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Xia L, Yu SX, Bai YS, Liang X, Wu FG, Gao Y, Chen XL, Xiao ZX, Li M. Effect of surgery on overall survival and cancer-specific survival in patients with primary HCC: A study based on PSM in the SEER cohort. Medicine (Baltimore) 2025; 104:e41521. [PMID: 39993067 PMCID: PMC11857015 DOI: 10.1097/md.0000000000041521] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 12/04/2024] [Accepted: 01/24/2025] [Indexed: 02/26/2025] Open
Abstract
This study was designed to assess the effects of surgery method on overall survival (OS) and cancer-specific survival (CSS) in patients with hepatocellular carcinoma (HCC). This is a retrospective study. Patients diagnosed with primary HCC (N = 10,174) were identified from the Surveillance, Epidemiology, and End Results Database from 2010 to 2017 and categorized into surgical (N = 4950) and nonsurgical (N = 5224) groups. The characteristics of patients were balanced by propensity score matching. Multivariate Cox analysis was used to explore independent prognostic factors for outcomes in both groups, and the Kaplan-Meier curve showed survival rates in each group. The surgical patients were subclassified by surgical method, whether local tumor destruction, wedge or segmental resection, lobotomy resection, or liver transplantation (LT). Finally, survival rates in the 2 groups were investigated by subgroup analysis. After propensity score matching, sex, grade, tumor node metastasis III/IV, surgery, chemotherapy, alpha-fetoprotein, number of regional lymph nodes, other race, and age > 70 were independent prognostic factors in the 2 groups. The OS (HR = 0.290, P < .001) and CSS (HR = 0.274, P < .001) rates of patients were higher in the surgical group than in the nonsurgical group. There was no obvious improvement in CSS in patients who received radiotherapy combined with surgery compared with patients who only received radiotherapy (HR = 0.813, P = .279). LT was consistently found to be the best of the 4 surgical methods. The OS of stage II patients undergoing LT was better than that of corresponding stage III patients, and lobectomy resection was the best choice for stage IV patients (HR = 0. 417, P = .023). In grade III patients, the median CSS time was longer than the OS time. The survival rate of patients treated with chemotherapy combined with LT was higher than that of patients who did not receive chemotherapy and only received LT. Patients with HCC who underwent surgery had better OS and CSS. Subgroup analysis showed that LT can improve the survival rate and median survival time of patients.
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Affiliation(s)
- Lin Xia
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shuai-Xin Yu
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yu-Shuai Bai
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao Liang
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fu-Gui Wu
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yang Gao
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiu-Li Chen
- Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China
| | | | - Man Li
- School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, China
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Hwang J, Sim DY, Ahn CH, Park SY, Koo JS, Shim BS, Kim B, Kim SH. Inhibition of LGR5/β-Catenin Axis and Activation of miR134 Are Critically Involved in Apoptotic Effect of Sanggenol L in Hepatocellular Carcinoma. Biol Pharm Bull 2025; 48:126-131. [PMID: 39956588 DOI: 10.1248/bpb.b24-00213] [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] [Indexed: 02/18/2025]
Abstract
Although Sanggenol L (SL), derived from the root bark of Morus alba, has hepatoprotective, neuroprotective, and antitumor effects, the antitumor mechanism of SL remains unclear to date. Thus, in the current work, the apoptotic mechanisms of SL were investigated in HepG2 and Huh hepatocellular carcinoma (HCC) cells in relation to leucine-rich repeat containing G protein-coupled receptor 5 (LGR5)/β-catenin and miR134 signaling axis. Herein, SL significantly incremented cytotoxicity, sub-G1 population, and the number of terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) positive apoptotic bodies and also inhibited proliferation in HCCs. Consistently, SL activated pro-Caspase7 and pro-Caspase3 and induced the cleavage of Poly ADP-ribose polymerase (PARP) in HCCs. Of note, the pivotal role of LGR5/β-catenin signaling was verified in SL-induced apoptosis in LGR5 overexpressed AML-12 cells and LGR5 depleted HepG2 cells. Furthermore, SL upregulated miR134 expression levels in HepG2 cells, while miR134 inhibitors disturbed the capacity of SL to cleave PARP and pro-Caspase3 in HepG2 cells. Taken together, our findings highlight evidence that inhibition of the LGR5/β-catenin axis and upregulation of miR134 play critical roles in SL-induced apoptosis in HCCs.
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Affiliation(s)
- Jisung Hwang
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Deok Yong Sim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Chi-Hoon Ahn
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Su-Yeon Park
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jin-Suk Koo
- Department of Forest Science, Andong National University, Andong, North Gyeongsang 36729, Republic of Korea
| | - Bum-Sang Shim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung-Hoon Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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3
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Qin L, Song CZ, Yuan FY, Wang XF, Yang Y, Ma YF, Chen ZL. ELOVL1 is upregulated and promotes tumor growth in hepatocellular carcinoma through regulating PI3K-AKT-mTOR signaling. Heliyon 2024; 10:e34961. [PMID: 39144963 PMCID: PMC11320299 DOI: 10.1016/j.heliyon.2024.e34961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/16/2024] Open
Abstract
Background The functions of the ELOVLs are mainly involved in the elongation of saturated and polyunsaturated fatty acids, thus influencing the metabolism of fatty acids. Abnormal lipid metabolism may result in NAFLD and NASH, which may lead to cirrhosis and liver cancer. These results suggest that ELOVLs-mediated metabolism might be involved in the development of HCC. The purpose of this study was to study the expression and function of ELOVL1 in human liver cancer. Method Using TCGA, GEPIA and other databases, we analyzed the relationship between the expression of ELOVL1 and liver cancer. The expression of ELOVL1 was detected by immunohistochemical method and Western blot method in hepatic carcinoma and hepatic carcinoma cells. Then, the effects of ELOVL1 on proliferation, apoptosis and invasion in vitro and in vivo were investigated by means of different methods. Result Our results indicate that ELOVL1 is more highly expressed in liver cancer than in normal tissues. Survival analysis showed that OS and DSS were shorter in patients with high ELOVL1 expression than in those with low expression. Multivariate Cox analysis further demonstrated that over-expression of ELOVL1 was an independent risk factor for overall survival in HCC. The results of ROC also confirmed the value of ELOVL1 in the diagnosis of liver cancer. The results of KEGG enrichment and GSEA indicate that ELOVL1 is associated with lipid metabolism and NAFLD, as well as PPAR, PI3K-AKT-mTOR. Compared with the control group, it was found that silencing ELOVL1 in Huh7 and HepG2 cells could inhibit the growth of cells, promote the apoptosis and decrease the metastasis and invasion. Changes in ELOVL1 induced cell proliferation and metastasis may be related to PI3K/AKT/mTOR. Low expression of ELOVL1 inhibited the growth of xenograft tumors in hepatocellular carcinoma xenograft model. Conclusion Our data indicate that the activation of PI3K/AKT/mTOR pathway in HCC may contribute to the promotion of cancer. Thus, ELOVL1 may be a promising therapeutic target for HCC.
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Affiliation(s)
- Liang Qin
- Clinical Medicine School of Surgery, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, 550000, China
| | - Cheng-ze Song
- Clinical Medicine School of Surgery, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, 550000, China
| | - Fa-yang Yuan
- Clinical Medicine School of Surgery, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, 550000, China
| | - Xue-fa Wang
- Clinical Medicine School of Surgery, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, 550000, China
| | - Yang Yang
- Clinical Medicine School of Surgery, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, 550000, China
| | - Yi-fei Ma
- Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Guizhou Medical University, NO.28 Gui Yi Street, Guiyang, 550000, China
| | - Zi-li Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, NO.28 Gui Yi Street, Guiyang, 550000, China
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Liu WF, Jiang QY, Qi ZR, Zhang F, Tang WQ, Wang HQ, Dong L. CD276 Promotes an Inhibitory Tumor Microenvironment in Hepatocellular Carcinoma and is Associated with Poor Prognosis. J Hepatocell Carcinoma 2024; 11:1357-1373. [PMID: 39011124 PMCID: PMC11247130 DOI: 10.2147/jhc.s469529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
Background CD276 is an emerging immune checkpoint molecule that has been implicated in various cancers. However, its specific role in hepatocellular carcinoma (HCC) remains unclear. This study examined the impact of CD276 on patient prognosis and the tumor microenvironment (TME). Methods The Cancer Genome Atlas (TCGA) database was utilized to evaluate CD276 expression in HCC and the association between CD276 and immune indicators was also analyzed. The signaling pathways correlated with CD276 expression were identified by gene set enrichment analysis (GSEA). Different algorithms were used to assess immune cell infiltration. The effect of CD276 knockdown on HCC cell phenotypes and its relationship with macrophage polarization was examined using the cell counting kit 8 (CCK-8) assay and co-culture system. Results CD276 was upregulated in HCC and associated with unfavorable clinical outcomes. Hgh CD276 expression was associated with enrichment of the G2/M checkpoint, E2F targets, and mitotic spindles. CD276 expression was correlated with the infiltration of immune cells, including high level of tumor-associated macrophages and low levels of CD8+ T cells. Knockdown of CD276 decreased HCC cell proliferation and increased apoptosis. CD276 silencing in HCC cells and co-culture with THP-1-derived macrophages had a regulatory effect on macrophage polarization and macrophage-mediated cell proliferation and migration. Conclusion CD276 expression in HCC is associated with unfavorable clinical outcomes and may contribute to the development of an immunosuppressive microenvironment. Specifically, CD276 was associated with alterations in immune cell infiltration, immune marker expression, and macrophage polarization during HCC progression, suggesting its potential as a prognostic indicator and promising target for immunotherapeutic intervention in HCC.
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Affiliation(s)
- Wen-Feng Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qiu-Yu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhuo-Ran Qi
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Feng Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wen-Qing Tang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hao-Qi Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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Wang T, Tang F, Li F, Yin W, Liang J. Retreatment with immunotherapy in a patient with hepatocellular carcinoma who received immune checkpoint inhibitors after primary curative treatment: a case report. Front Oncol 2024; 14:1321195. [PMID: 38646435 PMCID: PMC11026608 DOI: 10.3389/fonc.2024.1321195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a malignant pathology known for its high early recurrence rate following curative treatment, significantly impacting patient prognosis. Currently, effective strategies to mitigate early HCC recurrence remain undetermined. In this report, we document a case of HCC managed with curative radiofrequency ablation (RFA), particularly in a patient facing a high risk of early recurrence due to a substantial tumor size. In an effort to forestall recurrence, immune checkpoint inhibitors (ICIs) were preemptively administered for 6 months post-RFA. Despite this, early recurrence ensued upon ICIs cessation. Traditionally, the approach to advanced HCC has been conservative, yet recent years have seen promising outcomes with ICIs in advanced HCC. However, research on ICIs retreatment is limited. In the short term, this patient experienced widespread metastases post-ICIs discontinuation, yet exhibited prompt regression upon ICIs reinitiation. Notably, this represents the initial documented instance of employing ICIs to forestall recurrence subsequent to curative RFA in HCC. Following ICIs discontinuation, diffuse recurrence with multiple metastases emerged, with successful resolution upon ICIs retreatment.
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Affiliation(s)
| | | | | | | | - Jing Liang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
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6
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Jeon Y, Kim T, Kwon H, Kim JK, Park YT, Ham J, Kim YJ. Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3987. [PMID: 37568803 PMCID: PMC10417827 DOI: 10.3390/cancers15153987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research on combination therapy using cabozantinib to improve efficacy and safety when treating patients. Here, we investigated the effect of a combination treatment of cabozantinib and CBD on HCC cells. CBD treatment enhanced the sensitivity of HCC cells to cabozantinib-mediated anti-cancer activity by increasing cytotoxicity and apoptosis. Phospho-kinase array analysis demonstrated that the apoptotic effect of the combination treatment was mainly related to p53 phosphorylation regulated by endoplasmic reticulum (ER) stress when compared to other kinases. The inhibition of p53 expression and ER stress suppressed the apoptotic effect of the combination treatment, revealing no changes in the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, or cleaved caspase-9. Notably, the effect of the combination treatment was not associated with cannabinoid receptor 1 (CNR1) and the CNR2 signaling pathways. Our findings suggest that the combination therapy of cabozantinib and CBD provides therapeutic efficacy against HCC.
