inhibition effect of miR-646 mimic on HCC progression. Besides, our results also indicated that circ_0001955 promoted FZD4 expression by sponging miR-646. Animal experiment results showed that circ_0001955 silencing restrained HCC tumor growth in vivo. CONCLUSION Our findings suggested that circ_0001955 might play a positive role in HCC progression via regulating the miR-646/FZD4 axis, indicating that circ_0001955 might be a potential therapeutic target for HCC.
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Freemantle N, Mollon P, Meyer T, Cheng AL, El-Khoueiry AB, Kelley RK, Baron AD, Benzaghou F, Mangeshkar M, Abou-Alfa GK. Quality of life assessment of cabozantinib in patients with advanced hepatocellular carcinoma in the CELESTIAL trial. Eur J Cancer 2022; 168:91-98. [PMID: 35487183 DOI: 10.1016/j.ejca.2022.03.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/08/2022] [Accepted: 03/18/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND The CELESTIAL trial (NCT01908426) demonstrated overall survival benefit for cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (aHCC) who had received prior sorafenib treatment. This analysis of CELESTIAL compared the impact of cabozantinib versus placebo on health-related quality of life (HRQoL). MATERIALS AND METHODS Health status was assessed using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire over the 800-day follow-up period. EQ-5D-5L health states were mapped to health utility scores using reference values for the UK population. Quality-adjusted life years (QALYs) were calculated for each treatment group as the area under the curve for the plot of health utility score over time. The between-treatment group difference in restricted mean QALYs was calculated by generalized linear models and adjusted for baseline differences. A difference of 0.08 in health utility score (or in QALY) was deemed a minimally important difference and to be clinically significant. RESULTS At week 5, the difference in mean health utility score between cabozantinib and placebo was -0.097 (95% confidence interval [95% CI]: -0.126, -0.067; p ≤ 0.001). Between-group differences in health utility scores diminished over time and were generally non-significant. The cabozantinib group accrued more QALYs than the placebo group over follow-up. Differences in mean QALYs (cabozantinib minus placebo) were statistically and clinically significant, ranging from +0.092 (95% CI: 0.016, 0.169) to +0.185 (95% CI: 0.126, 0.243) in favour of cabozantinib, depending on the reference value set used. CONCLUSIONS These HRQoL findings support a positive benefit-risk profile for cabozantinib in previously treated patients with aHCC.
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Affiliation(s)
| | | | - Tim Meyer
- University College London, London, UK
| | - Ann-Lii Cheng
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taiwan, Republic of China
| | - Anthony B El-Khoueiry
- Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Robin K Kelley
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Ari D Baron
- California Pacific Medical Center, San Francisco, CA, USA
| | | | | | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College at Cornell University, New York, NY, USA
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Akce M, El-Rayes BF, Bekaii-Saab TS. Frontline therapy for advanced hepatocellular carcinoma: an update. Therap Adv Gastroenterol 2022; 15:17562848221086126. [PMID: 35432597 PMCID: PMC9006370 DOI: 10.1177/17562848221086126] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/21/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related mortality in the United States and is projected to be the third leading cause of cancer-related mortality in the United States by 2030. Main risk factors include alcoholic cirrhosis, chronic hepatitis B, hepatitis C, and nonalcoholic steatohepatitis (NASH). More than half of the patients have advanced-stage disease at presentation. Currently approved frontline systemic therapy options include sorafenib, lenvatinib, and atezolizumab/bevacizumab. Over the past decade, there has been a significant improvement in survival with a median overall survival of 19.2 months reported with first-line treatment with atezolizumab/bevacizumab. Based on positive results of randomized phase III HIMALAYA trial, durvalumab and tremelimumab combination could become another frontline option. Multiple frontline clinical trials with immune checkpoint inhibitor (ICI) or ICI combined with other novel agents are underway. In the frontline setting, identifying predictive biomarkers for ICI-based or tyrosine kinase (TKI)-based therapy is an unmet need. Subsequent treatment is poorly defined in patients with prior ICI-based therapy since all the available second-line and beyond therapy was studied after first-line sorafenib. Frontline systemic therapy is poorly defined in certain subgroups of HCC such as Child-Pugh B and post-transplant recurrent HCC. The landscape of frontline HCC treatment is rapidly changing, and this article reviews the most recent treatment approaches to frontline therapy for advanced HCC.
