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Alolyan A, Alshammari K, Arabi M, Alshehri A, Alsuhaibani H, Ibnshamsah F, Alsharm A, Mahrous M, Al Zanbagi A, Hassanain M, Bazarbashi S. Treatment Patterns and Recommendations for Improving the Management of Hepatocellular Carcinoma in Saudi Arabia. J Hepatocell Carcinoma 2024; 11:349-362. [PMID: 38385059 PMCID: PMC10879627 DOI: 10.2147/jhc.s442842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/17/2024] [Indexed: 02/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer in the world associated with high morbidity and mortality. Despite being a significant healthcare burden there is limited information on the unmet needs and current treatment practices for intermediate and advanced-stage HCC in Saudi Arabia. This article analyzes the gaps and provides expert consensus on the management strategies for unresectable HCC in Saudi Arabia. A pre-meeting online questionnaire, comprising 20 objective questions about the treatment landscape and diagnosis of HCC in Saudi Arabia, was distributed to experts in the field of HCC management. An advisory board meeting including a panel of 13 experts was held in September 2022 where the responses to the survey questionnaire were reviewed and discussed. The survey results and experts' discussion highlighted the growing incidence of liver cancer in Saudi Arabia. HCC comprised the majority of all liver cancer cases due to rising rates of chronic viral infections and lifestyle-related risk factors. Most physicians in Saudi Arabia follow the Barcelona Clinic Liver Cancer guidelines as a prognostic tool for the detection and staging of patients with HCC. Most of the patients with HCC in Saudi Arabia are diagnosed in the intermediate or advanced stages with poor prognoses and limited therapeutic options. Establishing evidence-based surveillance techniques, a multidisciplinary approach to diagnosis, and better accessibility of treatment options is vital for the management of HCC in Saudi Arabia.
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Affiliation(s)
- Ashwaq Alolyan
- Department of Medical Oncology, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Kanan Alshammari
- Department of Medical Oncology, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Mohammad Arabi
- Department of Medical Oncology, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Ahmed Alshehri
- Department of Oncology, King Khalid National Guard Hospital Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Hamad Alsuhaibani
- Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fahad Ibnshamsah
- Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Abdullah Alsharm
- Department of Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mervat Mahrous
- Department of Oncology, Prince Sultan Military Medical City Hospital, Riyadh, Saudi Arabia
- Department of Medicine, Minia University of Egypt, Faculty of Medicine, Minia, Egypt
| | - Adnan Al Zanbagi
- Department of Gastroenterology and Hepatology, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mazen Hassanain
- Department of Surgery, King Saudi University, Riyadh, Saudi Arabia
| | - Shouki Bazarbashi
- Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Abdelall EKA, Elshemy HAH, Labib MB, Mohamed FEA. Design, synthesis of novel chromene-based scaffolds targeting hepatocellular carcinoma: Cell cycle arrest, cytotoxic effect against resistant cancer cells, apoptosis induction, and c-Src inhibition. Drug Dev Res 2024; 85:e22133. [PMID: 37971069 DOI: 10.1002/ddr.22133] [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: 07/27/2023] [Revised: 10/05/2023] [Accepted: 10/29/2023] [Indexed: 11/19/2023]
Abstract
New chromene derivatives were synthesized based on 4-(3,4-dimethoxy)-4H-chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40-141.22 μM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c-Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c-Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI-38 cells was confirmed via its IC50 of 115.75 μM comparable with 5-FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5-FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29-fold increase in the total number of apoptotic cells indicating pre-G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase-3, caspase-7, caspase-9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c-Src kinase enzyme active site.
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Affiliation(s)
- Eman K A Abdelall
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Heba A H Elshemy
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Madlen B Labib
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Fatma E A Mohamed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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3
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He H, Jamal M, Zeng X, Lei Y, Xiao D, Wei Z, Zhang C, Zhang X, Pan S, Ding Q, Tan H, Xie S, Zhang Q. Matrin-3 acts as a potential biomarker and promotes hepatocellular carcinoma progression by interacting with cell cycle-regulating genes. Cell Cycle 2024; 23:15-35. [PMID: 38252499 PMCID: PMC11005806 DOI: 10.1080/15384101.2024.2305535] [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: 01/15/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.
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Affiliation(s)
- Hengjing He
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Muhammad Jamal
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xingruo Zeng
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yufei Lei
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Di Xiao
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Zimeng Wei
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Chengjie Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xiaoyu Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Shan Pan
- School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qianshan Ding
- School of Medicine, Northwest University, Xian, China
| | - Haiyan Tan
- Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Songping Xie
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
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Long J, Liu L, Yang X, Lu X, Qin L. Impact of combining Lenvatinib with Transarterial chemoembolization for unresectable hepatocellular carcinoma. Pak J Med Sci 2023; 39:1847-1852. [PMID: 37936761 PMCID: PMC10626123 DOI: 10.12669/pjms.39.6.7944] [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: 03/20/2023] [Revised: 04/01/2023] [Accepted: 08/08/2023] [Indexed: 11/09/2023] Open
Abstract
Objectives To investigate the impact of combining lenvatinib with transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC). Methods This was a retrospective observational study which reviewed the medical records of 103 unresectable HCC patients from January 2017 to June 2020 in The First Affiliated Hospital of Soochow University. It included 46 patients who received TACE plus lenvatinib and 57 patients who received TACE alone. The levels of serum indicators, clinical effect, adverse events, overall survival (OS), and progression-free survival (PFS) were compared between the two groups. Results AFP and VEGF levels in the TACE+lenvatinib group post-treatment were significantly lower than the TACE group (P<0.05). The clinical efficacy in the TACE+lenvatinib group (69.57%) was higher than that in the TACE group (40.35%) post-treatment (P<0.05). There were significant differences in hypertension, diarrhea, and bleeding (gingiva) between the two groups (P<0.05). There were no significant differences in one or two year PFS rate or one year OS between groups (P>0.05), while the two years survival rate in the TACE+lenvatinib group was significantly higher than that in the TACE group (P<0.05). Conclusions TACE combined with lenvatinib have a high clinical effective rate, with reduced AFP and VEGF levels, higher two year survival rate, and acceptable incidence of adverse events.
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Affiliation(s)
- Jianwu Long
- Jianwu Long, Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu province, P.R. China
| | - Longfei Liu
- Longfei Liu, Department of Hepatobiliary Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan province, P.R. China
| | - Xuefeng Yang
- Xuefeng Yang, Department of Hepatobiliary Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan province, P.R. China
| | - Xianzhou Lu
- Xianzhou Lu Department of General Surgery, Hengyang County People’s Hospital, Hengyang, Hunan province, P.R. China
| | - Lei Qin
- Lei Qin, Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu province, P.R. China
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Hu J, Liu N, Song D, Steer CJ, Zheng G, Song G. A positive feedback between cholesterol synthesis and the pentose phosphate pathway rather than glycolysis promotes hepatocellular carcinoma. Oncogene 2023; 42:2892-2904. [PMID: 37596320 PMCID: PMC10516751 DOI: 10.1038/s41388-023-02757-9] [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] [Received: 01/16/2023] [Revised: 05/25/2023] [Accepted: 06/16/2023] [Indexed: 08/20/2023]
Abstract
Hepatic cholesterol accumulation and hypercholesterolemia are implicated in hepatocellular carcinoma (HCC). However, the therapeutic effects of cholesterol-lowering drugs on HCC are controversial, indicating that the relationship between cholesterol metabolism and HCC is more complex than anticipated. A positive feedback between cholesterol synthesis and the pentose phosphate pathway (PPP) rather than glycolysis was formed in tumors of c-Myc mice. Blocking the PPP prevented cholesterol synthesis and thereby HCC in c-Myc mice, while ablating glycolysis did not affect cholesterol synthesis and failed to prevent c-Myc-induced HCC. Unexpectedly, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzymes of cholesterol synthesis and the PPP, were identified as direct targets of microRNA-206. By targeting Hmgcr and G6pd, microRNA-206 disrupted the positive feedback and fully prevented HCC in c-Myc mice, while 100% of control mice died of HCC. Disrupting the interaction of microRNA-206 with Hmgcr and G6pd restored cholesterol synthesis, the PPP and HCC growth that was inhibited by miR-206. This study identified a previously undescribed positive feedback loop between cholesterol synthesis and the PPP, which drives HCC, while microRNA-206 prevents HCC by disrupting this loop. Cholesterol synthesis as a process rather than cholesterol itself is the major contributor of HCC.
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Affiliation(s)
- Junjie Hu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, PR China
| | - Ningning Liu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - David Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
- American High School, Fremont, CA, USA
| | - Clifford J Steer
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Guohua Zheng
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, PR China.
| | - Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, 55455, USA.