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Affiliation(s)
- Youngsic Jeon
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | - Taejung Kim
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Hyukjoon Kwon
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | | | - Young-Tae Park
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | - Jungyeob Ham
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
- NeoCannBio Co., Ltd., Seoul 02792, Republic of Korea;
| | - Young-Joo Kim
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
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Abi-Jaoudeh N, Sadeghi B, Javan H, Na J, Beaton G, Tucci F, Ravula S, Imagawa DK. Drug-Eluting Embolic Loaded with Tyrosine Kinase Inhibitor Targeted Therapies for Transarterial Chemoembolization in a VX2 Model. Cancers (Basel) 2023; 15:3236. [PMID: 37370846 DOI: 10.3390/cancers15123236] [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: 04/26/2023] [Revised: 06/05/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.
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Affiliation(s)
- Nadine Abi-Jaoudeh
- Department of Radiological Sciences, University of California Irvine, Orange, CA 92697, USA
| | - Ben Sadeghi
- Department of Radiological Sciences, University of California Irvine, Orange, CA 92697, USA
| | - Hanna Javan
- Department of Radiological Sciences, University of California Irvine, Orange, CA 92697, USA
| | - Jim Na
- Cullgen, Inc., San Diego, CA 92130, USA
| | | | - Fabio Tucci
- Epigen Biosciences, San Diego, CA 92121, USA
| | | | - David K Imagawa
- Department of Surgery, University of California Irvine, Orange, CA 92697, USA
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Yamamoto N, Yamamoto C, Tajitsu T. Spontaneous regression of hepatocellular carcinoma in a pure palliative care setting. J Gen Fam Med 2023; 24:126-128. [PMID: 36909793 PMCID: PMC10000271 DOI: 10.1002/jgf2.588] [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: 12/14/2021] [Revised: 07/07/2022] [Accepted: 10/03/2022] [Indexed: 11/12/2022] Open
Abstract
We report a case of spontaneous remission of hepatocellular carcinoma in an 84-year-old woman who was managed in our best supportive care clinic. The tumor, once relapsed regardless of the application of conventional transcatheter arterial chemoembolization and radiofrequency ablation, regressed spontaneously within 4 months. The presence of an occlusive thrombus in the portal vein feeding to the site of the tumor suggests that the reduced blood supply might have caused tumor necrosis. Furthermore, the successful eradication of hepatitis C virus maintained performance status, and good nutrition might play other roles on it.
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Affiliation(s)
| | - Chikara Yamamoto
- Department of GastroenterologyHokushin General HospitalNaganoJapan
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Feng T, Yao Y, Luo L, Zou H, Xiang G, Wei L, Yang Q, Shi Y, Huang X, Lai C. ST8SIA6-AS1 contributes to hepatocellular carcinoma progression by targeting miR-142-3p/HMGA1 axis. Sci Rep 2023; 13:650. [PMID: 36635290 PMCID: PMC9837176 DOI: 10.1038/s41598-022-26643-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (LIHC) accounts for 90% of all liver cancers and is a serious health concern worldwide. Long noncoding RNAs (lncRNAs) have been observed to sponge microRNAs (miRNAs) and participate in the biological processes of LIHC. This study aimed to evaluate the role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis in regulating LIHC progression. RT-qPCR and western blotting were performed to determine the levels of ST8SIA6-AS1, miR-142-3p, and HMGA1 in LIHC. The relationship between ST8SIA6-AS1, miR-142-3p, and HMGA1 was assessed using luciferase assay. The role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis was evaluated in vitro using LIHC cells. Expression of ST8SIA6-AS1 and HMGA1 was significantly upregulated, whereas that of miR-142-3p was markedly lowered in LIHC specimens and cells. ST8SIA6-AS1 accelerated cell growth, invasion, and migration and suppressed apoptosis in LIHC. Notably, ST8SIA6-AS1 inhibited HMGA1 expression by sponging miR-142-3p in LIHC cells. In conclusion, sponging of miR-142-3p by ST8SIA6-AS1 accelerated the growth of cells while preventing cell apoptosis in LIHC cells, and the inhibitory effect of miR-142-3p was abrogated by elevating HMGA1 expression. The ST8SIA6-AS1-miR-142-3p-HMGA1 axis represents a potential target for the treatment of patients with LIHC.
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Affiliation(s)
- Tianhang Feng
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Yutong Yao
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Le Luo
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Haibo Zou
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Guangming Xiang
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Lingling Wei
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Qinyan Yang
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Ying Shi
- grid.54549.390000 0004 0369 4060Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000 Sichuan China
| | - Xiaolun Huang
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000, Sichuan, China. .,Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.4, Section 2, Jianshe North Road, Chengdu, 610000, Sichuan, China.
| | - Chunyou Lai
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West Section 1, Yihuan Road, Qingyang District, Chengdu, 610000, Sichuan, China.
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10
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Khan A, Zhang X. Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials. Bioengineering (Basel) 2022; 9:406. [PMID: 36004931 PMCID: PMC9405066 DOI: 10.3390/bioengineering9080406] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.
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Affiliation(s)
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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11
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Liu Z, Liu Y, Zhang W, Hong Y, Meng J, Wang J, Zheng S, Xu X. Deep learning for prediction of hepatocellular carcinoma recurrence after resection or liver transplantation: a discovery and validation study. Hepatol Int 2022; 16:577-589. [PMID: 35352293 PMCID: PMC9174321 DOI: 10.1007/s12072-022-10321-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/18/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is a growing need for new improved classifiers of prognosis in hepatocellular carcinoma (HCC) patients to stratify them effectively. METHODS A deep learning model was developed on a total of 1118 patients from 4 independent cohorts. A nucleus map set (n = 120) was used to train U-net to capture the nuclear architecture. The training set (n = 552) included HCC patients that had been treated by resection. The liver transplantation (LT) set (n = 144) contained patients with HCC that had been treated by LT. The train set and its nuclear architectural information extracted by U-net were used to train the MobileNet V2-based classifier (MobileNetV2_HCC_class). The classifier was then independently tested on the LT set and externally validated on the TCGA set (n = 302). The primary outcome was recurrence free survival (RFS). RESULTS The MobileNetV2_HCC_class was a strong predictor of RFS in both LT set and TCGA set. The classifier provided a hazard ratio of 3.44 (95% CI 2.01-5.87, p < 0.001) for high risk versus low risk in the LT set, and 2.55 (95% CI 1.64-3.99, p < 0.001) when known prognostic factors, remarkable in univariable analyses on the same cohort, were adjusted. The MobileNetV2_HCC_class maintained a relatively higher discriminatory power [time-dependent accuracy and area under curve (AUC)] than other factors after LT or resection in the independent validation set (LT and TCGA set). Net reclassification improvement (NRI) analysis indicated MobileNetV2_HCC_class exhibited better net benefits for the Stage_AJCC beyond other independent factors. A pathological review demonstrated that tumoral areas with the highest recurrence predictability featured the following features: the presence of stroma, a high degree of cytological atypia, nuclear hyperchromasia, and a lack of immune cell infiltration. CONCLUSION A prognostic classifier for clinical purposes had been proposed based on the use of deep learning on histological slides from HCC patients. This classifier assists in refining the prognostic prediction of HCC patients and identifies patients who have been benefited from more intensive management.
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Affiliation(s)
- Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 HuanSha Road, Hangzhou, 310006, China
| | - Yuanpeng Liu
- Department of Electrical Engineering and Computer Science, Syracuse University, 4-206 Center for Science and Technology, Syracuse, NY, 13244-4100, USA
| | - Wenhui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 HuanSha Road, Hangzhou, 310006, China
| | - Yuan Hong
- School of Mathematical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jinwen Meng
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 HuanSha Road, Hangzhou, 310006, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 HuanSha Road, Hangzhou, 310006, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 HuanSha Road, Hangzhou, 310006, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
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12
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Han L, Huang C, Wang X, Tong D. The RNA-binding protein GRSF1 promotes hepatocarcinogenesis via competitively binding to YY1 mRNA with miR-30e-5p. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:17. [PMID: 34998399 PMCID: PMC8742353 DOI: 10.1186/s13046-021-02217-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
Abstract
Background Dysregulation of RNA binding protein (RBP) expression has been confirmed to be causally linked with tumorigenesis. The detailed biological effect and underlying mechanisms of the RBP GRSF1 in hepatocellular carcinoma (HCC) remain unclear. Methods HCC cells with stable knockdown of GRSF1 were established using two sh-RNA-encoding lentiviruses. The functions of GRSF1 in HCC were explored using MTT, colony formation, flow cytometry, and Transwell assays and a xenograft model. Transcriptomic sequencing in GRSF1-deficient MHCC-97H cells was carried out to identify the downstream effector of GRSF1. The regulatory mechanisms among GRSF1, YY1 and miR-30e-5p were investigated via RNA immunoprecipitation, luciferase, RNA pull-down and ChIP assays. Several in vivo assays were used to assess the selectivity of the small-molecule compound VE-821 in HCC and to confirm the absence of general toxicity in animal models. Results GRSF1 was frequently increased in HCC tissue and cells and was associated with worse clinical outcomes. GRSF1 functions as a novel oncogenic RBP by enhancing YY1 mRNA stability, and the GUUU motifs within the YY1 3`UTR 2663-2847 were the specific binding motifs for GRSF1. YY1 feedback promoted GRSF1 expression by binding to the GRSF1 promoter. In addition, YY1 was a critical target of miR-30e-5p, which was confirmed in this study to inhibit HCC hepatocarcinogenesis. GRSF1 and miR-30e-5p competitively regulated YY1 by binding to its 3`UTR 2663-2847 region. Finally, we identified that VE-821 blocked HCC progression by inhibiting the GRSF1/YY1 pathway. Conclusion This study revealed the interaction network among GRSF1, YY1 and miR-30e-5p, providing new insight into HCC pathogenesis, and indicated that VE821 may serve as a novel agent with potential for HCC treatment through inhibition of the GRSF1/YY1 axis. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02217-w.
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Affiliation(s)
- Lili Han
- Department of Oncology, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
| | - Chen Huang
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, No.277 Yanta West Road, Xi'an, 710061, Shaanxi Province, China
| | - Xiaofei Wang
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, No.277 Yanta West Road, Xi'an, 710061, Shaanxi Province, China
| | - Dongdong Tong
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, No.277 Yanta West Road, Xi'an, 710061, Shaanxi Province, China
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13
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Zhang HZ, Zhang XD, Huang JX. Circ_0000212 affects proliferation, migration, invasion, apoptosis, and paclitaxel sensitivity of liver cancer cells by targeting miR-139-5p. Shijie Huaren Xiaohua Zazhi 2021; 29:1276-1285. [DOI: 10.11569/wcjd.v29.i22.1276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Circ_0000212 is a newly discovered non-coding RNA whose high expression promotes the progression of colorectal cancer. However, the expression patterns and roles of circ_0000212 in liver cancer remain unknown.
AIM To investigate the effect of circ_0000212 targeting miR-139-5p on cell proliferation, migration, invasion, apoptosis, and paclitaxel sensitivity in liver cancer.