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Affiliation(s)
- Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Bassel F. El-Rayes
- Division of Hematology and Oncology, Department of Internal Medicine, O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA
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Hong T, Tsai H, Lin Y, Chen C, Chuang C, Wu I, Chang T, Han M, Lin S, Chen S, Wang H, Chen P, Hsieh M, Chiang H, Liu C, Kuo H. Efficacy of Local‐regional Treatment Plus Sorafenib in Intermediate‐stage Hepatocellular Carcinoma Patients Refractory to Transarterial Chemoembolization. ADVANCES IN DIGESTIVE MEDICINE 2022. [DOI: 10.1002/aid2.13317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Tzu‐Chun Hong
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hong‐Ming Tsai
- Department of Diagnostic Radiology National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Yih‐Jyh Lin
- Department of Surgery National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chiung‐Yu Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chiao‐Hsiung Chuang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - I‐Chin Wu
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Ting‐Tsung Chang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Meng‐Zhi Han
- Department of Internal Medicine An Nan Hospital, China Medical University Tainan Taiwan
| | - Sheng‐Hsiang Lin
- Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Shang‐Hung Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- National Institute of Cancer Research, National Health Research Institutes Tainan Taiwan
| | - Hao‐Chen Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Po‐Jun Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Ming‐Tsung Hsieh
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hsueh‐chien Chiang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chieh‐Yen Liu
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hsin‐Yu Kuo
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
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Liu Y, Mao X, Ma Z, Chen W, Guo X, Yu L, Deng X, Jiang F, Li T, Lin N, Zhang Y. Aberrant regulation of LncRNA TUG1-microRNA-328-3p-SRSF9 mRNA Axis in hepatocellular carcinoma: a promising target for prognosis and therapy. Mol Cancer 2022; 21:36. [PMID: 35120500 PMCID: PMC8815183 DOI: 10.1186/s12943-021-01493-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/26/2021] [Indexed: 01/10/2023] Open
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Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, Himmelsbach V, Schulze K, von Felden J, Fründt TW, Stadler M, Heinzl H, Shmanko K, Spahn S, Radu P, Siebenhüner AR, Mertens JC, Rahbari NN, Kütting F, Waldschmidt DT, Ebert MP, Teufel A, De Dosso S, Pinato DJ, Pressiani T, Meischl T, Balcar L, Müller C, Mandorfer M, Reiberger T, Trauner M, Personeni N, Rimassa L, Bitzer M, Trojan J, Weinmann A, Wege H, Dufour JF, Peck-Radosavljevic M, Vogel A, Pinter M. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022; 76:353-363. [PMID: 34648895 DOI: 10.1016/j.jhep.2021.09.035] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 09/20/2021] [Accepted: 09/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Medicine I, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Fabian Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Oliver Waidmann
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Vera Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Kornelius Schulze
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johann von Felden
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben W Fründt
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Stadler
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria; Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Harald Heinzl
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Kateryna Shmanko
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stephan Spahn
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Pompilia Radu
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander R Siebenhüner
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland; Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
| | - Joachim C Mertens
- Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland
| | - Nuh N Rahbari
- Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Fabian Kütting
- Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
| | | | - Matthias P Ebert
- Department of Internal Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Internal Medicine II, Division of Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sara De Dosso
- Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Tobias Meischl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Michael Bitzer
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Jörg Trojan
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Henning Wege
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cancer Center Esslingen, Klinikum Esslingen, 73730 Esslingen am Neckar, Germany
| | - Jean-François Dufour
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.
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Perisetti A, Goyal H, Yendala R, Chandan S, Tharian B, Thandassery RB. Sarcopenia in hepatocellular carcinoma: Current knowledge and future directions. World J Gastroenterol 2022; 28:432-448. [PMID: 35125828 PMCID: PMC8790553 DOI: 10.3748/wjg.v28.i4.432] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/29/2021] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the second most occurring cancer worldwide and is one of the leading causes of cancer-related deaths. Hepatocellular carcinoma (HCC) is the most common (80%-90%) type among malignant liver cancers. Sarcopenia occurs very early in HCC and can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional, systemic, and transplant management. Multiple prognostic stating systems have been developed in HCC, such as Barcelona Clinic Liver Cancer, Child-Pugh score and Albumin-Bilirubin grade. However, the evaluation of patients' performance status is a major limitation of these scoring systems. In this review, we aim to summarize the current knowledge and recent advances about the role of sarcopenia in cirrhosis in general, while focusing specifically on HCC. Additionally, the role of sarcopenia in predicting clinical outcomes and prognostication in HCC patients undergoing loco-regional therapies, liver resection, liver transplantation and systematic therapy has been discussed. A literature review was performed using databases PubMed/MEDLINE, EMBASE, Cochrane, Web of Science, and CINAHL on April 1, 2021, to identify published reports on sarcopenia in HCC. Sarcopenia can independently predict HCC-related mortality especially in patients undergoing treatments such as loco-regional, surgical liver transplantation and systemic therapies. Basic research is focused on evaluating a balance of anabolic and catabolic pathways responsible for muscle health. Early clinical studies have shown promising results in methods to improve sarcopenia in HCC which can potentially increase prognosis in these patients. As sarcopenia occurs very early in HCC, it can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional, systemic, and transplant management. Further, sarcopenia measurement can obviate the confounding caused by the abdominal ascites in these patients. The use of sarcopenia can add to the existing scoring systems to better prognosticate the HCC.