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Surdea-Blaga T, Cărăguț RL, Caraiani C, Spârchez Z, Al Hajjar N, Dumitrașcu DL. Overlap syndrome of autoimmune hepatitis and primary biliary cholangitis complicated with atypical hepatocellular carcinoma: a case report. J Med Case Rep 2023; 17:328. [PMID: 37488645 PMCID: PMC10367410 DOI: 10.1186/s13256-023-03932-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 04/13/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a primary tumor of the liver. The majority of HCCs are associated most frequently with chronic B or C viral hepatitis, alcohol intake or aflatoxin exposure. Cirrhosis is a strong risk factor associated with HCC. The causes of liver cirrhosis are chronic viral hepatitis, alcohol intake, metabolic diseases (NAFLD), hemocromathosis, alfa 1 antitrypsisn deficiency. All aetiologic forms of cirrhosis are at risk to be complicated by HCC development, but the risk is higher for patients diagnosed with chronic viral hepatitis. Comparing to the above-mentioned causes, PBC and AIH are less associated with the risk of HCC development. A 71-year old Caucasian female previously diagnosed with overlap syndrome (AIH type 1 and PBC-ANA, SMA and AMA antibodies positive), liver cirrhosis, a nodule in the VI/VIIth hepatic segment, systemic sclerosis sine scleroderma, Hashimoto's thyroiditis, antiphospholipid syndrome, gastric antral vascular ectasia (GAVE) (with 2 previous sessions of argon plasma coagulation), cholecystectomy, arterial hypertension and nephro-angiosclerosis presented to the 2nd Department of Internal Medicine in Cluj-Napoca for a follow-up. The patient was following treatment with UDCA (Ursodeoxycholic acid), azathioprine, Plaquenil, calcium channel blockers, angiotensin-converting-enzyme inhibitor, calcium and vitamin D supplementation. The abdominal ultrasound showed a subcapsular hypoechoic nodule with a diameter of 29 mm (at the moment of the diagnosis the diameter was 9/10 mm) in the VI/VIIth hepatic segment. The contrast-enhanced ultrasound (CEUS) characterised the nodule as specific for hepatocellular carcinoma (LI-RADS 5). On MRI with gadoxetate disodium the nodule was hypovascular, non-specific, being classified as LI-RADS 3. An atypical resection of the VIIth hepatic segment was performed and the histohistological examination and imunohistochemistry (Hep Par-a positive, Glypican3 positive, CD34 positive) revealed a moderately differentiated hepatocellular carcinoma (G2), pT2 N0 M0 L0 V1 R0. CONCLUSION Autoimmune hepatitis, PBC and the overlap syndrome are less associated with the development of liver cirrhosis and HCC than other chronic liver diseases, especially if other risk factors are not associated. This case highlights the importance of a proper surveillance of cirrhotic patients every 6 months including abdominal ultrasound and AFP levels is crucial for an early diagnosis of a HCC.
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Affiliation(s)
- Teodora Surdea-Blaga
- "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, County Emergency Hospital, Cluj-Napoca, Romania
| | - Roxana L Cărăguț
- Regional Institute of Gastroenterology and Hepatology, No. 19-21 Croitorilor Street, 400162, Cluj-Napoca, Cluj, Romania.
| | - Cosmin Caraiani
- "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Zeno Spârchez
- "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Regional Institute of Gastroenterology and Hepatology, No. 19-21 Croitorilor Street, 400162, Cluj-Napoca, Cluj, Romania
| | - Nadim Al Hajjar
- "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Regional Institute of Gastroenterology and Hepatology, No. 19-21 Croitorilor Street, 400162, Cluj-Napoca, Cluj, Romania
| | - Dan L Dumitrașcu
- "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, County Emergency Hospital, Cluj-Napoca, Romania
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Wei D, Chen D, Mou H, Chakraborty S, Wei B, Tan L, Lorenzi PL, Qian X, Yang P. Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma. Mol Cancer Ther 2023; 22:693-705. [PMID: 36780187 PMCID: PMC11817653 DOI: 10.1158/1535-7163.mct-22-0490] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/18/2022] [Accepted: 02/08/2023] [Indexed: 02/14/2023]
Abstract
The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.
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Affiliation(s)
- Daoyan Wei
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Authors contributed equally to the manuscript
| | - Dongmei Chen
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Authors contributed equally to the manuscript
| | | | - Sharmistha Chakraborty
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bo Wei
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, Houston, TX 77030, USA
| | - Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, Houston, TX 77030, USA
| | - Philip L. Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, Houston, TX 77030, USA
| | | | - Peiying Yang
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Albarrak J, Al-Shamsi H. Current Status of Management of Hepatocellular Carcinoma in The Gulf Region: Challenges and Recommendations. Cancers (Basel) 2023; 15:cancers15072001. [PMID: 37046662 PMCID: PMC10093592 DOI: 10.3390/cancers15072001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/23/2023] [Accepted: 03/25/2023] [Indexed: 03/30/2023] Open
Abstract
The burden of hepatocellular carcinoma (HCC) is on the rise in the Gulf region, with most patients being diagnosed in the intermediate or advanced stages. Surgery is a treatment option for only a few, and the majority of patients receive either locoregional treatment (percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization [TACE], radioembolization, radiotherapy, or transarterial radioembolization) or systemic therapy (for those ineligible for locoregional treatments or who do not benefit from TACE). The recent emergence of novel immunotherapies such as immune checkpoint inhibitors has begun to change the landscape of systemic HCC treatment in the Gulf. The combination of atezolizumab and bevacizumab is currently the preferred first-line therapy in patients not at risk of bleeding. Additionally, the HIMALAYA trial has demonstrated the superiority of the durvalumab plus tremelimumab combination (STRIDE regimen) therapy in efficacy and safety compared with sorafenib in patients with unresectable HCC. However, there is a lack of data on post-progression treatment after first-line therapy with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab regimens, highlighting the need for better-designed studies for improved management of patients with unresectable HCC in the Gulf region.
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Affiliation(s)
- Jasem Albarrak
- Kuwait Cancer Control Center, Sabah Health Region, Kuwait City 8WF3+WR8, Kuwait;
| | - Humaid Al-Shamsi
- Burjeel Medical City- Burjeel Holding, Abu Dhabi 92510, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Emirates Oncology Society, Dubai 22107, United Arab Emirates
- Correspondence:
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9
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Lorente L, Rodriguez ST, Sanz P, González-Rivero AF, Pérez-Cejas A, Padilla J, Díaz D, González A, Martín MM, Jiménez A, Cerro P, Portero J, Barrera MA. Patients with hepatocellular carcinoma that die during the first year of liver transplantation have high blood sFasL concentrations. World J Clin Cases 2023; 11:1753-1760. [PMID: 36970008 PMCID: PMC10037289 DOI: 10.12998/wjcc.v11.i8.1753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/20/2023] [Accepted: 02/21/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Fas ligand (FasL) is one ligand that activates extrinsic apoptosis pathway. High expression in lymphocytes of FasL have been found in patients with acute rejection of liver transplantation (LT). No high blood concentrations of soluble FasL (sFasL) have been found in patients with acute LT rejection; however, the samples size of those studies was small.
AIM To determine whether patients with hepatocellular carcinoma (HCC) that dead during the first year of LT have higher blood sFasL concentrations previously to LT that those who that remain alive in a study of higher sample size.
METHODS Patients underwent LT due to HCC were included in this retrospective study. Serum sFasL levels prior to LT were measured and one-year LT mortality was registered.
RESULTS Non-surviving patients (n = 14) showed higher serum sFasL levels [477 (269-496) vs 85 (44-382) pg/mL; P < 0.001] than surviving patients (n = 113). Serum sFasL levels (pg/mL) were associated with mortality (OR = 1.006; 95%CI = 1.003-1.010; P = 0.001) independently of age of LT donor in the logistic regression analysis.