METHODS RT-qPCR was applied to detect the expression of circ_0000212 and miR-139-5p in liver cancer tissues and adjacent tissues. Pearson correlation analysis was performed to determine the relationship between circ_0000212 and miR-139-5p expression in liver cancer tissues. Dual luciferase reporter assay was used to verify the targeting relationship between circ_0000212 and miR-139-5p. Liver cancer HCC9204 cells were divided into a control group, circ_0000212 interference group, circ_0000212 interference + miR-139-5p inhibitor group, paclitaxel group, paclitaxel + circ_0000212 interference group, and paclitaxel + circ_0000212 interference + miR-139-5p inhibitor group. The rate of inhibited HCC9204 cells was detected using CCK-8 method; the number of clones formed by HCC9204 cells was calculated using colony formation assay; the apoptotic rate of HCC9204 cells was evaluated by flow cytometry; and the migration and invasion of HCC9204 cells were detected by Transwell assay.
RESULTS Compared with adjacent tissue, the expression level of circ_0000212 in liver cancer tissue was significantly increased (P < 0.05), while the expression level of miR-139-5p was significantly decreased (P < 0.05). There was a negative correlation between the expression of circ_0000212 and miR-139-5p in liver cancer tissues. Circ_0000212 directly interacted with miR-139-5p. Compared with the control group, circ_0000212 expression in HCC9204 cells in the paclitaxel group was significantly reduced (P < 0.05), while miR-139-5p expression was significantly increased (P < 0.05). Compared with the control group, the numbers of clones formed and migrating and invading HCC9204 cells in the interference circ_0000212 group and paclitaxel group were significantly reduced (P < 0.05), and the inhibition rate and apoptosis rate were significantly increased (P < 0.05). Compared with the circ_0000212 interference group, the numbers of clone formed and migrating and invading HCC9204 cells in the interference circ_0000212+miR-139-5p inhibitor group were significantly increased (P < 0.05), and the inhibition rate and apoptosis rate were significantly reduced (P < 0.05). Compared with the paclitaxel group, the numbers of clones formed and migrating and invading HCC9204 cells in the paclitaxel + circ_0000212 interference group were significantly reduced (P < 0.05), and the inhibition rate and apoptosis rate were significantly increased (P < 0.05). Compared with the paclitaxel + circ_0000212 interference group, the numbers of clones formed and migrating and invading HCC9204 cells in the paclitaxel + circ_0000212 interference + miR-139-5p inhibitor group were significantly increased (P < 0.05), and the inhibition rate and apoptosis rate were significantly reduced (P < 0.05).
CONCLUSION Interfering with circ_0000212 can inhibit cell proliferation, migration, and invasion, induce cell apoptosis, and increase its sensitivity to paclitaxel in liver cancer cells by targeting and up-regulating miR-139-5p.
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Affiliation(s)
- Hui-Zhong Zhang
- Department of Hepatobiliary and Pancreatogastric Surgery, Jinhua Guangfu Cancer Hospital, Jinhua 321111, Zhejiang Province, China
| | - Xiao-Dong Zhang
- Department of Hepatobiliary and Pancreatogastric Surgery, Jinhua Guangfu Cancer Hospital, Jinhua 321111, Zhejiang Province, China
| | - Jian-Xin Huang
- Department of Hepatobiliary and Pancreatogastric Surgery, Jinhua Guangfu Cancer Hospital, Jinhua 321111, Zhejiang Province, China
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Li J, Zhou W, Mao Q, Gao D, Xiong L, Hu X, Zheng Y, Xu X. HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway. Front Oncol 2021; 11:739145. [PMID: 34778055 PMCID: PMC8578906 DOI: 10.3389/fonc.2021.739145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/12/2021] [Indexed: 12/26/2022] Open
Abstract
Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.
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Affiliation(s)
- Junhua Li
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Wei Zhou
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Qiang Mao
- Department of Statistics, The First People's Hospital of Jingmen, Jingmen, China
| | - Dandan Gao
- Department of Infectious Diseases, The First People's Hospital of Jingmen, Jingmen, China
| | - Lin Xiong
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongfa Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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15
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Zhang H, Xia P, Ma W, Yuan Y. Development and Validation of an RNA Binding Protein-associated Prognostic Model for Hepatocellular Carcinoma. J Clin Transl Hepatol 2021; 9:635-646. [PMID: 34722178 PMCID: PMC8516832 DOI: 10.14218/jcth.2020.00103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 02/24/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Background and Aims The survival rate of patients with hepatocellular carcinoma is variable. The abnormal expression of RNA-binding proteins (RBPs) is closely related to the occurrence and development of malignant tumors. The primary aim of this study was to identify RBPs related to the prognosis of liver cancer and to construct a prognostic model of liver cancer. Methods We downloaded the hepatocellular carcinoma gene sequencing data from The Cancer Genome Atlas (cancergenome.nih.gov/) database, constructed a protein-protein interaction network, and used Cytoscape to realize the visualization. From among 325 abnormally expressed genes for RBPs, 9 (XPO5, enhancer of zeste 2 polycomb repressive complex 2 subunit [EZH2], CSTF2, BRCA1, RRP12, MRPL54, EIF2AK4, PPARGC1A, and SEPSECS) were selected for construction of the prognostic model. Then, we further verified the results through the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/) database and in vitro experiments. Results A prognostic model was constructed, which determined that the survival time of patients in the high-risk group was significantly shorter than that of the low-risk group (p<0.01). Univariate and multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor (p<0.01). We also constructed a nomogram based on the risk score, survival time, and survival status. At the same time, we verified the high expression and cancer-promoting effects of EZH2 in tumors. Conclusions Survival, receiver operating characteristic curve and independent prognostic analyses demonstrated that we constructed a good prognostic model, which might be useful for estimating the survival of patients with hepatocellular carcinoma.
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Affiliation(s)
- Hao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Peng Xia
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weijie Ma
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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16
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Xu J, Gu M, Hooi L, Toh TB, Thng DKH, Lim JJ, Chow EKH. Enhanced penetrative siRNA delivery by a nanodiamond drug delivery platform against hepatocellular carcinoma 3D models. NANOSCALE 2021; 13:16131-16145. [PMID: 34542130 DOI: 10.1039/d1nr03502a] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Small interfering RNA (siRNA) can cause specific gene silencing and is considered promising for treating a variety of cancers, including hepatocellular carcinoma (HCC). However, siRNA has many undesirable physicochemical properties that limit its application. Additionally, conventional methods for delivering siRNA are limited in their ability to penetrate solid tumors. In this study, nanodiamonds (NDs) were evaluated as a nanoparticle drug delivery platform for improved siRNA delivery into tumor cells. Our results demonstrated that ND-siRNA complexes could effectively be formed through electrostatic interactions. The ND-siRNA complexes allowed for efficient cellular uptake and endosomal escape that protects siRNA from degradation. Moreover, ND delivery of siRNA was more effective at penetrating tumor spheroids compared to liposomal formulations. This enhanced penetration capacity makes NDs ideal vehicles to deliver siRNA against solid tumor masses as efficient gene knockdown and decreased tumor cell proliferation were observed in tumor spheroids. Evaluation of ND-siRNA complexes within the context of a 3D cancer disease model demonstrates the potential of NDs as a promising gene delivery platform against solid tumors, such as HCC.
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Affiliation(s)
- Jingru Xu
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Mengjie Gu
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Lissa Hooi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Tan Boon Toh
- The N.1 Institute for Health, National University of Singapore, 117456, Singapore
| | - Dexter Kai Hao Thng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Jhin Jieh Lim
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
- The N.1 Institute for Health, National University of Singapore, 117456, Singapore
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore
- The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
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17
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Zhou X, Shi M, Cao J, Yuan T, Yu G, Chen Y, Fang W, Li H. S100 Calcium Binding Protein A10, A Novel Oncogene, Promotes the Proliferation, Invasion, and Migration of Hepatocellular Carcinoma. Front Genet 2021; 12:695036. [PMID: 34178044 PMCID: PMC8226228 DOI: 10.3389/fgene.2021.695036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/17/2021] [Indexed: 01/03/2023] Open
Abstract
Hepatocarcinogenesis is a highly complicated process that is promoted by a series of oncogenes. Our study aims to identify novel oncogenes promoting hepatocellular carcinoma (HCC) by bioinformatic analysis and experimental validation. Here, we reported that S100 calcium binding protein A10 (S100A10) was screened out as a potential novel oncogene in HCC by integrated analysis of OEP000321 dataset and the Cancer Genome Atlas (TCGA)-Liver-Cancer data. Furthermore, S100A10 was highly expressed in HCC samples and observably associated with patients’ overall survival (OS). Overexpression of S100A10 in Hep3B and Huh-7 increased the cell proliferation, whereas downregulation of S100A10 in SK-Hep-1 and HepG2 cells reduced the cell viability to almost stop growing. In vivo tumor growth assays showed that S100A10-overexpressing Hep3B cells had a larger tumor size than control. Moreover, S100A10 overexpression promoted Hep3B cells migration and invasion, and S100A10 knockdown inhibited SK-Hep-1 cells migration and invasion, in vitro. In conclusion, it is demonstrated that S100A10 is a novel oncogene in HCC, indicating a possible novel therapeutic strategy of HCC.
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Affiliation(s)
- Xing Zhou
- Department of Interventional Oncology, Dahua Hospital, Shanghai, China
| | - Min Shi
- Department of Pathology, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Cao
- Department of Interventional Oncology, Dahua Hospital, Shanghai, China
| | - Tianwen Yuan
- Department of Interventional Oncology, Dahua Hospital, Shanghai, China
| | - Guanzhen Yu
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, Shanghai, China
| | - Ying Chen
- Department of Gastroenterology, Naval Medical University, Shanghai, China
| | - Wenzheng Fang
- Department of Oncology, Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fujian, China
| | - Hongwei Li
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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18
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Xiong Q, Bai Y, Shi R, Wang J, Xu W, Zhang M, Song T. Preferentially released miR-122 from cyclodextrin-based star copolymer nanoparticle enhances hepatoma chemotherapy by apoptosis induction and cytotoxics efflux inhibition. Bioact Mater 2021; 6:3744-3755. [PMID: 33898875 PMCID: PMC8056416 DOI: 10.1016/j.bioactmat.2021.03.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/12/2021] [Accepted: 03/12/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy, as one of the most commonly used treatment modalities for cancer therapy, provides limited benefits to hepatoma patients, owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepatoma. Bioinformatic analysis identified the therapeutic role of a liver-specific microRNA — miR-122 for enhancing chemo-therapeutic efficacy in hepatoma. Herein, a cyclodextrin-cored star copolymer nanoparticle system (sCDP/DOX/miR-122) is constructed to co-deliver miR-122 with doxorubicin (DOX) for hepatoma therapy. In this nanosystem, miR-122 is condensed by the outer cationic poly (2-(dimethylamino) ethyl methacrylate) chains of sCDP while DOX is accommodated in the inner hydrophobic cyclodextrin cavities, endowing a sequential release manner of miR-122 and DOX. The preferentially released miR-122 not only directly induces cell apoptosis by down regulation of Bcl-w and enhanced p53 activity, but also increases DOX accumulation through inhibiting cytotoxic efflux transporter expression, which realizes synergistic performance on cell inhibition. Moreover, sCDP/DOX/miR-122 displays remarkably increased anti-tumor efficacy in vivo compared to free DOX and sCDP/DOX alone, indicating its great promising in hepatoma therapy.
Cyclodextrin-based polymeric nanoparticle was developed to co-deliver miR-122 and doxorubicin. The nanoparticle sequentially released miR-122 and doxorubicin into HepG2 cells. The preferentially released miR-122 induces cell apoptosis and inhibits doxorubicin efflux. Enhanced anti-tumor effects with reduced cardiotoxicity were achieved in vivo.