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Affiliation(s)
- Abhilash Perisetti
- Department of Internal Medicine, Gastroenterology and Hepatology Division, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
- Department of Interventional Oncology and Surgical Endoscopy, Parkview Health, Fort Wayne, IN 46825, United States
| | - Hemant Goyal
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, The Wright Center for Graduate Medical Education, Scranton, PA 18501, United States
| | - Rachana Yendala
- Department of Hematology and Oncology, Conway Regional Medical Center, Conway, AR 72034, United States
| | - Saurabh Chandan
- Department of Internal Medicine, Gastroenterology and Hepatology Division, CHI Creighton University Medical Center, Omaha, NE 68107, United States
| | - Benjamin Tharian
- Department of Internal Medicine, Gastroenterology and Hepatology Division, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Ragesh Babu Thandassery
- Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States
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Extracellular Vesicle-Encapsulated MicroRNA-375 from Bone Marrow-Derived Mesenchymal Stem Cells Inhibits Hepatocellular Carcinoma Progression through Regulating HOXB3-Mediated Wnt/β-Catenin Pathway. Anal Cell Pathol (Amst) 2022; 2022:9302496. [PMID: 35127344 PMCID: PMC8813296 DOI: 10.1155/2022/9302496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 12/16/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023] Open
Abstract
Nowadays, microRNA-375 (miR-375) has been implicated in many types of cancers, including hepatocellular carcinoma (HCC), and the functions of miRNAs encapsulated by extracellular vesicles (EV) in HCC progression have also been extensively investigated. In this research, we aimed to probe into the mechanism of EV-encapsulated miR-375 from bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCC progression. At first, miR-375 expression in HCC tissues and cells was detected using RT-qPCR, and miR-375 was overexpressed to specify the effects of miR-375 on the malignant phenotype of HCC cells. miR-375 was downregulated in HCC, and overexpression of miR-375 suppressed HCC cell growth. Then, BM-MSCs and EV were isolated and identified, and, EV were cocultured with HCC cells for further functional assays. It was found that miR-375 encapsulated by EV could restrict the malignant phenotypes of HCC cells. Furthermore, the downstream genes and signaling cascades involved in HCC growth were investigated. HOXB3 was determined to be a downstream target of miR-375, and upregulation of miR-375 decreased Wnt1 and β-catenin protein expression. Furthermore, HOXB3 blocked the repressive effects of miR-375 on HCC cells and Wnt1 and β-catenin expression. This study highlights that miR-375 encapsulated by EV inhibits HCC development via modulating the HOXB3/Wnt/β-catenin axis.
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Liu YM, Cao Y, Zhao PS, Wu LY, Lu YM, Wang YL, Zhao JF, Liu XG. CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway. Int J Biol Sci 2022; 18:637-651. [PMID: 35002514 PMCID: PMC8741844 DOI: 10.7150/ijbs.66915] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/31/2021] [Indexed: 02/07/2023] Open
Abstract
Background: Circular RNAs (circRNAs), which generally act as microRNA (miRNA) sponges to competitively regulate the downstream target genes of miRNA, play an essential role in cancer biology. However, few studies have been reported on the role of circRNA based competitive endogenous RNA (ceRNA) network in hepatocellular carcinoma (HCC). Herein, we aimed to screen and establish the circRNA/miRNA/mRNA networks related to the prognosis and progression of HCC and further explore the underlying mechanisms of tumorigenesis. Methods: GEO datasets GSE97332, GSE108724, and GSE101728 were utilized to screen the differentially expressed circRNAs (DE-circRNAs), DE-miRNAs, and DEmRNAs between HCC and matched para-carcinoma tissues. After six RNA-RNA predictions and five intersections between DE-RNAs and predicted RNAs, the survival-related RNAs were screened by the ENCORI analysis tool. The ceRNA networks were constructed using Cytoscape software, based on two models of up-regulated circRNA/down-regulated miRNA/up-regulated mRNA and down-regulated circRNA/up-regulated miRNA/down-regulated mRNA. The qRT-PCR assay was utilized for detecting the RNA expression levels in HCC cells and tissues. The apoptosis, Edu, wound healing, and transwell assays were performed to evaluate the effect of miR-106b-5p productions on the proliferation, invasion, and metastasis of HCC cells. In addition, the clone formation, cell cycle, and nude mice xenograft tumor assays were used to investigate the influence of hsa_circ_0001495 (circCCNB1) silencing and overexpression on the proliferation of HCC cells in vitro and in vivo. Furthermore, the mechanism of downstream gene DYNC1I1 and AKT/ERK signaling pathway via the circCCNB1/miR-106b-5p/GPM6A network in regulating the cell cycle was also explored. Results: Twenty DE-circRNAs with a genomic length less