CONCLUSION We report for the first time that HCC patients who die within the first year of HT have higher blood sFasL concentrations prior to HT than those who remain alive.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, La Laguna 38320, Spain
| | - Sergio T Rodriguez
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Pablo Sanz
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife 38010, Spain
| | | | - Antonia Pérez-Cejas
- Department of Laboratory, Hospital Universitario de Canarias, La Laguna 38320, Spain
| | - Javier Padilla
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Dácil Díaz
- Department of Digestive, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Antonio González
- Department of Digestive, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife 38010, Spain
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, La Laguna 38320, Spain
| | - Purificación Cerro
- Transplant Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Julián Portero
- Department of Radiology, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife 38010, Spain
| | - Manuel A Barrera
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife 38010, Spain
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10
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Gaber DA, Shaker O, Younis AT, El-Kassas M. LncRNA HULC and miR-122 Expression Pattern in HCC-Related HCV Egyptian Patients. Genes (Basel) 2022; 13:1669. [PMID: 36140836 PMCID: PMC9498747 DOI: 10.3390/genes13091669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 11/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly prevalent malignancy. It is a common type of cancer in Egypt due to chronic virus C infection (HCV). Currently, the frequently used lab test is serum α-fetoprotein. However, its diagnostic value is challenging due to its low sensitivity and specificity. Genetic biomarkers have recently provided new insights for cancer diagnostics. Herein, we quantified Lnc HULC and miR-122 gene expression to test their potential in diagnosis. Both biomarkers were tested in the sera of 60 HCC patients and 60 with chronic HCV using real-time RT-PCR. miR-122 was highly expressed in HCV patients with a significant difference from the HCC group (p = 0.004), which points towards its role in prognosis value as a predictor of HCC in patients with chronic HCV. HULC was more highly expressed in HCC patients than in the HCV group (p = 0.018), indicating its potential use in screening and the early diagnosis of HCC. The receiver operating characteristic (ROC) curve analysis showed their reliable sensitivity and specificity. Our results reveal that miR-122 can act as a prognostic tool for patients with chronic HCV. Furthermore, it is an early predictor of HCC. LncRNA HULC can be used as an early diagnostic tool for HCC.
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Affiliation(s)
- Dalia A. Gaber
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
- College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
| | - Olfat Shaker
- Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11956, Egypt
| | - Alaa Tarek Younis
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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Hu J, Yang L, Peng X, Mao M, Liu X, Song J, Li H, Chen F. METTL3 promotes m6A hypermethylation of RBM14 via YTHDF1 leading to the progression of hepatocellular carcinoma. Hum Cell 2022; 35:1838-1855. [PMID: 36087219 DOI: 10.1007/s13577-022-00769-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/09/2022] [Indexed: 11/27/2022]
Abstract
Liver is a well-known immunological organ with unique microenvironment. In normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as Kupffer cells (KCs). The presence of liver immunosuppressive microenvironment underlines the importance to dissect this interaction to understand how this cross-talk promotes tumor growth in hepatocellular carcinoma (HCC). Therefore, the aim of the study here was to probe the role of methyltransferase-like 3 (METTL3) in the HCC progression and its effect on the polarization of KCs. KCs showed M2 polarization, and METTL3 was overexpressed in our collected HCC tissues relative to adjacent tissues. METTL3 depletion inhibited the M2 polarization of KCs, thereby reverting the malignant phenotype of HCC cells in vitro and growth and metastasis in vivo. Mechanistically, YTH domain-containing family protein 1 (YTHDF1) bound to RNA-binding protein 14 (RBM14), whereas METTL3 knockdown in KCs cells suppressed RBM14 expression by decreasing N-methyladenosine (m6A) methylation. Overexpression of RBM14 mitigated the anti-tumor effects of sh-METTL3 in vitro and in vivo. It is suggested that the mechanism of sh-METTL3 suppressing the polarization of KCs and the progression of HCC is to regulate the RBM14 expression via YTHDF1-dependent m6A modification.
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Affiliation(s)
- Jingyao Hu
- The Seventh Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, No. 4, Donggu Road, Chonggu District, Shenyang, 110000, Liaoning, People's Republic of China
| | - Liang Yang
- The Third Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China
| | - Xueqiang Peng
- The Third Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China
| | - Minghuan Mao
- Department of Urology Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China
| | - Xiaodan Liu
- The Fifth Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China
| | - Jianbo Song
- Interventional Department, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China
| | - Hangyu Li
- The Third Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, Liaoning, People's Republic of China.
| | - Fu Chen
- The Seventh Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, No. 4, Donggu Road, Chonggu District, Shenyang, 110000, Liaoning, People's Republic of China.
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12
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Liu N, Wang X, Steer CJ, Song G. MicroRNA-206 promotes the recruitment of CD8 + T cells by driving M1 polarisation of Kupffer cells. Gut 2022; 71:1642-1655. [PMID: 34706869 PMCID: PMC9279850 DOI: 10.1136/gutjnl-2021-324170] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/02/2021] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. DESIGN FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system. RESULTS Hydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8+ T cells impaired the ability of miR-206 to prevent HCC. CONCLUSIONS M2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8+ T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach.
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Affiliation(s)
- Ningning Liu
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Xiaomei Wang
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Clifford John Steer
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Guisheng Song
- Department of Medicine, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
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Lorente L, Rodriguez ST, Sanz P, González-Rivero AF, Pérez-Cejas A, Padilla J, Díaz D, González A, Martín MM, Jiménez A, Cerro P, Portero J, Barrera MA. DNA and RNA oxidative damage in hepatocellular carcinoma patients and mortality during the first year of liver transplantation. World J Hepatol 2022; 14:1182-1189. [PMID: 35978670 PMCID: PMC9258248 DOI: 10.4254/wjh.v14.i6.1182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/28/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Oxidative damage of DNA and RNA has been associated with mortality of patients with different diseases. However, there is no published data on the potential use of DNA and RNA oxidative damage to predict the prognosis of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT).
AIM To determine whether patients with increased DNA and RNA oxidative damage prior to LT for HCC have a poor LT prognosis.
METHODS Patients with HCC who underwent LT were included in this observational and retrospective study. Serum levels of all three oxidized guanine species (OGS) were measured prior to LT since guanine is the nucleobase that forms DNA and RNA most prone to oxidation. LT mortality at 1 year was the end-point study.
RESULTS Surviving patients (n = 101) showed lower serum OGS levels (P = 0.01) and lower age of the liver donor (P = 0.03) than non-surviving patients (n = 13). An association between serum OGS levels prior to LT and 1-year LT (odds ratio = 2.079; 95% confidence interval = 1.356-3.189; P = 0.001) was found in the logistic regression analysis.
CONCLUSION The main new finding was that high serum OGS concentration prior to LT was associated with the mortality 1 year after LT in HCC patients.
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Affiliation(s)
- Leonardo Lorente
- Department ofIntensive Care, Hospital Universitario de Canarias, La Laguna 38320, Tenerife, Spain
| | - Sergio T Rodriguez
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Pablo Sanz
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
| | | | - Antonia Pérez-Cejas
- Department of Laboratory, Hospital Universitario de Canarias, La Laguna 38320, Spain
| | - Javier Padilla
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Dácil Díaz
- Department of Digestive, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Antonio González
- Department of Digestive, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, La Laguna 38320, Spain
| | - Purificación Cerro
- Transplant Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Julián Portero
- Department of Radiology, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife 38010, Spain
| | - Manuel A Barrera
- Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
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Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022; 23:ijms23073778. [PMID: 35409139 PMCID: PMC8998420 DOI: 10.3390/ijms23073778] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.
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Liu N, Chang CW, Steer CJ, Wang XW, Song G. MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication Between Kupffer Cells and Regulatory T Cells. Gastroenterology 2022; 162:575-589. [PMID: 34678217 DOI: 10.1053/j.gastro.2021.10.015] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 10/05/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is characterized by intratumoral accumulation of regulatory T cells (Tregs), which suppresses antitumor immunity. This study was designed to investigate how microRNAs regulate immunosuppression in HCC. METHODS FVB/NJ mice were hydrodynamically injected with AKT/Ras or c-Myc and Sleeping Beauty transposon to induce HCC. The Sleeping Beauty system was used to deliver microRNA-15a/16-1 into livers of mice. Flow cytometry and immunostaining were used to determine changes in the immune system. RESULTS Hydrodynamic injection of AKT/Ras or c-Myc into mice resulted in hepatic enrichment of Tregs and reduced cytotoxic T cells (CTLs) and HCC development. HCC impaired microRNA-15a/16-1 biogenesis in Kupffer cells (KCs) of AKT/Ras and c-Myc mice. Hydrodynamic injection of microRNA-15a/16-1 fully prevented HCC in AKT/Ras and c-Myc mice, while 100% of control mice died of HCC. Therapeutically, microRNA-15a/16-1 promoted a regression of HCC in both mouse models, impaired hepatic enrichment of Tregs, and increased hepatic CTLs. Mechanistically, a significant increase was observed in serum C-C motif chemokine 22 (CCL22) and transcription of Ccl22 in KCs of AKT/Ras and c-Myc mice. MicroRNA-15a/16-1 prevented KCs from overproducing CCL22 by inhibiting nuclear factor-κB that activates transcription of Ccl22. By reducing CCL22 binding to C-C chemokine receptor type 4 on Tregs, microRNA-15a/16-1 impaired Treg chemotaxis. Disrupting the interaction between microRNA-15a/16-1 and nuclear factor-κB impaired the ability of microRNA-15a/16-1 to prevent hepatic Treg accumulation and HCC. Depletion of cluster of differentiation 8+ T cells and additional treatment of CCL22 recovered growth of HCC that was fully prevented by microRNA-15a/16. CONCLUSIONS MicroRNA-15a/16-1 attenuates immunosuppression by disrupting CCL22-mediated communication between KCs and Tregs. MicroRNA-15a/16-1 represents a potential immunotherapy against HCC.