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Affiliation(s)
- Qingqing Xiong
- Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
- Corresponding author.
| | - Yang Bai
- Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
| | - Run Shi
- Faculty of Medicine, Ludwig-Maximilians-Universität München, München, D-80333, Germany
| | - Jian Wang
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, PR China
| | - Weiguo Xu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Mingming Zhang
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, PR China
- Corresponding author.
| | - Tianqiang Song
- Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
- Corresponding author.
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Li H, Liu Y, Jiang W, Xue J, Cheng Y, Wang J, Yang R, Zhang X. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma. BMC Cancer 2021; 21:318. [PMID: 33765973 PMCID: PMC7992931 DOI: 10.1186/s12885-021-08043-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 03/15/2021] [Indexed: 11/10/2022] Open
Abstract
Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08043-9.
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Affiliation(s)
- Hui Li
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China.
| | - Yujuan Liu
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Wei Jiang
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Junhui Xue
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Yuning Cheng
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Jiyin Wang
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Ruixiang Yang
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
| | - Xiaowei Zhang
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China
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20
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Suceveanu AI, Micu IS, Baltatescu GI, Petcu LC, Dobrin N, Brinzan C, Nitipir C, Mazilu L, Botea F, Herlea V, Voinea F, Suceveanu AP. Overexpression of Survivin-1, TAG-72 and HERC5 in patients diagnosed with hepatocellular carcinoma in the Black Sea coast geographical area. Exp Ther Med 2021; 21:284. [PMID: 33603891 PMCID: PMC7851649 DOI: 10.3892/etm.2021.9715] [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: 10/27/2020] [Accepted: 11/26/2020] [Indexed: 11/06/2022] Open
Abstract
Epidemiological data regarding hepatocellular carcinoma (HCC) report unsatisfactory morbimortality rates despite the global efforts to decrease the incidence and prolong patient survival. Current guidelines lack diagnostic biomarkers to better characterize patients with HCC. We aimed to validate the overexpression of Survivin-1, tumor-associated glyocoprotein 72 (Tag-72), and HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) as tissue biomarkers for HCC characterization in patients from our geographical area and to standardize a local biomarker panel to be introduced in the current management guideline. Thirty samples of histologically confirmed HCC were compared to an equal number of samples of benign tumors in terms of Survivin-1, TAG-72, and HERC5 overexpression. Student's t-test, Mann-Whitney U test and Chi-square test were used to find differences between the two studied groups and to compare the categorical variables. The discriminative power of Survivin-1, Tag-72, and HERC5 overexpression was assessed using ROC curves. The multivariate linear regression analysis revealed that Survivin, Tag-72, and HERC5 were significantly overexpressed in older male patients, with α-fetoprotein (AFP) >200 ng/dl, low serum albumin, as well as in patients with imaging features of portal thrombosis and ascites. The diagnostic performance of Survivin-1, Tag-72 and HERC5 tissue biomarkers for HCC characterization was superior to that of the gold-standard AFP. Our study results validate the overexpression of Survivin-1, Tag-72, and HERC5 as tissue biomarkers for HCC characterization in patients from our geographical region and could be standardized in the current HCC management guideline.
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Affiliation(s)
| | - Ioan Sergiu Micu
- Department of Gastroenterology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Gabriela-Izabela Baltatescu
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Lucian Cristian Petcu
- Dentistry Faculty, Biophysics and Biostatistics Disciplines, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Nicolae Dobrin
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Costel Brinzan
- Doctoral School of Medicine, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Cornelia Nitipir
- Department of Oncology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laura Mazilu
- Department of Oncology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Florin Botea
- Liver Transplant and General Surgery Centre, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Felix Voinea
- Department of Urology, ‘Ovidius’ University, 900527 Constanta, Romania
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21
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Moriya K, Namisaki T, Takaya H, Kaji K, Kawaratani H, Shimozato N, Sawada Y, Douhara A, Sato S, Furukawa M, Kitagawa K, Akahane T, Yoshiji H. Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy. J Clin Med 2021; 10:629. [PMID: 33562238 PMCID: PMC7914951 DOI: 10.3390/jcm10040629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/25/2022] Open
Abstract
Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.
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Affiliation(s)
- Kei Moriya
- Department of Gastroenterology and Hepatology, Nara Medical University, Nara 634-8521, Japan; (T.N.); (H.T.); (K.K.); (H.K.); (N.S.); (Y.S.); (A.D.); (S.S.); (M.F.); (K.K.); (T.A.); (H.Y.)
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22
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Hu K, Yuan J, Tang B, Zhang F, Lu S, Chen R, Zhang L, Ren Z, Yin X. Albumin-bilirubin index and platelet-albumin-bilirubin index contribute to identifying survival benefit candidates in patients with hepatocellular carcinoma and Child-Pugh grade A undergoing transcatheter arterial chemoembolization with sorafenib treatment. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:237. [PMID: 33708864 PMCID: PMC7940911 DOI: 10.21037/atm-20-3118] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background Combined therapy of transcatheter arterial chemoembolization (TACE) with sorafenib is used for a large number of patients with intermediate-stage or advanced-stage hepatocellular carcinoma (HCC), but its implementation is limited by the evaluation of pre-treatment liver function reserve. This study aimed to validate the performance of the albumin-bilirubin index (ALBI) and platelet-albumin-bilirubin index (PALBI) in predicting survival benefits in patients with HCC and Child-Pugh grade A receiving TACE combined with sorafenib treatment. Methods From 2004 to 2018, 418 patients with intermediate/advanced-stage HCC and Child-Pugh grade A receiving TACE combined with sorafenib treatment were retrospectively enrolled. The predictive performance of ALBI and PALBI was explored by survival analysis and receiver operating characteristic curve (ROC) analysis. Results The median overall survival (mOS) was 24 and 12 months in patients with ALBI grade 1 and grade 2, respectively. The mOS of patients with PALBI grade 1, grade 2, and grade 3 was 23, 16, and 7 months, respectively. The multivariate analysis showed that ALBI grade 2 [hazard ratio (HR) =1.39, 95% confidence interval (CI): 1.11–1.74] and PALBI grade 3 (HR =3.72, 95% CI: 2.26–6.06) were associated with unfavorable prognosis. The ROC analysis revealed that ALBI and PALBI scores had better prediction performance compared with the Child-Pugh score. Subgroup analysis confirmed that by using ALBI or PALBI, patients could be stratified into subgroups with different liver function reserves and distinctive prognosis, regardless of Barcelona Clinic Liver Cancer (BCLC) stage, combination modality, or α-fetoprotein (AFP) levels. Conclusions Both ALBI and PALBI could predict prognosis in patients with HCC and Child-Pugh grade A receiving TACE and sorafenib. Patients with ALBI or PALBI grade 1 harbored a more favorable survival outcome compared with those with ALBI or PALBI grade 2–3, and hence should be recommended as the best candidates for TACE combined with sorafenib treatment.
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Affiliation(s)
- Keshu Hu
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jia Yuan
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Bei Tang
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Feng Zhang
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Shenxin Lu
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Rongxin Chen
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Lan Zhang
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xin Yin
- Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
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23
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Liu Q, Dong X. Targeting De Novo Lipogenesis and Cholesterol Biosynthesis Simultaneously is a Novel Therapeutic Option for Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:19-21. [PMID: 33537248 PMCID: PMC7850393 DOI: 10.2147/jhc.s278517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/13/2021] [Indexed: 01/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and serious types of cancer in the world. Currently, the treatment options for patients with HCC are limited. Lipid metabolic alterations are being recognized as a therapeutic target in the past few years. De novo lipogenesis has been frequently observed in HCC. Fatty acid synthase (FASN) is the key enzyme of de novo lipogenesis. Previous studies have indicated that loss of FASN suppresses the growth of HCC cells, but it cannot completely prevent HCC formation in vivo. Thus, other mechanisms that can support HCC tumor formation in the absence of de novo lipogenesis maybe existed. In a study recently published in Gut, Che and colleague investigated the functions of Fasn in HCC mouse model and explore the crosstalk between de novo lipogenesis and cholesterol biosynthesis-associated pathway during HCC development. These findings highlight the simultaneous inhibition of de novo lipogenesis and cholesterol biosynthesis as a novel therapeutic and prevention strategy for HCC.
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Affiliation(s)
- Qian Liu
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300020, People's Republic of China
| | - Xifeng Dong
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300020, People's Republic of China
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24
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Effect of radiotherapy on survival in advanced hepatocellular carcinoma patients treated with sorafenib: a nationwide cancer-registry-based study. Sci Rep 2021; 11:1614. [PMID: 33452421 PMCID: PMC7810734 DOI: 10.1038/s41598-021-81176-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/01/2021] [Indexed: 12/18/2022] Open
Abstract
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) patients. This study aims to determine whether combining radiotherapy with sorafenib administration increases its efficacy. The study cohort included 4763 patients with diagnosed advanced HCC who received sorafenib between January 2012 and December 2015, as reported in medical records in the Taiwan Cancer Registry database. The effect of sorafenib with or without radiotherapy on survival was calculated using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Patients receiving sorafenib plus radiotherapy had greater 1-year survival than did those receiving sorafenib alone (P < 0.001). Uni- and multivariate analyses also showed that radiotherapy increased survival after adjusting for confounders (adjusted HR 0.57; 95% CI 0.51–0.63). Further stratified analysis according to the timing of radiotherapy relative to sorafenib treatment revealed that patients who underwent radiotherapy after sorafenib had greater 1-year survival than did those undergoing radiotherapy within sorafenib use or sorafenib alone (adjusted HR 0.39; 95% CI 0.27–0.54). Combined treatment with sorafenib and radiotherapy results in greater HCC patient survival and should be considered an option for treating this challenging disease.
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25
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Zhang H, Ye Y, Li W. Perspectives of Molecular Therapy-Targeted Mitochondrial Fission in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1039312. [PMID: 33457401 PMCID: PMC7785342 DOI: 10.1155/2020/1039312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/16/2020] [Accepted: 12/21/2020] [Indexed: 12/21/2022]
Abstract
Current advances of molecular-targeting therapies for hepatocellular carcinoma (HCC) have improved the overall survival significantly, whereas the results still remain unsatisfied. Recently, much attention has been focused on organelles, such as the mitochondria, to reveal novel strategies to control the cancers. The mitochondria are vital organelles which supply energy and maintain metabolism in most of the eukaryotic cells. They not only execute critical bioenergetic and biosynthetic functions but also regulate ROS homeostasis and apoptosis. Existing in a dynamic equilibrium state, mitochondria constantly undergo the fission and fusion processes in normal situation. Increasing evidences have showed that mitochondrial fission is highly related to the diseases and cancers. Distinctive works have proved the significant effects of mitochondrial fission on HCC behaviors and the crosstalks with other molecular pathways. Here, we provide an overview of the mitochondrial fission and the link with HCC, emphasizing on the underlying molecular pathways and several novel materials that modulate HCC behaviors.