than 2000bp, 11 survival-related DE-miRNAs, and 61 survival-related DE-mRNAs were screened out and used to construct five HCC related ceRNA networks. Then, the circCCNB1/miR-106b-5p/GPM6A network was randomly selected for subsequent experimental verification and mechanism exploration at in vitro and in vivo levels. The expression of circCCNB1 and GPM6A were significantly down-regulated in HCC cells and cancer tissues, while miR-106b-5p expression was up-regulated. After transfections, miR-106b-5p mimics notably enhanced the proliferation, invasion, and metastasis of HCC cells, while the opposite was seen with miR-105b-5p inhibitor. In addition, circCCNB1 silencing promoted the clone formation ability, the cell cycle G1-S transition, and the growth of xenograft tumors of HCC cells via GPM6A downregulation. Subsequently, under-expression of GPM6A increased DYNC1I1 expression and activated the phosphorylation of the AKT/ERK pathway to regulate the HCC cell cycle. Conclusions: We demonstrated that circCCNB1 silencing promoted cell proliferation and metastasis of HCC cells by weakening sponging of oncogenic miR-106b-5p to induce GPM6A underexpression. DYNC1I1 gene expression was up-regulated and further led to activation of the AKT/ERK signaling pathway.
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Affiliation(s)
- Yan-Ming Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan, Guangdong, China.,Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Yue Cao
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Department of Medical Technology, Medical College of Shaoguan University, Shaogguan, Guangdong, China
| | - Ping-Sen Zhao
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Liang-Yin Wu
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Ya-Min Lu
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Yu-Long Wang
- Department of Anesthesiology, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Jia-Feng Zhao
- Department of Hepatobiliary Surgery, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Xin-Guang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan, Guangdong, China
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Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3. Cell Death Dis 2022; 13:32. [PMID: 35013102 PMCID: PMC8748962 DOI: 10.1038/s41419-021-04345-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/07/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023]
Abstract
Macrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.
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Cai L, Liao B, Luo F, Zhang S, Deng Z. Rehmanniae Radix-Induced apoptosis via inhibition of PI3K/AKT/mTOR signaling pathways in human hepatocellular carcinoma cell lines SMMC-7721. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_147_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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47
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Pomej K, Balcar L, Scheiner B, Semmler G, Meischl T, Mandorfer M, Reiberger T, Müller C, Trauner M, Pinter M. Antibiotic Therapy is Associated with Worse Outcome in Patients with Hepatocellular Carcinoma Treated with Sorafenib. J Hepatocell Carcinoma 2021; 8:1485-1493. [PMID: 34877268 PMCID: PMC8643200 DOI: 10.2147/jhc.s317957] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Background Antibiotic treatment (ABT) affects the outcome of cancer patients treated with immune checkpoint inhibitors (ICIs) and chemotherapy, possibly by altering the gut microbiome. We investigated the impact of ABT on overall survival (OS) and progression-free survival (PFS) in patients with advanced HCC treated with sorafenib. Methods HCC patients treated with sorafenib between 05/2006 and 03/2020 at the Medical University of Vienna were retrospectively analyzed. ABT was defined as antibiotic use within 30 days prior to or after sorafenib initiation. Results Of 206 patients, the majority was male (n=171, 83%) with a mean age of 66±9.6 years. Half of patients (n=94, 46%) had impaired liver function (Child-Pugh stage B). Median time of follow-up was 10.8 (95% CI: 9.2-12.3) months. ABT was administered in 23 (11%) patients due to different types of proven or clinically suspected bacterial infections (n=17, 74%) and hepatic encephalopathy (n=6, 26%). The median duration of ABT was 14 (IQR: 12-30) days. Penicillin (n=13, 57%), followed by rifaximin (n=6, 26%), fluoroquinolones (n=3, 13%), and cephalosporins (n=1, 4%), was administered in the ABT group. The ABT group had a significantly shorter median OS (4.7 (95% CI: 3.2-6.1) months vs 11.4 (95% CI: 9.9-12.9) months, p=0.012), which was confirmed in multivariable analysis (HR: 1.91 (95% CI: 1.1-3.2), p=0.014). Similarly, PFS trended to be shorter in the ABT group (3.5 (95% CI: 1.6-5.4) months vs 4.8 (95% CI: 3.9-5.7) months, p=0.099). None of the 10 patients with complete or partial response was found in the ABT group. Conclusion ABT was independently associated with worse outcomes in sorafenib-treated HCC patients. Prospective studies are needed to elucidate the underlying mechanism.