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Affiliation(s)
- Ningning Liu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Ching Wen Chang
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Clifford J Steer
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota
| | - Xin Wei Wang
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota.
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Altaf S, Saleem F, Sher AA, Ali A. Potential therapeutic strategies to combat HCC. Curr Mol Pharmacol 2022; 15:929-942. [PMID: 34979895 DOI: 10.2174/1874467215666220103111009] [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: 02/16/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a complex, life threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous and involve various molecular mechanisms and stimulation of several signaling pathways such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, mammalian goal of rapamycin (mTOR), c-mesenchymal-epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patient's multi-kinase cascade blockers such as sorafenib, selumetinib and regorafenib have increased survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitations can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase cure rate of patients. This article reviews the complete consideration of focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.
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Affiliation(s)
- Sidra Altaf
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Faiza Saleem
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Azam Ali Sher
- Department of Epidemiology, Michigan State University, Michigan, USA
| | - Ashiq Ali
- Department of Pathology, University of Agriculture, Faisalabad, Pakistan
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Liu C, Zhu X, Jia Y, Chi F, Qin K, Pei J, Zhang C, Mu X, Zhang H, Dong X, Xu J, Yu B. Dasatinib inhibits proliferation of liver cancer cells, but activation of Akt/mTOR compromises dasatinib as a cancer drug. Acta Biochim Biophys Sin (Shanghai) 2021; 53:823-836. [PMID: 33961012 DOI: 10.1093/abbs/gmab061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Indexed: 12/15/2022] Open
Abstract
Dasatinib is a multi-target protein tyrosine kinase inhibitor. Due to its potent inhibition of Src, Abl, the platelet-derived growth factor receptor (PDGFR) family kinases, and other oncogenic kinases, it has been investigated as a targeted therapy for a broad spectrum of cancer types. However, its efficacy has not been significantly extended beyond leukemia. The mechanism of resistance to dasatinib in a wide array of cancers is not clear. In the present study, we investigated the effect of dasatinib on hepatocellular carcinoma cell growth and explored the underlying mechanisms. Our results showed that dasatinib potently inhibited the proliferation of SNU-449 cells, but not that of other cell lines, such as SK-Hep-1, even though it inhibited the phosphorylation of Src on both negative and positive regulation sites in all these cells. Dasatinib activated the phosphoinositide-dependent protein kinase1 (PDK1)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in SK-Hep-1 cells, but not in SNU-449 cells. Blocking the Akt/mTOR signaling pathway strongly promoted the efficacy of dasatinib in SK-Hep-1 cells. In SNU-449 cells, dasatinib promoted apoptosis and the cleavage of caspase-3 and caspase-7, induced cell cycle arrest in the G1 phase, and inhibited the expression of Cyclin-dependent kinase (CDK4)/6/CyclinD1 complex. These findings demonstrate that dasatinib exerts its anti-proliferative effect on hepatocellular cell proliferation by blocking the Src family kinases; however, it causes Akt activation, which compromises dasatinib as an anti-cancer drug.
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Affiliation(s)
- Chang Liu
- Department of Biochemistry and Molecular Biology, Changzhi Medical College, Changzhi 046000, China
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Xiaoxia Zhu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Yuqi Jia
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Fenqing Chi
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Keru Qin
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Jinhong Pei
- Department of Biochemistry and Molecular Biology, Changzhi Medical College, Changzhi 046000, China
| | - Chan Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Xiuli Mu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Hongwei Zhang
- Department of Hematology, Affiliated Tumor Hospital of Shanxi Medical University, Taiyuan 030013, China
| | - Xiushan Dong
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan 030032, China
| | - Jun Xu
- Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Baofeng Yu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
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Ji Z, Li J, Wang J. Up-regulated RFC2 predicts unfavorable progression in hepatocellular carcinoma. Hereditas 2021; 158:17. [PMID: 34022962 PMCID: PMC8141224 DOI: 10.1186/s41065-021-00179-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Replication factor C (RFC) is closely related to tumor progression and metastasis. However, the functional significance of RFC2 in hepatocellular carcinoma remains unclear. MATERIALS AND METHODS In order to solve this problem, the expression of RFC2 in liver cancer patients was analyzed through ONCOMINE, UALCAN, Human Protein Atlas. Survival analysis was conducted using Kaplan-Meier plotter and GEPIA. GO and KEGG enrichment analyses were carried out. The protein-protein interaction (PPI) network was performed through Metascape. Western blotting, cell counting kit-8 and transwell assay were used to detect the effect of RFC2 on cell proliferation and migration. RESULTS The transcription and protein level of RFC2 in HCC were overexpressed, which was significantly related to the clinical individual cancer stage and pathological tumor grade of HCC patients. In addition, in patients with liver cancer, higher RFC2 expression was found to be significantly correlated with shorter OS and DFS. Furthermore, the function of RFC2 in liver cancer was DNA replication, and its main mechanism was the phase transition of the cell cycle. Biological experiments demonstrated that knockdown of RFC2 reduced the proliferation and migration of HCC cells. CONCLUSION RFC2 might promote the development of liver cancer, which might be achieved by regulating cell cycle and DNA replication. It could be used as a novel biomarker for the prognosis of liver cancer.
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Affiliation(s)
- Zaixiong Ji
- Department of Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, 200233, China
| | - Jiaqi Li
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jianbo Wang
- Department of Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, 200233, China.
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Zhang B, Li F, Zhu Z, Ding A, Luo J. CircRNA CDR1as/miR-1287/Raf1 Axis Modulates Hepatocellular Carcinoma Progression Through MEK/ERK Pathway. Cancer Manag Res 2020; 12:8951-8964. [PMID: 33061591 PMCID: PMC7522432 DOI: 10.2147/cmar.s252679] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 08/18/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a common lethal malignant tumor worldwide. Circular RNAs (circRNAs) have been reported to affect the development of human cancers, including HCC. In this project, we aim to clarify the functional effect of circular CDR1as (circ_CDR1as) on HCC progression. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot is implemented to detect the expression of circ_CDR1as, microRNA (miR)-1287 and Raf-1 proto-oncogene, serine/threonine kinase (Raf1). Cell proliferation is assessed via colony formation and 3-(4, 5)-dimethylthiazole-2-y1)-2, 5-biphenyl tetrazolium bromide (MTT) assays. Cell migration and invasion are measured by Transwell assay. The target relationship between miR-1287 and circ_CDR1as or Raf1 is validated through dual-luciferase reporter assay. The levels of epithelia–mesenchymal transition (EMT) markers and the MEK/ERK signal pathway-related proteins are examined by Western blot. Model in nude mice is constructed to determine the role of circ_CDR1as in vivo. Results Expression of circ_CDR1as and Raf1 is elevated, while miR-1287 expression is decreased in HCC. Depletion of circ_CDR1as or Raf1 could inhibit proliferation and metastasis of HCC cells. Besides, circ_CDR1as regulates Raf1 expression by targeting miR-1287. MiR-1287 upregulation or Raf1 depletion could partially counterbalance circ_CDR1as depletion-mediated inhibitory effects on HCC cell behaviors. Moreover, circ_CDR1as depletion represses HCC progression through inactivating MEK/ERK pathway. In addition, circ_CDR1as depletion suppresses tumor growth in vivo via regulating miR-1287/Raf1 pathway. Conclusion Circ_CDR1as depletion inhibits HCC cell proliferation and metastasis by miR-1287/Raf1 and MEK/ERK pathways, highlighting a promising molecular target for HCC treatment.