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Affiliation(s)
- Hanwen Zhang
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yanshuo Ye
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
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26
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Wang Y, Yang L, Dong X, Yang X, Zhang X, Liu Z, Zhao X, Wen T. Overexpression of NNT-AS1 Activates TGF- β Signaling to Decrease Tumor CD4 Lymphocyte Infiltration in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8216541. [PMID: 33426064 PMCID: PMC7775131 DOI: 10.1155/2020/8216541] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/25/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023]
Abstract
Nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) is a long noncoding RNA (lncRNA) that has been shown to be overexpressed in hepatocellular carcinoma (HCC). However, the molecular mechanism involving NNT-AS1 in HCC remains to be extensively investigated. The activation of TGF-β signaling inhibits tumor-infiltrating lymphocytes (TILs) and results in tumor immune evasion. We thus planned to explore the mechanism by which NNT-AS1 activates the TGF-β signaling pathway and inhibits TILs in HCC. High levels of NNT-AS1 were detected in HCC tissues by both RNAscope and real-time quantitative PCR (RT-qPCR) assays. The levels of proteins involved in TGF-β signaling and those of CD4 T lymphocytes were quantified by immunohistochemistry (IHC). HCC cell lines (HepG2 and Huh7) were used to explore the effects of NNT-AS1 on TGF-β signaling activation. In these analyses, RNAscope detection demonstrated that NNT-AS1 levels were significantly increased in HCC cancer tissues (P = 0.0001). In addition, the elevated NNT-AS1 levels in cancer tissue were further confirmed by RT-qPCR analysis of HCC cancer tissues (n = 64) and normal tissues (n = 26) (P = 0.0003). Importantly, the overall survival time of HCC patients who exhibited higher levels of NNT-AS1 expression was significantly shorter than that of HCC patients who had lower levels of NNT-AS1 expression (P = 0.0402). Further mechanistic investigation indicated that NNT-AS1 inhibition significantly decreased the levels of TGF-β, TGFBR1, and SMAD5 in HCC cells. In HCC tissues, IHC detection showed that relatively high NNT-AS1 levels were associated with a reduction in infiltrated CD4 lymphocyte numbers. In conclusion, this research identifies a novel mechanism by which NNT-AS1 impairs CD4 T cell infiltration via activation of the TGF-β signaling pathway in HCC.
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Affiliation(s)
- Yakun Wang
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, China
| | - Lei Yang
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, China
| | - Xichen Dong
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, China
| | - Xin Yang
- Pathology Department, Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China
| | - Xinxue Zhang
- Hepatobiliary Surgery Department, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zhe Liu
- Hepatobiliary Surgery Department, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xin Zhao
- Hepatobiliary Surgery Department, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tao Wen
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, China
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27
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Pogostemon cablin Triggered ROS-Induced DNA Damage to Arrest Cell Cycle Progression and Induce Apoptosis on Human Hepatocellular Carcinoma In Vitro and In Vivo. Molecules 2020; 25:molecules25235639. [PMID: 33266043 PMCID: PMC7731310 DOI: 10.3390/molecules25235639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 12/18/2022] Open
Abstract
The purpose of the study was to elucidate the anti-hepatoma effects and mechanisms of Pogostemon cablin essential oils (PPa extract) in vitro and in vivo. PPa extract exhibited an inhibitory effect on hepatocellular carcinoma (HCC) cells and was less cytotoxic to normal cells, especially normal liver cells, than it was to HCC cells, exerting a good selective index. Additionally, PPa extract inhibited HCC cell growth by blocking the cell cycle at the G0/G1 phase via p53 dependent or independent pathway to down regulated cell cycle regulators. Moreover, PPa extract induced the FAS-FASL-caspase-8 system to activate the extrinsic apoptosis pathway, and it increased the bax/bcl-2 ratio and reduced ΔΨm to activate the intrinsic apoptosis pathway that might be due to lots of reactive oxygen species (ROS) production which was induced by PPa extract. In addition, PPa extract presented to the potential to act synergistically with sorafenib to effectively inhibit HCC cell proliferation through the Akt/mTOR pathway and reduce regrowth of HCC cells. In an animal model, PPa extract suppressed HCC tumor growth and prolonged lifespan by reducing the VEGF/VEGFR axis and inducing tumor cell apoptosis in vivo. Ultimately, PPa extract demonstrated nearly no or low system-wide, physiological, or pathological toxicity in vivo. In conclusion, PPa extract effectively inhibited HCC cell growth through inducing cell cycle arrest and activating apoptosis in vitro and in vivo. Furthermore, PPa extract exhibits less toxicity toward normal cells and organs than it does toward HCC cells, which might lead to fewer side effects in clinical applications. PPa extract may be developed into a clinical drug to suppress tumor growth or functional food to prevent HCC initiation or chemoprotection of HCC recurrence.
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28
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Shigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, Aoki S, Kitahara S, Inoue K, Shigeta A, Hato T, Ramjiawan RR, Staiculescu D, Zopf D, Fiebig L, Hobbs GS, Quaas A, Dima S, Popescu I, Huang P, Munn LL, Cobbold M, Goyal L, Zhu AX, Jain RK, Duda DG. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer 2020; 8:jitc-2020-001435. [PMID: 33234602 PMCID: PMC7689089 DOI: 10.1136/jitc-2020-001435] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. BASIC PROCEDURES We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. MAIN FINDINGS Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. PRINCIPAL CONCLUSIONS Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
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Affiliation(s)
- Kohei Shigeta
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aya Matsui
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hiroto Kikuchi
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sebastian Klein
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.,Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Emilie Mamessier
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ivy X Chen
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shuichi Aoki
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shuji Kitahara
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Koetsu Inoue
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ayako Shigeta
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Tai Hato
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rakesh R Ramjiawan
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniel Staiculescu
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dieter Zopf
- Drug Discovery, Bayer Pharma AG, Berlin, Germany
| | - Lukas Fiebig
- Drug Discovery, Bayer Pharma AG, Berlin, Germany
| | - Gabriela S Hobbs
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Simona Dima
- Center for General Surgery and Liver Transplantation, Clinical Institute Fundeni, Bucharest, Romania
| | - Irinel Popescu
- Center for General Surgery and Liver Transplantation, Clinical Institute Fundeni, Bucharest, Romania
| | - Peigen Huang
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lance L Munn
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mark Cobbold
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lipika Goyal
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Andrew X Zhu
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rakesh K Jain
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dan G Duda
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
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29
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Buonaguro FM, Botti G, Ascierto PA, Pignata S, Ionna F, Delrio P, Petrillo A, Cavalcanti E, Di Bonito M, Perdonà S, De Laurentiis M, Fiore F, Palaia R, Izzo F, D'Auria S, Rossi V, Menegozzo S, Piccirillo M, Celentano E, Cuomo A, Normanno N, Tornesello ML, Saviano R, Barberio D, Buonaguro L, Giannoni G, Muto P, Miscio L, Bianchi AAM. The clinical and translational research activities at the INT - IRCCS "Fondazione Pascale" cancer center (Naples, Italy) during the COVID-19 pandemic. Infect Agent Cancer 2020; 15:69. [PMID: 33292365 PMCID: PMC7681193 DOI: 10.1186/s13027-020-00330-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/01/2020] [Indexed: 01/19/2023] Open
Abstract
COVID-19 pandemic following the outbreak in China and Western Europe, where it finally lost the momentum, is now devastating North and South America. It has not been identified the reason and the molecular mechanisms of the two different patterns of the pulmonary host responses to the virus from a minimal disease in young subjects to a severe distress syndrome (ARDS) in older subjects, particularly those with previous chronic diseases (including diabetes) and cancer. The Management of the Istituto Nazionale Tumori - IRCCS "Fondazione Pascale" in Naples (INT-Pascale), along with all Health professionals decided not to interrupt the treatment of those hospitalized and to continue, even if after a careful triage in order not to allow SARS-CoV-2 positive subjects to access, to take care of cancer patients with serious conditions. Although very few (n = 3) patients developed a symptomatic COVID-19 and required the transfer to a COVID-19 area of the Institute, no patients died during the hospitalization and completed their oncology treatment. Besides monitoring of the patients, all employees of the Institute (physicians, nurses, researchers, lawyers, accountants, gatekeepers, guardians, janitors) have been tested for a possible exposure. Personnel identified as positive, has been promptly subjected to home quarantine and subdued to health surveillance. One severe case of respiratory distress has been reported in a positive employees and one death of a family member. Further steps to home monitoring of COVID-19 clinical course have been taken with the development of remote Wi-Fi connected digital devices for the detection of early signs of respiratory distress, including heart rate and oxygen saturation.In conclusion cancer care has been performed and continued safely also during COVID-19 pandemic and further remote home strategies are in progress to ensure the appropriate monitoring of cancer patients.
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Affiliation(s)
| | - Gerardo Botti
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | | | - Sandro Pignata
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Franco Ionna
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Paolo Delrio
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | | | | | | | - Sisto Perdonà
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | | | - Francesco Fiore
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Raffaele Palaia
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Francesco Izzo
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Stefania D'Auria
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Virginia Rossi
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Simona Menegozzo
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Mauro Piccirillo
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Egidio Celentano
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Arturo Cuomo
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Nicola Normanno
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | | | - Rocco Saviano
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Daniela Barberio
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Luigi Buonaguro
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | | | - Paolo Muto
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Leonardo Miscio
- Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
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Cheng R, Wang B, Cai XR, Chen ZS, Du Q, Zhou LY, Ye JM, Chen YL. CD276 Promotes Vasculogenic Mimicry Formation in Hepatocellular Carcinoma via the PI3K/AKT/MMPs Pathway. Onco Targets Ther 2020; 13:11485-11498. [PMID: 33204103 PMCID: PMC7667184 DOI: 10.2147/ott.s271891] [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: 07/16/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose CD276 protein expression and vasculogenic mimicry (VM) formation are associated with the poor prognosis of hepatocellular carcinoma (HCC) patients. Although both the effects of CD276 and VM formation involve the activation of matrix metalloproteinases, and their relationship has not yet been explored. The following study investigated the effect of CD276 expression on VM formation and the potential mechanisms. Materials and Methods CD276 expression and VM were examined in commercial tissue microarrays by immunohistochemistry and CD31/PAS double staining. Tumor cell proliferation, invasion, migration and, tube formation were detected in vitro after transfecting HCC cell lines with an shRNA lentiviral vector against CD276. The expression of MMP14, MMP2, VE-cadherin, E-cadherin, and vimentin and MMPs activation was detected by Western blot, immunofluorescence and gelatin zymography assay. In addition, an orthotopic xenograft model of HCC cells was established in vivo, after which VM was detected, along with its marker molecules. Results CD276 expression was associated with VM and poor prognosis in HCC patients. RNA interference of CD276 reduced tumor cell proliferation, invasion, migration, and VM formation in vitro and in vivo. Furthermore, CD276 knockdown up-regulated the expression of E-cadherin but inhibited the phosphorylation of AKT, the expression of MMP14, MMP2, VE-cadherin, vimentin and the activation of MMP2 and MMP9 in HCC cell lines. Conclusion CD276 may promote VM formation by activating the PI3K/AKT/MMPs pathway and inducing the EMT process in HCC. CD276 may serve as a promising candidate for the anti-VM treatment of HCC.