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Affiliation(s)
- Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.,Rare Liver Disease (RALID) Centre of the ERN RARE-LIVER, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Tobias Meischl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.,Rare Liver Disease (RALID) Centre of the ERN RARE-LIVER, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.,Rare Liver Disease (RALID) Centre of the ERN RARE-LIVER, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Rare Liver Disease (RALID) Centre of the ERN RARE-LIVER, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.,Rare Liver Disease (RALID) Centre of the ERN RARE-LIVER, Medical University of Vienna, Vienna, Austria
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Huang X, Xu L, Ma T, Yin X, Huang Z, Ran Y, Ni Y, Bi X, Che X. Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study. Front Oncol 2021; 11:751159. [PMID: 34868952 PMCID: PMC8637826 DOI: 10.3389/fonc.2021.751159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
Background Nivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC. Method Between June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed. Results All the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis. Conclusion The combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.
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Affiliation(s)
- Xiaozhun Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Lin Xu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Teng Ma
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xin Yin
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhangkan Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Yihong Ran
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Yong Ni
- Department of Hepatological Surgery, Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Che
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.,Department of Gastrointestinal & Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Rohr-Udilova N, Tsuchiya K, Timelthaler G, Salzmann M, Meischl T, Wöran K, Stift J, Herac M, Schulte-Hermann R, Peck-Radosavljevic M, Sieghart W, Eferl R, Jensen-Jarolim E, Trauner M, Pinter M. Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation. Hepatol Commun 2021; 5:1939-1952. [PMID: 34558826 PMCID: PMC8557312 DOI: 10.1002/hep4.1770] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/10/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.
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Affiliation(s)
- Nataliya Rohr-Udilova
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Kaoru Tsuchiya
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria.,Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Gerald Timelthaler
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Martina Salzmann
- Institute of Pathophysiology and Allergy ResearchCenter of Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria
| | - Tobias Meischl
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Katharina Wöran
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Judith Stift
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Merima Herac
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Rolf Schulte-Hermann
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology, Central Admission, and First AidPublic Hospital Klagenfurt am WoertherseeKlagenfurtAustria
| | | | - Robert Eferl
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy ResearchCenter of Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria.,Comparative MedicineInteruniversity Messerli Research Institute of the University of Veterinary Medicine ViennaMedical University of Vienna and University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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Xie Y, Liu C, Zhou S, Wang Q, Tang X. Lupeol-Loaded Nanoparticles Enhance the Radiosensitivity of Hepatocellular Carcinoma by Inhibiting the Hyperactivation in Raf/Mitogen-Activated Protein Kinase and Phospatidylinositol-3 Kinase/mTOR Pathways. J Biomed Nanotechnol 2021; 17:2247-2258. [PMID: 34906285 DOI: 10.1166/jbn.2021.3194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Radioresistance limits the effectiveness of radiotherapy for hepatocellular carcinoma. Raf and PI3K signaling cascades promote the formation of radioresistance in hepatocellular carcinoma (HCC). Lupeol has anticancer activity despite itspoor solubility in water and is toxic effect on normal tissue. In this study, nanoparticles (lupeol-NPs) were constructed using PEG-PLGA diblock copolymer vector, and results revealed that Lupeol-NPs reversed the radioresistance of hepatocellular carcinoma by inhibiting cellular proliferation and cell-cycle progression and promoting cellular apoptosis through blocking Raf/MAPK and PI3K/Akt signal transduction in radioresistant Huh-7R cells. In vivo, Lupeol-NPs combined with radiotherapy inhibited the growth of radioresistant hepatocellular carcinoma in a xenogenic nude mouse model. Ki-67 proliferation index decreased significantly (p < 0.05). We conclude that Lupeol-NPs can increase the sensitivity of radioresistant hepatocellular carcinoma to radiotherapy through inhibiting the Raf and PI3K signal cascades.
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Affiliation(s)
- Yinghai Xie
- Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China
| | - Changwei Liu
- Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China
| | - Shuping Zhou
- Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China
| | - Qi Wang
- Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China
| | - Xiaolong Tang
- Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China
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