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Affiliation(s)
- Bashan Zhang
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Fei Li
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Zinian Zhu
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Aijiao Ding
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Jintong Luo
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
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Diagnostische und prognostische Bedeutung des α-Feto-Proteins beim hepatozellulären Karzinom. Chirurg 2020; 91:769-777. [DOI: 10.1007/s00104-020-01118-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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21
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Chen X, Hu X, Hu J, Qiu Z, Yuan M, Zheng G. Celastrol-Loaded Galactosylated Liposomes Effectively Inhibit AKT/c-Met-Triggered Rapid Hepatocarcinogenesis in Mice. Mol Pharm 2020; 17:738-747. [PMID: 31904241 DOI: 10.1021/acs.molpharmaceut.9b00428] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Our previous study proved that celastrol was a potential candidate for hepatocellular carcinoma (HCC) therapy. However, poor water solubility and toxic side effects may restrict its clinical application. To overcome these shortcomings and optimize its antitumor efficacy, we developed galactosylated liposomes using galactose-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) to deliver celastrol (C-GPL). C-GPL improved the water solubility of celastrol and exhibited high encapsulation efficiency, good stability in serum, and slow drug release profile. In vitro studies showed that C-GPL increased the cellular uptake of celastrol through receptor-mediated endocytosis, thereby enhancing celastrol cytotoxicity and cancer cell apoptosis. Particularly, in vivo antitumor activity of C-GPL was assessed in rapid HCC mouse models established via hydrodynamic transfection of the activated forms of AKT and c-Met. Compared to free celastrol, C-GPL significantly prevented liver weight gain, decreased liver damage biomarkers (glutamic-oxalacetic transaminase and alanine aminotransferase) and HCC marker (alpha-fetoprotein), and led to tumor disappearance on the liver surface. The improved therapeutic effect of C-GPL may be attributed to suppression of AKT activation, induction of apoptosis, and retardation of cell proliferation. Importantly, C-GPL exerted low toxicity to normal tissues without causing severe weight loss in mice. Taken together, C-GPL may become a promising drug delivery system for HCC treatment.
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Affiliation(s)
- Xinyan Chen
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Xianxian Hu
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Junjie Hu
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Zhenpeng Qiu
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Ming Yuan
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Guohua Zheng
- Key Laboratory of Chinese Medicine Resource and Compound Prescription, Ministry of Education, Hubei University of Chinese Medicine, Wuhan 430065, China
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Lorente L, Rodriguez ST, Sanz P, González-Rivero AF, Pérez-Cejas A, Padilla J, Díaz D, González A, Martín MM, Jiménez A, Cerro P, Portero J, Barrera MA. High serum caspase-3 levels in hepatocellular carcinoma prior to liver transplantation and high mortality risk during the first year after liver transplantation. Expert Rev Mol Diagn 2019; 19:635-640. [PMID: 31084510 DOI: 10.1080/14737159.2019.1619549] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background: Higher liver caspase-3 activity has been found in patients with different liver diseases. However, there is no published data about circulating caspase-3 levels in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). Therefore, our objective in this study was to determine whether an association between circulating caspase-3 levels in HCC patients prior to LT and one-year mortality after LT exists. Methods: In this observational and retrospective study, we included HCC patients who underwent LT. We measured serum levels of caspase-3 (as the main executor of apoptosis) and caspase-cleaved cytokeratin (CCCK)-18 (to estimate apoptosis degree) before LT. Results: One-year surviving LT patients (n = 129) showed lower serum levels of caspase-3 (p = 0.004) and CCCK-18 (p = 0.001) than non-surviving LT patients (n = 16). Logistic regression analysis showed that serum caspase-3 levels prior to LT were associated with one-year after LT mortality (Odds Ratio = 2.612; 95% CI = 1.519-4.493; p = 0.001). We found a positive association between serum levels of caspase-3 and CCCK-18 (rho = 0.26; p = 0.002). Conclusions: Our study is the first one reporting data of circulating caspase-3 levels prior to LT for HCC, and an association between high serum caspase-3 levels previously to LT and survival at first year after LT.
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Affiliation(s)
- Leonardo Lorente
- a Intensive Care Unit , Hospital Universitario de Canarias , Santa Cruz de Tenerife , Spain
| | - Sergio T Rodriguez
- b Intensive Care Unit , Hospital Universitario Nuestra Señora Candelaria , Santa Cruz Tenerife , Spain
| | - Pablo Sanz
- c Deparment of Surgery , Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz Tenerife , Spain
| | | | - Antonia Pérez-Cejas
- d Laboratory Deparment , Hospital Universitario de Canarias , Santa Cruz de Tenerife , Spain
| | - Javier Padilla
- c Deparment of Surgery , Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz Tenerife , Spain
| | - Dácil Díaz
- e Deparment of Digestive , Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz Tenerife , Spain
| | - Antonio González
- e Deparment of Digestive , Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz Tenerife , Spain
| | - María M Martín
- b Intensive Care Unit , Hospital Universitario Nuestra Señora Candelaria , Santa Cruz Tenerife , Spain
| | - Alejandro Jiménez
- f Research Unit , Hospital Universitario de Canarias , Santa Cruz de Tenerife , Spain
| | - Purificación Cerro
- g Transplant Unit , Hospital Universitario Nuestra Señora Candelaria , Santa Cruz Tenerife , Spain
| | - Julián Portero
- h Department of Radiology , Hospital Universitario Nuestra Señora Candelaria , Santa Cruz Tenerife , Spain
| | - Manuel A Barrera
- c Deparment of Surgery , Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz Tenerife , Spain
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23
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Low Serum Melatonin Levels Prior to Liver Transplantation in Patients with Hepatocellular Carcinoma are Associated with Lower Survival after Liver Transplantation. Int J Mol Sci 2019; 20:ijms20071696. [PMID: 30959735 PMCID: PMC6480689 DOI: 10.3390/ijms20071696] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023] Open
Abstract
Melatonin administration has been associated with different benefits in animals and patients suffering from liver diseases. However, there is no published data about circulating melatonin levels in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). Thus, the objective of this observational and retrospective study was to determine whether patients with HCC with lower serum melatonin levels prior to LT have a higher risk of one-year mortality after LT. We measured serum levels of melatonin, malondialdehyde (to assess lipid peroxidation), and total antioxidant capacity (to assess antioxidant state) before LT. One-year surviving LT patients (n = 129) showed higher serum levels of melatonin (p = 0.001) and total antioxidant capacity (p = 0.001) and lower serum levels of malondialheyde (p = 0.01) than non-surviving LT patients (n = 16). Logistic regression analysis showed that high serum melatonin levels prior to LT were associated with lower one-year LT mortality (odds ratio = 0.525; 95% confidence interval (CI) = 0.331–0.834; p = 0.006). We found an association between serum levels of melatonin with serum levels of malondialheyde (rho = −0.22; p = 0.01) and total antioxidant capacity (rho = 0.21; p = 0.01). Thus, the novel findings of our study were the association between high serum melatonin levels prior to LT and survival at first year after LT and the association between serum levels of melatonin with malondialheyde and total antioxidant capacity.
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24
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Cheng Q, Tong TJ, Li Z, Hu SH, Chen DB, Wang SQ, Zhu JY. Paradoxical effects of cellular senescence-inhibited gene involved in hepatocellular carcinoma migration and proliferation by ERK pathway and mesenchymal-like markers. Onco Targets Ther 2019; 12:2035-2046. [PMID: 30936720 PMCID: PMC6421901 DOI: 10.2147/ott.s188449] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cellular senescence-inhibited gene (CSIG) strongly prolongs the progression of replicative senescence. However, roles and mechanisms of CSIG in tumor progression have not been studied widely. METHODS Roles of CSIG in migration and proliferation of SMMC7721 and Huh7 cells were analyzed by transwell or cell viability assays, respectively. Tumorigenicity assays were used to study whether CSIG knockdown could affect SMMC7721 proliferation in vivo. Next, Western blotting and RT-PCR were preformed to evaluate the effects of CSIG on P-ERK cascade and epithelial mesenchymal transformation markers. Then, the location and expression of CSIG protein was detected by immunofluorescence and Western blotting, respectively. Finally, the Cancer Genome Atlas dataset was used to analyze CSIG mRNA levels in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues. RESULTS In this study, we found that CSIG overexpression promoted SMMC7721 cell migration, and CSIG knockdown suppressed tumorigenicity of SMMC7721 cells. In contrast to expectation, CSIG up-regulation could significantly inhibit Huh7 cell growth and migration. CSIG could promote P-ERK activation and levels of mesenchymal-like markers in SMMC7721 cells, whereas CSIG suppressed P-ERK activation and levels of mesenchymal-like markers in Huh7 cells. CSIG protein was located in nucleoli as well as nucleoplasm of SMMC7721 cells, whereas CSIG protein was mainly expressed in the nucleoli rather than nucleoplasm of Huh7 cells. Finally, due to individual differences, raised or down-regulated trends of CSIG in HCC as compared with adjacent non-tumor tissues are different among various patient populations. CONCLUSION In summary, these results indicate that CSIG might play different roles in SMMC7721 and Huh7 cells through regulating P-ERK pathway and mesenchymal-like markers. The differential distribution of CSIG might be an important factor that causes its different functions in SMMC7721 and Huh7 cells. CSIG might play different roles in various patient populations.