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Affiliation(s)
- Rui Cheng
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Bi Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Xin-Ran Cai
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Zhi-Shan Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Qiang Du
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Liang-Yi Zhou
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Jing-Min Ye
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Yan-Ling Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Fujian Medical University Cancer Center, Fuzhou, Fujian 350001, People's Republic of China
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31
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Chang Y, Lee YB, Cho EJ, Lee JH, Yu SJ, Kim YJ, Yoon JH. CKD-5, a novel pan-histone deacetylase inhibitor, synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma. BMC Cancer 2020; 20:1001. [PMID: 33059615 PMCID: PMC7559883 DOI: 10.1186/s12885-020-07471-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 09/29/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. A recent phase I/II study reported the possibility of HDACI as a chemosensitizer in sorafenib-resistant patients. In this study, we evaluated whether CKD-5, a novel pan-HDACI, can potentiate the efficacy of sorafenib. METHODS The anticancer effect of CKD-5 with and without sorafenib was evaluated in vitro using an MTS assay with human HCC cells (SNU-3058 and SNU-761) under both normoxic and hypoxic conditions. Microarray analysis was performed to investigate the mechanism of cell death, which was also evaluated by small interfering RNA (siRNA) transfection and subsequent immunoblot assays. In vivo experiments were conducted using two different murine HCC models. C3H mice implanted with MH134 cells and C57BL/6 mice implanted with RIL-175 cells were treated with weekly CKD-5 with and without sorafenib for 2 weeks. RESULTS CKD-5 treatment significantly suppressed human HCC cell growth in both normoxic and hypoxic conditions. Microarray analysis and real-time PCR showed that CKD-5 treatment significantly increased peripherin expression in HCC cells and that downregulation of peripherin by siRNA decreased CKD-5-induced apoptosis. The combination of CKD-5 and sorafenib decreased cell viability more effectively than sorafenib or CKD-5 monotherapy in human and murine HCC cells. The effectiveness of the combination therapy was consistently demonstrated in the animal models. Histological and biochemical analyses demonstrated good tolerance of CKD-5 plus sorafenib in vivo. CONCLUSION CKD-5 may enhance sorafenib efficacy through epigenetic regulation. The combination of CKD-5 and sorafenib might be a novel therapeutic option for the treatment of HCC.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Huang XF, Chang KF, Lee SC, Sheu GT, Li CY, Weng JC, Hsiao CY, Tsai NM. Extract Derived from Cedrus atlantica Acts as an Antitumor Agent on Hepatocellular Carcinoma Growth In Vitro and In Vivo. Molecules 2020; 25:molecules25204608. [PMID: 33050385 PMCID: PMC7594045 DOI: 10.3390/molecules25204608] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023] Open
Abstract
Cedrus atlantica is widely used in herbal medicine. However, the anti-cancer activity of C. atlantica extract (CAt extract) has not been clarified in hepatocellular carcinoma. In the study, we elucidated the anti-hepatoma capacity of CAt extract on HCC in vitro and in vivo. To explore the anti-hepatoma mechanisms of the CAt extract in vitro, HCC and normal cells were treated with the CAt extract, which showed marked inhibitory effects on HCC cells in a dose-dependent manner; in contrast, the CAt extract treatment was less cytotoxic to normal cells. In addition, our results indicate that the CAt extract induced apoptosis via caspase-dependent and independent apoptosis pathways. Furthermore, the CAt extract inhibited HCC tumor cell growth by restraining cell cycle progression, and it reduced the signaling of the AKT, ERK1/2, and p38 pathways. In the xenograft model, the CAt extract suppressed HCC tumor cell growth and prolonged lifespan by inhibiting PCNA protein expression, repressing part of the VEGF-induced autocrine pathway, and triggering strong expression of cleaved caspase-3, which contributed to cell apoptosis. Moreover, the CAt extract did not induce any obvious changes in pathological morphology or body weight, suggesting it had no toxicity. CAt extract exerted anti-tumor effects on HCC in vitro and in vivo. Thus, CAt extract could be used as a potential anti-cancer therapeutic agent against HCC.
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Affiliation(s)
- Xiao-Fan Huang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (X.-F.H.); (K.-F.C.); (G.-T.S.)
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Kai-Fu Chang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (X.-F.H.); (K.-F.C.); (G.-T.S.)
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Shan-Chih Lee
- Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Gwo-Tarng Sheu
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (X.-F.H.); (K.-F.C.); (G.-T.S.)
| | - Chia-Yu Li
- Department of Life and Death, Nanhua University, Chiayi 62249, Taiwan;
| | - Jun-Cheng Weng
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Chih-Yen Hsiao
- Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
- Correspondence: (C.-Y.H.); (N.-M.T.); Tel.: +886-4-2473-0022 (ext. 12411) (N.-M.T.); Fax: +886-4-2324-8171 (N.-M.T.)
| | - Nu-Man Tsai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Correspondence: (C.-Y.H.); (N.-M.T.); Tel.: +886-4-2473-0022 (ext. 12411) (N.-M.T.); Fax: +886-4-2324-8171 (N.-M.T.)
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33
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Deepak P, Siddalingam R, Kumar P, Anand S, Thakur S, Jagdish B, Jaiswal S. Gene based nanocarrier delivery for the treatment of hepatocellular carcinoma. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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34
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LncRNA ST8SIA6-AS1 promotes hepatocellular carcinoma progression by regulating MAGEA3 and DCAF4L2 expression. Biochem Biophys Res Commun 2020; 533:1039-1047. [PMID: 33012505 DOI: 10.1016/j.bbrc.2020.09.115] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. In this study, we aimed to explore the role and mechanism of lncRNA ST8SIA6-AS1 in HCC. We found that ST8SIA6-AS1 was upregulated in HCC tissues and associated with poorer overall survival of HCC patients from TCGA. Moreover, ST8SIA6-AS1 was highly expressed in HCC in-house tissues and cells, and ST8SIA6-AS1 upregulation was related to aggressive tumor phenotypes and the poor overall survival of HCC patients. Downregulation of ST8SIA6-AS1 suppressed HCC cell proliferation, migration and invasion in vitro and restrained HCC tumorigenesis in vivo. In terms of mechanism, ST8SIA6-AS1 regulated melanoma-associated antigen (MAGE)-A3 (MAGEA3) and DDB1-and Cul4-associated factor 4-like 2 (DCAF4L2) expression, and rescue experiments verified that ST8SIA6-AS1 played a protumorigenic role in HCC via the regulation of MAGEA3 and DCAF4L2. ST8SIA6-AS1 partly directly bound to miR-129-5p and functioned as a competing endogenous RNA (ceRNA), subsequently facilitating the expression of the miR-129-5p target gene DCAF4L2 to play its role in HCC. In summary, our results identified ST8SIA6-AS1 as an oncogenic lncRNA predicting poor clinical outcomes of patients with HCC. These findings suggest that ST8SIA6-AS1 is a potential therapeutic target for HCC.
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35
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Li Y, Chen G, Han Z, Cheng H, Qiao L, Li Y. IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells. Onco Targets Ther 2020; 13:9721-9730. [PMID: 33061451 PMCID: PMC7533247 DOI: 10.2147/ott.s262089] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022] Open
Abstract
Background Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive. Methods In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, β-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC. Results The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial–mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib. Conclusion LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.
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Affiliation(s)
- Yu Li
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Gang Chen
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Zhijian Han
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Huijuan Cheng
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Liang Qiao
- Storr Liver Unit at the Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Sydney, NSW 2145, Australia
| | - Yumin Li
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
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36
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Yu X, Lin Q, Wu Z, Zhang Y, Wang T, Zhao S, Song X, Chen C, Wang Z, Xu L, Li C, Gao L, Liang X, Yue X, Ma C. ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p. J Pathol 2020; 252:358-370. [PMID: 32770671 DOI: 10.1002/path.5530] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/21/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Xiangguo Yu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Qinghai Lin
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yankun Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Songbai Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Chaojia Chen
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Leiqi Xu
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xuetian Yue
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China.,Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, PR China
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Walton M, Wade R, Claxton L, Sharif-Hurst S, Harden M, Patel J, Rowe I, Hodgson R, Eastwood A. Selective internal radiation therapies for unresectable early-, intermediate- or advanced-stage hepatocellular carcinoma: systematic review, network meta-analysis and economic evaluation. Health Technol Assess 2020; 24:1-264. [PMID: 33001024 PMCID: PMC7569721 DOI: 10.3310/hta24480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma is the most common type of primary liver cancer. Treatment choice is dependent on underlying liver dysfunction and cancer stage. Treatment options include conventional transarterial therapies for patients with intermediate-stage disease and systemic therapy [e.g. sorafenib (Nexavar®; Bayer plc, Leverkusen, Germany)] for patients with advanced-stage disease. Selective internal radiation therapies deliver radiation to liver tumours via microspheres that are injected into the hepatic artery. There are three selective internal radiation therapies: TheraSphere™ [BTG Ltd, London, UK (now Boston Scientific, Marlborough, MA, USA)], SIR-Spheres® (Sirtex Medical Ltd, Woburn, MA, USA) and QuiremSpheres® (Quirem Medical BV, Deventer, the Netherlands). OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of selective internal radiation therapies for treating patients with unresectable early-, intermediate- or advanced-stage hepatocellular carcinoma. METHODS A search was undertaken to identify clinical effectiveness literature relating to selective internal radiation therapies and relevant comparators for the treatment of hepatocellular carcinoma. Studies were critically appraised and summarised. The network of evidence was mapped to estimate the relative effectiveness of the different selective internal radiation therapies and comparator treatments. An economic analysis evaluated the cost-effectiveness. RESULTS Twenty studies were included in the clinical effectiveness review. Two large randomised controlled trials rated as having a low risk of bias [SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled Phase 3 trial. Lancet Oncol 2017;18:1624-36; and SIRveNIB: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018;36:1913-21] found no significant difference in overall survival or progression-free survival between SIR-Spheres and sorafenib (systemic therapy) in an advanced population, despite greater tumour response in the SIR-Spheres arm of both trials. There were some concerns regarding generalisability of the SARAH and SIRveNIB trials to UK practice. All other studies of SIR-Spheres, TheraSphere or QuiremSpheres were either rated as being at a high risk of bias or caused some concerns regarding bias. A network meta-analysis was conducted in adults with unresectable hepatocellular carcinoma who had Child-Pugh class A liver cirrhosis and were ineligible for conventional transarterial therapies. The analysis included the SARAH and SIRveNIB trials as well as a trial comparing lenvatinib (Kisplyx®; Eisai Ltd, Tokyo, Japan) (systemic therapy) with sorafenib. There were no meaningful differences in overall survival between any of the treatments. The base-case economic analysis suggested that TheraSphere may be cost-saving relative to both SIR-Spheres and QuiremSpheres. However, incremental cost differences between TheraSphere and SIR-Spheres were small. In a fully incremental analysis, which included confidential Patient Access Scheme discounts, lenvatinib was the most cost-effective treatment and dominated all selective internal radiation therapies. In pairwise comparisons of sorafenib with each selective internal radiation therapy, sorafenib also dominated all selective internal radiation therapies. LIMITATIONS The existing evidence cannot provide decision-makers with clear guidance on the comparative effectiveness of treatments in early- and intermediate-stage hepatocellular carcinoma or on the efficacy of TheraSphere or QuiremSpheres. CONCLUSIONS In the advanced-stage hepatocellular carcinoma population, two large randomised trials have shown that SIR-Spheres have similar clinical effectiveness to sorafenib. None of the selective internal radiation therapies was cost-effective, being more costly and less effective than lenvatinib, both at list price and with Patient Access Scheme discounts. FUTURE WORK Future studies may wish to include early- and intermediate-stage hepatocellular carcinoma patients and the low tumour burden/albumin-bilirubin 1 subgroup of advanced-stage patients. Future high-quality studies evaluating alternative selective internal radiation therapies would be beneficial. STUDY REGISTRATION This study is registered as PROSPERO CRD42019128383. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 48. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Matthew Walton
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Ros Wade
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Lindsay Claxton
- Centre for Reviews and Dissemination, University of York, York, UK
| | | | - Melissa Harden
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Jai Patel
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Ian Rowe
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Robert Hodgson
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Alison Eastwood
- Centre for Reviews and Dissemination, University of York, York, UK
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Li J, Zhu D, Ma W, Yang Y, Wang G, Wu X, Wang K, Chen Y, Wang F, Liu W, Yuan Y. Rapid synthesis of a Bi@ZIF-8 composite nanomaterial as a near-infrared-II (NIR-II) photothermal agent for the low-temperature photothermal therapy of hepatocellular carcinoma. NANOSCALE 2020; 12:17064-17073. [PMID: 32785323 DOI: 10.1039/d0nr03907a] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths globally. Advanced nanomaterials have emerged as effective approaches to liver cancer therapy such as photothermal therapy. However, limited penetration depth of photothermal agents (PTAs) activated in the NIR-I bio-window and thermoresistance due to heat shock proteins restrict the therapeutic efficacy of PTT in HCC. Herein, we prepared a Bi@ZIF-8 (BZ) nanomaterial by a simple one-step reduction method. Then, gambogic acid, a natural inhibitor of Hsp90, was efficiently loaded onto the BZ nanomaterial via physical mixing. The characterization of the nanomaterial and release of GA due to pH change or NIR-light irradiation were separately studied. Photothermal conversion efficiency was calculated, and therapeutic studies were carried out in vitro and in vivo. This nanomaterial exhibited a significantly enhanced drug release rate when the temperature was increased under acidic conditions and had good light stability under laser irradiation and a photothermal conversion efficiency of about 24.4%. In addition, this novel nanomaterial achieved good therapeutic effects with less toxicity in vitro. The BZ nanomaterial loaded with GA caused tumor shrinkage as well as disappearance and effectively downregulated Hsp90 expression in tumors in vivo. Moreover, this novel nanomaterial exhibited good biocompatibility and potential for application in low-temperature PTT with excellent tumor destruction efficacy.