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Affiliation(s)
- Qian Cheng
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
| | - Tan-Jun Tong
- Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China
| | - Zhao Li
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
| | - Shi-Hua Hu
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
| | - Ding-Bao Chen
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
| | - Si-Qi Wang
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
| | - Ji-Ye Zhu
- Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China,
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25
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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26
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Umeh-Garcia M, Sweeney C. Cancer prevention through miRNAs: miR-206 prevents the initiation and progression of hepatocellular carcinoma by attenuating c-MET signaling and cell-cycle progression via cyclin D1 and CDK6. ACTA ACUST UNITED AC 2018; 2. [PMID: 31930188 DOI: 10.21037/ncri.2018.06.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Maxine Umeh-Garcia
- Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA
| | - Colleen Sweeney
- Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA
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Xing T, Yan T, Zhou Q. Identification of key candidate genes and pathways in hepatocellular carcinoma by integrated bioinformatical analysis. Exp Ther Med 2018; 15:4932-4942. [PMID: 29805517 PMCID: PMC5958738 DOI: 10.3892/etm.2018.6075] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 03/13/2018] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms worldwide, however the underlying mechanisms and gene signatures of HCC are unknown. In the present study the profile datasets of four cohorts were integrated to elucidate the pathways and candidate genes of HCC. The expression profiles GSE25097, GSE45267, GSE57957 and GSE62232 were downloaded from the Gene Expression Omnibus database, including 436 HCC and 94 normal liver tissues. A total of 185 differentially expressed genes (DEGs) were identified in HCC, including 92 upregulated genes and 92 downregulated genes. Gene ontology (GO) was performed, which revealed that the upregulated DEGs were primarily enriched in cell division, mitotic nuclear division, mitotic cytokinesis and G1/S transition of the mitotic cell cycle. Pathway enrichment was analyzed based on the Kyoto Encyclopedia of Genes and Genomes database to assess the functional relevance of DEGs. The most significant module was selected from protein-protein interactions and 15 important hub genes were identified. The sub-networks of hub genes were involved in cell division, p53 signaling, and T lymphotropic virus type I infection signaling pathways. In conclusion, the present study revealed that the identified DEG candidate genes may promote the understanding of the cause and molecular mechanisms underlying the development of HCC and that these candidates and signal pathways may be potential targets of clinical therapy for HCC.
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Affiliation(s)
- Tonghai Xing
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Tingmang Yan
- Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Qiang Zhou
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
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28
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Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma. Biochem Biophys Res Commun 2018; 497:1117-1122. [PMID: 29496454 DOI: 10.1016/j.bbrc.2018.02.189] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 02/25/2018] [Indexed: 12/16/2022]
Abstract
Precise and early diagnosis is critical to improve the survival rate of hepatocellular carcinoma (HCC) patients. Although several genetic and protein markers have been developed and are currently used for diagnosis, prognosis, risk stratification, and therapeutic monitoring, application of these markers still needs to be improved for better specificity and efficacy. In this study, we investigated the relative expression of mitochondrial dynamics-regulating factors including T-cell intercellular antigen protein-1 (TIA-1), mitochondrial fission factor (MFF), microRNA (miR)-200a-3p, and miR-27a/b in the liver tissues from HCC patients. The expressions of TIA-1 and MFF were augmented in the cancerous liver tissues compared to the corresponding non-tumor tissues at mRNA and protein level, while the levels of miR-200a-3p and miR-27a/b were relatively lower in the cancerous liver tissues. In addition, high levels of TIA-1 and MFF mRNA were related to the poor survival rate of HCC patients. Our results indicated that the expressions of TIA-1, MFF, miR-200a-3p, and miR-27a/b in the cancerous liver tissues differed to these in non-cancerous tissues of HCC patients, demonstrating that these gene expressions could be potential markers for the diagnosis and prognosis of HCC.
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29
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Wu H, Tao J, Li X, Zhang T, Zhao L, Wang Y, Zhang L, Xiong J, Zeng Z, Zhan N, Steer CJ, Che L, Dong M, Wang X, Niu J, Li Z, Yan G, Chen X, Song G. MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto-oncogene and cyclin-dependent kinase 6 in mice. Hepatology 2017; 66:1952-1967. [PMID: 28714063 PMCID: PMC5696004 DOI: 10.1002/hep.29374] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 05/15/2017] [Accepted: 07/05/2017] [Indexed: 12/22/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. CONCLUSION In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952-1967).
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Affiliation(s)
- Heng Wu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
| | - Junyan Tao
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA,School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei Province 430060, China
| | - Xiaolei Li
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA
| | - Tianpeng Zhang
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
| | - Lei Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China
| | - Yao Wang
- School of First Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei Province 430060, China
| | - Lei Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China
| | - Jun Xiong
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China
| | - Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China
| | - Na Zhan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China
| | - Clifford J. Steer
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA,Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA
| | - Mingjie Dong
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA
| | - Xiaomei Wang
- Institute for Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin Province 130021, China
| | - Junqi Niu
- Institute for Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin Province 130021, China
| | - Zhuoyu Li
- Institute of Biotechnology, Shanxi University, Taiyuan, Shanxi Province 030006, China
| | - Guiqing Yan
- Colleges of Life Science, Shanxi Normal University, 1 Gongyuan Street, Linfen City, Shanxi Province 041004, China
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA,To whom correspondence should be addressed: Guisheng Song, Ph.D., Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, 406 Harvard Street SE, MMC36, Minneapolis MN 55455, ; Xin Chen, Ph.D., Departments of Bioengineering and Therapeutic Sciences, University of California San Francisco, 513 Parnassus Avenue, S816, San Francisco CA 94143:
| | - Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA,Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA,Colleges of Life Science, Shanxi Normal University, 1 Gongyuan Street, Linfen City, Shanxi Province 041004, China,To whom correspondence should be addressed: Guisheng Song, Ph.D., Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, 406 Harvard Street SE, MMC36, Minneapolis MN 55455, ; Xin Chen, Ph.D., Departments of Bioengineering and Therapeutic Sciences, University of California San Francisco, 513 Parnassus Avenue, S816, San Francisco CA 94143:
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30
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Gong Y, Zhang J, Wu X, Wang T, Zhao J, Yao Z, Zhang Q, Liu X, Jian X. Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy. Oncol Lett 2017; 14:4158-4166. [PMID: 28943923 PMCID: PMC5592876 DOI: 10.3892/ol.2017.6724] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 05/16/2017] [Indexed: 12/13/2022] Open
Abstract
Proton-coupled oligopeptide transporter 1 (PEPT1) is a membrane protein which expressed predominantly in intestine and recognized as the target of dietary nutrients (di/tripeptide) or peptidomimetic drug for delivery. The information on the existence of PEPT1 in carcinomas were limited. Our study aimed to investigate the expression profile and transport activity of PEPT1 both in human hepatocarcinoma tissues and cell lines. Western blotting and an immunofluorescence assay revealed the high level of PEPT1 protein expression in hepatocarcinoma Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cell lines. Quantitative real time PCR showed the mRNA expression of PEPT1 in Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cells. High level PEPT1 expression in hepatocarcinoma patient samples were observed by Immunohistology and showed a significant correlation between protein level and pathological grade. Functional activities were also studied using D-Ala-Lys-AMCA (a substrate of peptide transporter) in above five hepatocarcinoma cell lines. The uptake tests performed by fluorescent microscopy suggested that PEPT1 can transport both D-Ala-Lys-AMCA into the hepatocarcinoma cells and the uptake can be competitively inhibited by three PEPT1 substrates (Gly-sar, Gly-gln and Glyglygly). In conclusion, our findings provided the novel information on the expression and function of PEPT1 in human hepatocarcinoma and expanded the potential values for tumor specific drug delivery.
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Affiliation(s)
- Yanxia Gong
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.,Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, P.R. China
| | - Jie Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xiang Wu
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Tao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jia Zhao
- Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhi Yao
- Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Qingyu Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xu Jian
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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31
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Giorgio A, Merola MG, Montesarchio L, Merola F, Gatti P, Coppola C, Giorgio V, Calisti G. Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years. Br J Radiol 2017; 90:20160804. [PMID: 28402124 PMCID: PMC5602175 DOI: 10.1259/bjr.20160804] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 04/02/2017] [Accepted: 04/11/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To report on our 20 years' experience on complications after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) in patients with cirrhosis. METHODS From 1994 to 2014, 1787 RFA procedures were performed percutaneously in 1162 patients with cirrhosis (852 Child A and 310 Child B) with HCC nodules (1.2-7 cm), prothrombin time >50%, platelet count of 50.000 mm3 and total bilirubin ranging from 0.80 to 4.5 mg dl-1. In 67 patients, RFA was performed on both intraparenchymal HCC nodule and tumour thrombus extended in the main portal vein and/or its branches. RESULTS Four patients (0.3%) died after RFA. 39 patients (3.2%) changed in Child's class: 26 out of 28 Child A patients with cirrhosis changed to Child B and 2 changed to Child C class; 11 Child B patients changed to Child C class. On multivariate analysis, the total bilirubin pre-RFA was the only independent risk factor for impairment of liver function and death. Complications were hemoperitoneum, abscess and intrahepatic haematoma. CONCLUSION RFA of HCC in patients with cirrhosis is safe, even in case of invasion of the portal venous system. Functional liver reserve should be strictly monitored, mainly when pre-RFA total bilirubin value is >2.5 mg dl-1. The study was approved by our institutional review board. Advances in knowledge: The total bilirubin value >2.5 mg dl-1 represents the main marker of functional liver reserve that predicts decompensation of liver cirrhosis in patients undergoing RFA for HCC.
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Affiliation(s)
- Antonio Giorgio
- Interventional Ultrasound Unit, D Cotugno Hospital, Naples, Italy
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Maria G Merola
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Luca Montesarchio
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Francesca Merola
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Pietro Gatti
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Carmine Coppola
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Valentina Giorgio
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
| | - Giorgio Calisti
- Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno, Italy
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32
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Kudou M, Shiozaki A, Kosuga T, Shimizu H, Ichikawa D, Konishi H, Morimura R, Komatsu S, Ikoma H, Fujiwara H, Okamoto K, Marunaka Y, Otsuji E. Heat shock exerts anticancer effects on liver cancer via autophagic degradation of aquaporin 5. Int J Oncol 2017; 50:1857-1867. [PMID: 28358429 DOI: 10.3892/ijo.2017.3940] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 03/22/2017] [Indexed: 11/06/2022] Open
Abstract
Previous studies described that the expression of aquaporin 5 (AQP5) was altered in tumors of various organs. AQP5 is attracting attention as a new cancer therapeutic target. In the present study, heat shock-induced changes in AQP5 expression were evaluated by immunofluorescent staining (IF) and western blotting (WB) of liver cancer cells. AQP5 knockdown experiments or a heat shock treatment were conducted, and their effects on cell volume, proliferation, cell cycle, the activity of apoptosis and migration/invasion were compared. Cycloheximide (CHX) chase experiments and double IF of AQP5 and light chain 3B (LC3B) were performed to investigate the mechanisms underlying changes in AQP5 expression. The results showed that IF and WB revealed decrease in AQP5 expression on cellular membranes and in the cytoplasm of heated cells. AQP5 knockdown and heat shock similarly decreased cell volume, suppressed migration/invasion and proliferation, and induced early apoptosis and partial G0/G1 arrest. CHX chase experiments revealed that heat shock accelerated the degradation of AQP5, which was rescued under CHX and the autophagy inhibitor, bafilomycin A1 (BafA1). Double IF showed the co-localization of AQP5 and LC3B on BafA1-treated heated cells. In conclusion, we demonstrated that heat shock decreased AQP5 on cellular membranes and in the cytoplasm by activating autophagic degradation, and heat shock and AQP5 knockdown exerted similar anticancer effects, suggesting that heat shock exerts anticancer effects via the autophagic degradation of AQP5.
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Affiliation(s)
- Michihiro Kudou
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yoshinori Marunaka
- Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Lai XB, Nie YQ, Huang HL, Li YF, Cao CY, Yang H, Shen B, Feng ZQ. NIMA-related kinase 2 regulates hepatocellular carcinoma cell growth and proliferation. Oncol Lett 2017; 13:1587-1594. [PMID: 28454295 PMCID: PMC5403431 DOI: 10.3892/ol.2017.5618] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 10/27/2016] [Indexed: 12/29/2022] Open
Abstract
NIMA-related kinase 2 (Nek2) is often upregulated in human cancer and is important in regulating the cell cycle and gene expression, and maintaining centrosomal structure and function. The present study aimed to investigate the expression pattern, clinical significance, and biological function of Nek2 in hepatocellular carcinoma (HCC). mRNA and protein levels of Nek2 were examined in HCC and corresponding normal liver tissues. The MTT and soft agar colony formation assays, and flow cytometry were employed to assess the roles of Nek2 in cell proliferation and growth. In addition, western blot analysis was performed to assess the expression of cell cycle- and proliferation-related proteins. The results revealed that Nek2 was upregulated in HCC tissues and cell lines. The clinical significance of Nek2 expression was also analyzed. Inhibiting Nek2 expression by siRNA suppressed cell proliferation, growth, and colony formation in hepatocellular carcinoma cell line HepG2 cells, induced cell cycle arrest in the G2/M phase by retarding the S-phase, and promoted apoptosis. Furthermore, Nek2 depletion downregulated β-catenin expression in HepG2 cells and diminished expression of Myc proto-oncogene protein (c-Myc), cyclins D1, B1, and E and cyclin-dependent kinase 1, whilst increasing protein levels of p27. This demonstrates that overexpression of Nek2 is associated with the malignant evolution of HCC. Targeting Nek2 may inhibit HCC cell growth and proliferation through the regulation of β-catenin by the Wnt/β-catenin pathway and therefore may be developed as a novel therapeutic strategy to treat HCC.
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Affiliation(s)
- Xiao-Bo Lai
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Yu-Qiang Nie
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Hong-Li Huang
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Ying-Fei Li
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Chuang-Yu Cao
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Hui Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Bo Shen
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
| | - Zhi-Qiang Feng
- Department of Gastroenterology and Hepatology, The First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China
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Bauschke A, Altendorf-Hofmann A, Malessa C, Schüle S, Zanow J, Settmacher U. Which factors affect the long-term survival of patients with hepatocellular carcinoma UICC stage IV? J Cancer Res Clin Oncol 2016; 142:2593-2601. [PMID: 27630023 DOI: 10.1007/s00432-016-2260-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/06/2016] [Indexed: 12/14/2022]
Abstract
AIM In the 7th edition of the TNM classification, not only HCC with distant metastases but also those with regional lymph node metastases are classified as stage IV. MATERIALS AND METHODS, RESULTS From our prospectively recorded tumor registry, 138 patients (17 %) with HCC were in stage IV. Among those were 68 and 70, respectively, in stage IVA (regional lymph node metastases) and IVB (distant metastases). The tumors were less frequently treated with resection or local ablative treatment (chemoembolization, RFA, SIRT, percutaneous radiation) than patients in stage I-III. Ten HCCs were resected. Five of the resected patients were in stage IVA and five in stage IVB. After tumor resection, patients lived longer than those who underwent local or systemic treatment only (p = 0.003 or p = 0.001, respectively). In the univariate survival analysis, the stage IV patients' long-term survival was decreased statistically significantly through elevated bilirubin, low albumin, Okuda stage III and BCLC stage D. Patients' age and sex, pre-treatment AFP level, Child stage and the presence of venous invasion did not influence survival. In the multivariate analysis (Cox regression), tumor resection and BCLC stage were independent prognostic factors. CONCLUSION Patients with HCC in TNM stage IV have a very poor prognosis. Only few patients are eligible for resection because of the extent of tumor growth, comorbidities and general condition. These, however, benefit markedly from tumor resection with lymph node dissection and possibly resection of distant metastases.