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Affiliation(s)
- Jinghua Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Daoming Zhu
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education School of Physics and Technology, Wuhan University, Wuhan 430071, China
| | - Weijie Ma
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Yang Yang
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education School of Physics and Technology, Wuhan University, Wuhan 430071, China
| | - Ganggang Wang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Xiaoling Wu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Kunlei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Yiran Chen
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Fubing Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Liu
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education School of Physics and Technology, Wuhan University, Wuhan 430071, China and Wuhan University Shenzhen Institution, Shenzhen 518057, China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
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Ji B, Cai H, Yang Y, Peng F, Song M, Sun K, Yan F, Liu Y. Hybrid membrane camouflaged copper sulfide nanoparticles for photothermal-chemotherapy of hepatocellular carcinoma. Acta Biomater 2020; 111:363-372. [PMID: 32434082 DOI: 10.1016/j.actbio.2020.04.046] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Biomimetic nanoparticles (NPs) coated with cell membranes show enhanced biocompatibility and specificity for homotypic cells, and have gained considerable attention for targeted anti-tumor therapy. We constructed cancer cell-macrophage hybrid membrane-coated near infrared (NIR)-responsive hollow copper sulfide nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR (CuS-SF@CMV NPs). These CuS-SF@CMV NPs expressed the characteristic membrane proteins of both cancer cells and macrophages, and selectively accumulated in cancer cells in vitro and tumors in vivo, compared to the CuS NPs. In addition, the CuS-SF@CMV NPs achieved synergistic photo-thermal and chemotherapy in cancer cells upon NIR irradiation, with 94.3% inhibition of tumor growth in a murine hepatoma model. While the initial increase in temperature rapidly killed the tumor cells, sorafenib and the anti-VEGFR antibody sustained the tumor killing effect by respectively inhibiting tumor cell proliferation and angiogenesis via the Ras/Raf/MEK/ERK and PI3K/AKT pathways. Taken together, the CuS-SF@CMV NPs have immune evasion, tumor cell targeting and drug loading capacities, along with an inherent photo-thermal conversion ability, making them ideal for synergistic photo-thermal/chemo therapy against HCC. STATEMENT OF SIGNIFICANCE: We created cancer cell-macrophage hybrid membrane-coated hollow CuS NPs encapsulating sorafenib and surface modified with anti-VEGFR antibodies (CuS-SF@CMV). These CuS-SF@CMV NPs enhanced synergistic PTT and chemotherapy against hepatoma cells through homotypic cell targeting, immune escape and inhibition of a tumorigenic signaling pathway. A long-term inhibition of tumor growth and metastasis was achieved owing to the rapid destruction of the cancer cells through photo-thermal conversion by the CuS NPs, and sustained clearance of the tumor cells by sorafenib and anti-VEGFR antibodies. Our findings suggest that CuS-SF@CMV NPs present great treating effects in preclinical models of HCC, providing the framework for further study in clinical trials to improve patient outcome in hepatocellular carcinoma.
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Affiliation(s)
- Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital, Jilin University, 71 Xinmin Street, Changchun 130021, China
| | - Hongqiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital, Jilin University, 71 Xinmin Street, Changchun 130021, China
| | - Yang Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital, Jilin University, 71 Xinmin Street, Changchun 130021, China
| | - Fenghui Peng
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital, Jilin University, 71 Xinmin Street, Changchun 130021, China
| | - Meiyu Song
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin street, Changchun 130012, China
| | - Kaiju Sun
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin street, Changchun 130012, China
| | - Fei Yan
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), International Research Center for Chemistry-Medicine Joint Innovation, College of Chemistry, Jilin University, 2699 Qianjin street, Changchun 130012, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital, Jilin University, 71 Xinmin Street, Changchun 130021, China.
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Jiang G, Shi L, Zheng X, Zhang X, Wu K, Liu B, Yan P, Liang X, Yu T, Wang Y, Cai X. Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma. Aging (Albany NY) 2020; 12:11466-11484. [PMID: 32579541 PMCID: PMC7343489 DOI: 10.18632/aging.103231] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/29/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8+T function in vitro. We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.
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Affiliation(s)
- Guangyi Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xueyong Zheng
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xinjie Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ke Wu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Boqiang Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Peijian Yan
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tunan Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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He H, Lin X, Guo J, Wang J, Xu B. Perimitochondrial Enzymatic Self-Assembly for Selective Targeting the Mitochondria of Cancer Cells. ACS NANO 2020; 14:6947-6955. [PMID: 32383849 PMCID: PMC7316614 DOI: 10.1021/acsnano.0c01388] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Emerging evidence indicates that mitochondria contribute to drug resistance in cancer, but how to selectively target the mitochondria of cancer cells remains less explored. Here, we show perimitochondrial enzymatic self-assembly for selectively targeting the mitochondria of liver cancer cells. Nanoparticles of a peptide-lipid conjugate, being a substrate of enterokinase (ENTK), encapsulate chloramphenicol (CLRP), a clinically used antibiotic that is deactivated by glucuronidases in cytosol but not in mitochondria. Perimitochondrial ENTK cleaves the Flag-tag on the conjugate to deliver CLRP selectively into the mitochondria of cancer cells, thus inhibiting the mitochondrial protein synthesis, inducing the release of cytochrome c into the cytosol and resulting in cancer cell death. This strategy selectively targets liver cancer cells over normal liver cells. Moreover, blocking the mitochondrial protein synthesis sensitizes the cancer cells, relying on glycolysis and/or OXPHOS, to cisplatin. This work illustrates a facile approach, selectively targeting mitochondria of cancer cells and repurposing clinically approved ribosome inhibitors, to interrupt the metabolism of cancer cells for cancer treatment.
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Affiliation(s)
| | | | | | | | - Bing Xu
- Corresponding Author: Bing Xu-Department of Chemistry, Brandeis University,
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42
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Li C, Ge S, Zhou J, Peng J, Chen J, Dong S, Feng X, Su N, Zhang L, Zhong Y, Deng L, Tang X. Exploration of the effects of the CYCLOPS gene RBM17 in hepatocellular carcinoma. PLoS One 2020; 15:e0234062. [PMID: 32497093 PMCID: PMC7272028 DOI: 10.1371/journal.pone.0234062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/18/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal and malignant tumours worldwide. New therapeutic targets for HCC are urgently needed. CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes have been noted to be associated with cancer-targeted therapies. Therefore, we intended to explore the effects of the CYCLOPS gene RBM17 on HCC oncogenesis to determine if it could be further used for targeted therapy. METHODS We collected data on 12 types of cancer from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) queries for comparison with adjacent non-tumour tissues. RBM17 expression levels, clinicopathological factors and survival times were analysed. RNAseq data were downloaded from the Encyclopaedia of DNA Elements database for molecular mechanism exploration. Two representative HCC cell models were built to observe the proliferation capacity of HCC cells when RBM17 expression was inhibited by shRBM17. Cell cycle progression and apoptosis were also examined to investigate the pathogenesis of RBM17. RESULTS Based on 6,136 clinical samples, RBM17 was markedly overexpressed in most cancers, especially HCC. Moreover, data from 442 patients revealed that high RBM17 expression levels were related to a worse prognosis. Overexpression of RBM17 was related to the iCluster1 molecular subgroup, TNM stage, and histologic grade. Pathway analysis of RNAseq data suggested that RBM17 was involved in mitosis. Further investigation revealed that the proliferation rates of HepG2 (P = 0.003) and SMMC-7721 (P = 0.030) cells were significantly reduced when RBM17 was knocked down. In addition, RBM17 knockdown also arrested the progression of the cell cycle, causing cells to halt at the G2/M phase. Increased apoptosis rates were also found in vitro. CONCLUSION These results suggest that RBM17 is a potential therapeutic target for HCC treatment.
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Affiliation(s)
- Can Li
- Queen Mary School, Medical College of Nanchang University, Nanchang, China
| | - Shanghua Ge
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Jialu Zhou
- The Second Clinical College, Medical College of Nanchang University, Nanchang, China
| | - Jie Peng
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Jiayu Chen
- The Fourth Clinical College, Medical College of Nanchang University, Nanchang, China
| | - Shuhui Dong
- The Fourth Clinical College, Medical College of Nanchang University, Nanchang, China
| | - Xiaofang Feng
- The Fourth Clinical College, Medical College of Nanchang University, Nanchang, China
| | - Ning Su
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Lunli Zhang
- Department of Infectious Diseases & Key Laboratory of Liver Regenerative Medicine of Jiangxi Province, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanbin Zhong
- Department of Infectious Diseases & Key Laboratory of Liver Regenerative Medicine of Jiangxi Province, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Libin Deng
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
- College of Basic Medical Science, Nanchang University, Nanchang, China
| | - Xiaoli Tang
- College of Basic Medical Science, Nanchang University, Nanchang, China
- * E-mail:
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Chen M, Hu J, Cao J, Cai X. Comprehensive Consideration before the Decision-Making of the Systemic Treatment in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer 2020; 9:221-222. [PMID: 32399435 PMCID: PMC7206608 DOI: 10.1159/000502775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 08/15/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Mingyu Chen
- *Mingyu Chen, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No.3 East Qingchun Road, Hangzhou, Zhejiang 310016 (China), E-Mail
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Liu G, Yang ZF, Zhou PY, Zhou C, Guan RY, Sun BY, Fan J, Zhou J, Yi Y, Qiu SJ. ROR-α-1 inhibits the proliferation, invasion, and migration of hepatocellular carcinoma MHCC97H via downregulation of chemokine CXCL5. Cytokine 2020; 129:155004. [PMID: 32058275 DOI: 10.1016/j.cyto.2020.155004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 12/17/2022]
Abstract
Hepatocarcinogenesis is a complicated process that is affected by a variety of microenvironmental factors, such as secretory chemokines and cell-extracellular matrix (ECM). Retinoic acid receptor-related orphan receptor (ROR)-α has been shown to attenuate tumor invasiveness by inducing suppressive cell microenvironment, and its low expression was associated with a worse prognosis in HCC patients. In the present study, we attempted to investigate the role and mechanism of the dominant transcript of ROR-α, ROR-α-1, in HCC development and progression. Among the four transcripts (ROR-α-1/-2/-3/-4), overexpression of ROR-α-1 dramatically suppressed the capacity of MHCC97H cells to proliferate, migrate and invade. We analyzed the differentially expressed genes in ROR-α-1-overexpressed and non-overexpressed MHCC97H cells, performed Gene Ontology (GO) enrichment analysis on these differentially-expressed genes, and found out that factors involved in the tumor microenvironment and ECM are related to the anti-tumor effects of ROR-α-1. Among these factors, chemokine CXCL5 was significantly downregulated by ROR-α-1 overexpression. Overexpression of ROR-α-1 remarkably inhibited the capacity of HCC cells to proliferate, migrate, invade, and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1, and N-cadherin, suggesting the tumor-suppressive role of ROR-α-1 in MHCC97H cells. Moreover, overexpression of CXCL5 dramatically attenuated the suppressive effects of cell proliferation, migration and invasion induced by ROR-α-1 overexpression in MHCC97H, suggesting that ROR-α-1 exerts its anti-tumor effects via downregulating CXCL5. In conclusion, we demonstrate the tumor-suppressive role of ROR-α-1 in MHCC97H cells and that ROR-α-1 might play a tumor-suppressive role via regulation of chemokine CXCL5.