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Affiliation(s)
- A Bauschke
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany.
| | - A Altendorf-Hofmann
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - C Malessa
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - S Schüle
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - J Zanow
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - U Settmacher
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
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Xi S, Peng Y, Minuk GY, Shi M, Fu B, Yang J, Li Q, Gong Y, Yue L, Li L, Guo J, Peng Y, Wang Y. The combination effects of Shen-Ling-Bai-Zhu on promoting apoptosis of transplanted H22 hepatocellular carcinoma in mice receiving chemotherapy. JOURNAL OF ETHNOPHARMACOLOGY 2016; 190:1-12. [PMID: 27235019 DOI: 10.1016/j.jep.2016.05.055] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 05/22/2016] [Accepted: 05/23/2016] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shen-Ling-Bai-Zhu Powder (SLBZP) is a classic traditional Chinese medical formula that has been used for several decades in the treatment of patients with gastrointestinal malignancies. Whether SLBZP is best employed as single agent or adjunctive therapy has yet to be determined as does the mechanism whereby SLBZP exerts its anti-tumor effects. AIM OF THE STUDY To investigate the effects of SLBZP alone and in combination with Cytoxan (CTX) on tumor growth, malignant cell apoptosis and Akt/Nuclear Factor kappa B (NF-КB) signaling in a murine model of hepatocellular carcinoma (HCC) receiving chemotherapy. MATERIALS AND METHODS Sixty-four adult mice developed HCC following subcutaneous inoculation with H22 hepatocellular carcinoma cells. Seven days later, all received chemotherapy with CTX (200mg/kg) once. Mice were then randomized into eight study groups (N=8/group). Three groups were treated with different concentrations of SLBZP alone (6.00, 3.00, 1.5g/kg), three with SLBZP (6.00, 3.00, 1.5g/kg) plus CTX (20mg/kg), one with CTX (20mg/kg) alone (positive control), and one with physiologic saline (untreated, negative control). All groups were treated for 14 days. Tumor size, histology and serum or tissue levels and/or mRNA expression of PDGF-BB, VEGF, Ang-1, Ang-2, NF-КB, B-cell lymphoma-2 (Bcl-2); B-cell lymphoma-extra large (Bcl-xL); X-linked inhibitor of apoptosis (XIAP), Survivin, Caspase-3, Caspase-9, Caspase-7, Akt and phosphorylated Akt expression were documented at the end of treatment. RESULTS Compared to untreated negative controls, tumor sizes were decreased in the CTX alone, SLBZP (M)+CTX and SLBZP (H)+CTX groups (-52%,-53% and -58% respectively). Tumor cell density was decreased in all treated groups but most apparent in the SLBZP (H)+CTX group. Electron microscopic evidence of apoptosis was also most apparent in this group. Serum and/or tissue levels and expression of PDGF-BB, VEGF, Ang-1, Ang-2, their downstream signaling proteins and anti-apoptotic markers were lowest and pro-apoptotic markers highest in SLBZP (H)+CTX treated mice. CONCLUSIONS In this chemotherapy-induced animal model of HCC, SLBZP was most efficacious as adjunctive therapy and appears to act by inhibiting tumor growth promoters and anti-apoptotic proteins while enhancing pro-apoptotic proteins.
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MESH Headings
- Angiogenic Proteins/genetics
- Angiogenic Proteins/metabolism
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Apoptosis/drug effects
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/ultrastructure
- Cell Line, Tumor
- Cisplatin/pharmacology
- Dose-Response Relationship, Drug
- Drugs, Chinese Herbal/pharmacology
- Female
- Gene Expression Regulation, Neoplastic
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/ultrastructure
- Male
- Mice
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Signal Transduction/drug effects
- Time Factors
- Tumor Burden/drug effects
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Affiliation(s)
- Shengyan Xi
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China; Cancer Research Center of Xiamen University, Xiamen 361102, People's Republic of China.
| | - Ying Peng
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
| | - Gerald Y Minuk
- Department of Internal Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg R3E 3P4, Manitoba, Canada
| | - Mengmeng Shi
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
| | - Biqian Fu
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
| | - Jiaqi Yang
- College of Pharmacy, University of Manitoba, Winnipeg R3E 0T5, Manitoba, Canada
| | - Qian Li
- Department of Internal Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg R3E 3P4, Manitoba, Canada
| | - Yuewen Gong
- College of Pharmacy, University of Manitoba, Winnipeg R3E 0T5, Manitoba, Canada
| | - Lifeng Yue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, People's Republic of China
| | - Lili Li
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
| | - Jinhua Guo
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
| | - Yang Peng
- College of Pharmacy, University of Manitoba, Winnipeg R3E 0T5, Manitoba, Canada
| | - Yanhui Wang
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China
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Wang W, Liu WB, Huang DB, Jia W, Ji CS, Hu B. Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma. Am J Cancer Res 2016; 6:1681-1694. [PMID: 27648358 PMCID: PMC5004072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 06/01/2016] [Indexed: 06/06/2023] Open
Abstract
Drug resistance is one of the main hurdles for the successful treatment of hepatic carcinoma. However, the detailed mechanisms underlying resistance remain largely unknown and therapeutic approaches are limited. In the present study, we show that miR-122 confers resistance to 5-fluorouracil induced hepatocellular carcinoma cell apoptosis in vitro and reduces the potency of 5-fluorouracil in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-122 modulates drug resistance through down-regulation of expression of PCDH20, which belongs to the protocadherin gene family and negatively regulates Akt activation. Knockdown of PCDH20 expression increases Akt phosphorylation, which leads to elevated mTOR activity and enhanced 5-fluorouracil resistance; whereas rescue of PCDH20 expression in miR-122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis. Moreover, a specific and potent Akt inhibitor reverses miR-122-conferred 5-fluorouracil resistance. These findings indicate that the miR-122/PCDH20/Akt/mTOR signaling axis has an important role in mediating response to chemotherapy in human hepatocellular carcinoma. A major implication of our study is that inhibition of miR-122 or restoration of PCDH20 expression may have significant therapeutic potential to overcome drug resistance in hepatocellular carcinoma and that the combined use of an Akt inhibitor with 5-fluorouracil may increase efficacy in liver cancer treatment.
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Affiliation(s)
- Wei Wang
- Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
| | - Wen Bin Liu
- Department of Hepatic Surgery, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary SurgeryHefei 230001, PR China
| | - Da Bing Huang
- Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
| | - Wei Jia
- Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
| | - Chu Shu Ji
- Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
| | - Bing Hu
- Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical UniversityHefei 230001, PR China
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37
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Kudou M, Shiozaki A, Kosuga T, Ichikawa D, Konishi H, Morimura R, Komatsu S, Ikoma H, Fujiwara H, Okamoto K, Hosogi S, Nakahari T, Marunaka Y, Otsuji E. Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma. J Cancer 2016; 7:1524-33. [PMID: 27471568 PMCID: PMC4964136 DOI: 10.7150/jca.15181] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 06/04/2016] [Indexed: 12/16/2022] Open
Abstract
Background: Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods: Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results: Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion: The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone.
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Affiliation(s)
- Michihiro Kudou
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Toshiyuki Kosuga
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Ryo Morimura
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Shigekuni Hosogi
- 2. Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Takashi Nakahari
- 2. Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yoshinori Marunaka
- 2. Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan;; 3. Japan Institute for Food Education and Health, Heian Jogakuin (St. Agnes') University, Kyoto, 602-8013, Japan
| | - Eigo Otsuji
- 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
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38
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Garancini M, Pinotti E, Nespoli S, Romano F, Gianotti L, Giardini V. Hepatic resection beyond barcelona clinic liver cancer indication: When and how. World J Hepatol 2016; 8:513-519. [PMID: 27099652 PMCID: PMC4832093 DOI: 10.4254/wjh.v8.i11.513] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 02/18/2016] [Accepted: 03/24/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the main common primary tumour of the liver and it is usually associated with cirrhosis. The barcelona clinic liver cancer (BCLC) classification has been approved as guidance for HCC treatment algorithms by the European Association for the Study of Liver and the American Association for the Study of Liver Disease. According to this algorithm, hepatic resection should be performed only in patients with small single tumours of 2-3 cm without signs of portal hypertension (PHT) or hyperbilirubinemia. BCLC classification has been criticised and many studies have shown that multiple tumors and large tumors, as wide as those with macrovascular infiltration and PHT, could benefit from liver resection. Consequently, treatment guidelines should be revised and patients with intermediate/advanced stage HCC, when technically resectable, should receive the opportunity to be treated with radical surgical treatment. Nevertheless, the surgical treatment of HCC on cirrhosis is complex: The goal to be oncologically radical has always to be balanced with the necessity to minimize organ damage. The aim of this review was to analyze when and how liver resection could be indicated beyond BCLC indication. In particular, the role of multidisciplinary approach to assure a proper indication, of the intraoperative ultrasound for intra-operative restaging and resection guidance and of laparoscopy to minimize surgical trauma have been enhanced.
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Affiliation(s)
- Mattia Garancini
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Enrico Pinotti
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Stefano Nespoli
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Fabrizio Romano
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Luca Gianotti
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Vittorio Giardini
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
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39
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Association between Pre-Transplant Serum Malondialdehyde Levels and Survival One Year after Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:500. [PMID: 27058525 PMCID: PMC4848956 DOI: 10.3390/ijms17040500] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 12/16/2022] Open
Abstract
Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT) has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02). Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI) = from 1.580 to infinite; p = 0.007) adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT.
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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YAO ZHICHENG, HU KUNPENG, HUANG HE, XU SHILEI, WANG QINGLIANG, ZHANG PENG, YANG PEISHENG, LIU BO. shRNA-mediated silencing of the RFC3 gene suppresses hepatocellular carcinoma cell proliferation. Int J Mol Med 2015; 36:1393-9. [DOI: 10.3892/ijmm.2015.2350] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 09/09/2015] [Indexed: 11/06/2022] Open
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