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Affiliation(s)
- Gao Liu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Pei-Yun Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Ruo-Yu Guan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China.
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Liver Cancer Institute, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, China.
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Li H, Guo D, Zhang Y, Yang S, Zhang R. miR-664b-5p Inhibits Hepatocellular Cancer Cell Proliferation Through Targeting Oncogene AKT2. Cancer Biother Radiopharm 2020; 35:605-614. [PMID: 31967930 DOI: 10.1089/cbr.2019.3043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: miR-664b-5p accelerates the development of certain cancers, but the role of miR-664b-5p in hepatocellular carcinoma (HCC) has been less reported. Therefore, the authors aimed to study the role of miR-664b-5p in HCC progression. Materials and Methods: miR-664b-5p expression in liver cancer and adjacent tissues, and in HepG2 and SUN-475 cells, was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Relationship between miR-664b-5p and AKT2 was predicted by TargetScan and confirmed by dual-luciferase reporter assay, and gene or protein expressions were determined by performing qRT-PCR and Western blotting. The viability and apoptosis, and the migration and invasion of HepG2 and SUN-475 cells were determined by CCK-8 assay and flow cytometry, and transwell assay, respectively. Results: Downregulated miR-664b-5p was observed in hepatocellular cancer tissues. Functional analyses revealed that miR-664b-5p mimic suppressed viability, migration, and invasion, but promoted apoptosis in HepG2 and SUN-475 cells. AKT2 was a target of miR-664b-5p, whose mimics inhibited the expression of AKT2. However, upregulated AKT2 promoted viability, migration, and invasion, but inhibited apoptosis in HepG2 and SUN-475 cells, and such effects were reversed by miR-664b-5p mimics. Conclusions: miR-664b-5p acts as a cancer suppressor through negatively regulating AKT2 expression in HepG2 and SUN-475 cells, suggesting that miR-664b-5p could be a protective target for HCC patients.
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Affiliation(s)
- Hongwei Li
- The First Inpatient Ward of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Dawei Guo
- The First Department of General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuhong Zhang
- The First Inpatient Ward of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Shiming Yang
- The First Inpatient Ward of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Rui Zhang
- The First Inpatient Ward of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
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46
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Che L, Chi W, Qiao Y, Zhang J, Song X, Liu Y, Li L, Jia J, Pilo MG, Wang J, Cigliano A, Ma Z, Kuang W, Tang Z, Zhang Z, Shui G, Ribback S, Dombrowski F, Evert M, Pascale RM, Cossu C, Pes GM, Osborne TF, Calvisi DF, Chen X, Chen L. Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut 2020; 69:177-186. [PMID: 30954949 PMCID: PMC6943247 DOI: 10.1136/gutjnl-2018-317581] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/14/2019] [Accepted: 03/15/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DESIGN We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. RESULTS Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. CONCLUSION Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.
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Affiliation(s)
- Li Che
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China,Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
| | - Wenna Chi
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China,Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yu Qiao
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA,Department of Oncology, National Center of Gerontology, Beijing Hospital, Beijing, China
| | - Jie Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China,Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
| | - Xinhua Song
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
| | - Ye Liu
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China
| | - Lei Li
- School of Pharmacy, Huazhong University of Science and Technology Tongji Medical College, Wuhan, Hubei, China
| | - Jiaoyuan Jia
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA,Department of Oncology and Hematology, The Second Hospital, Jilin University, Changchun, Jilin, China
| | - Maria G Pilo
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Sardegna, Italy
| | - Jingxiao Wang
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA,Beijing University of Chinese Medicine, Beijing, China
| | - Antonio Cigliano
- Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany
| | - Zhilong Ma
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China
| | - Wenhua Kuang
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China
| | - Zefang Tang
- BIOPIC, Beijing Advanced Innovation Center for Genomics, and School of Life Sciences, Peking University, Beijing, China,Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Zemin Zhang
- BIOPIC, Beijing Advanced Innovation Center for Genomics, and School of Life Sciences, Peking University, Beijing, China,Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, China
| | - Silvia Ribback
- Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Rosa Maria Pascale
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Sardegna, Italy
| | - Carla Cossu
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Sardegna, Italy
| | - Giovanni Mario Pes
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Sardegna, Italy
| | - Timothy F Osborne
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Diego F Calvisi
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Sardegna, Italy
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
| | - Ligong Chen
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China,Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Dihydroartemisinin Sensitizes Mutant p53 (R248Q)-Expressing Hepatocellular Carcinoma Cells to Doxorubicin by Inhibiting P-gp Expression. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8207056. [PMID: 31976328 PMCID: PMC6955115 DOI: 10.1155/2019/8207056] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/04/2019] [Indexed: 02/07/2023]
Abstract
Mutant p53 (R248Q) induces doxorubicin (ADM) resistance in hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) can synergistically enhance anticancer effect of many chemotherapeutic agents. However, whether DHA could increase therapeutic efficacy of ADM in p53 (R248Q)-expressing HCC cells remains unknown. In the present study, we established mutant p53 (R248Q)-expressing Hep3B cells to study the effect and mechanism of DHA on ADM resistance and the synergistic effect of DHA with ADM. We found that P-gp was highly expressed in p53 (R248Q)-expressing Hep3B cells. As a result, cells expressing p53 (R248Q) displayed higher cell viability and lower cell apoptosis level upon ADM treatment. Meanwhile, phosphorylation levels of ERK1/2 and p65 were elevated in p53 (R248Q)-expressing Hep3B cells. However, combination of DHA and ADM treatment decreased cell viability and elevated cell apoptosis level in p53 (R248Q)-expressing Hep3B cells. Molecular dynamics simulations showed that DHA had the potential to bind with mutant p53 (R248Q) protein. Furthermore, DHA treatment decreased P-gp expression and inhibited phosphorylation levels of ERK1/2 and p65 in p53 (R248Q)-expressing Hep3B cells. Finally, DHA treatment could significantly reduce ADM efflux in p53 (R248Q)-expressing cells. Our results indicate that DHA could decrease P-gp expression via inhibiting the p53 (R248Q)-ERK1/2-NF-κB signaling pathway, which eventually confers sensitization of p53 (R248Q)-expressing HCC cells to ADM. Our study provides evidence for the potential application of DHA and ADM combination in treatment of mutant p53 (R248Q)-harbored HCC.
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48
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MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo. Biochem Biophys Res Commun 2019; 523:147-152. [PMID: 31836141 DOI: 10.1016/j.bbrc.2019.12.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 12/05/2019] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma which is featured with the extensive vascularization is the third most frequent cause of cancer-related deaths with limited therapeutic options, particularly for advanced disease. Cobimetinib, a MEK inhibitor, has been approved for the treatment of melanomas with a BRAF mutation. In this work, we investigated the efficacy of cobimetinib in sensitive and resistant HCC cells. Using a panel of HCC cell lines and normal hepatocellular cells as control, we showed that cobimetinib is active against HCC cells and spare normal hepatocellular cells. Cobimetinib at nanomolar concentration inhibited proliferation and induced apoptosis in sorafenib-resistant HCC cells (Hep3B-r), suggesting its ability to overcome HCC resistance to standard of care. This was further demonstrated by our results that cobimetinib significantly augmented the inhibitory effects of sorafenib and doxorubicin in HCC cells. Notably, cobimetinib dose-dependently inhibited tumor angiogenesis by inhibiting HCC endothelial cell (HCCEC) growth, survival and capillary network work formation. Cobimetinib suppressed ERK/RSK without affecting JNK or p38 signaling pathways in Hep3B-r and HCCEC cells. In addition, cobimetinib negatively influenced the apoptosis pathways by increasing pro-apoptotic protein Bim and decreasing anti-apoptotic proteins Mcl-1 and Bcl-2. In addition, we validated the in vitro findings in HCC xenograft mouse model and demonstrated that cobimetinib inhibited ERK signaling, promoted apoptosis, and was active against resistant HCC growth and angiogenesis in vivo, without causing significant toxicity in mice. Our findings support the clinical trials of cobimetinib for HCC treatment and highlight the therapeutic value of inhibiting MEK/ERK/RSK to overcome HCC resistance.
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49
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Han L, Huang C, Zhang S. The RNA-binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA. Liver Int 2019; 39:2190-2203. [PMID: 31365778 DOI: 10.1111/liv.14202] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/13/2019] [Accepted: 07/25/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Numerous studies have revealed that dysregulation of RNA-binding protein (RBP) expression is causally linked with human cancer tumourigenesis. However, the detailed biological effect and underlying mechanisms of most RBPs remain unclear. METHODS Expression of sorbin and SH3 domain-containing 2 (SORBS2) in hepatocellular carcinoma (HCC) was detected by qRT-PCR, immunohistochemistry assay and Western blot assay. Proliferation, migration, invasion and cell cycle progression of HCC cells were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony-forming assay, Transwell assay and flow cytometry assay respectively. A xenograft model and metastatic model were established to evaluate the proliferation and metastasis of HCC cells in vivo. Western blot assays were performed to assess the expression of epithelial-mesenchymal transition markers. Luciferase reporter assay, RNA immunoprecipitation and pull-down assay elucidated the effect of SORBS2 on one of its downstream genes. RESULTS The expression of SORBS2 was significantly decreased in HCC and was associated with metastasis, advanced TNM clinical stage and poor clinical outcome of HCC patients. Furthermore, our results suggested that SORBS2 inhibited HCC cell proliferation, invasion, migration and EMT both in vivo and in vitro. Mechanistically, we revealed that retinoic acid receptor-related orphan receptor (RORA) was a major target of SORBS2 and was critical to sustaining the antitumour effect of SORBS2 on HCC cells. SORBS2 reduced RORA mRNA degradation by directly binding to the 3'UTR of RORA mRNA. CONCLUSIONS In this study, we found for the first time that SORBS2 contributed to the suppression of HCC tumourigenesis and metastasis via post-transcriptional regulation of RORA expression as an RBP.
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Affiliation(s)
- Lili Han
- Department of Oncology, College of Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Chen Huang
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, China
| | - Shuqun Zhang
- Department of Oncology, College of Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, P.R. China
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50
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Michel M, Hollenbach M, Pohl S, Ripoll C, Zipprich A. Inhibition of Glyoxalase-I Leads to Reduced Proliferation, Migration and Colony Formation, and Enhanced Susceptibility to Sorafenib in Hepatocellular Carcinoma. Front Oncol 2019; 9:785. [PMID: 31482070 PMCID: PMC6710403 DOI: 10.3389/fonc.2019.00785] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 08/02/2019] [Indexed: 12/17/2022] Open
Abstract
Background: Glyoxalase-I (Glo-I) is essential for detoxification of methylglyoxal (MGO), a byproduct of glycolysis. Overexpression of Glo-I has been linked to multi-drug resistance in cancer therapy. The aim of this study was to analyze Glo-I in hepatocellular carcinoma (HCC) and the effect of the multi-tyrosine kinase inhibitor sorafenib on Glo-I. Methods: Expression and specific activity of Glo-I was measured in human HCC samples, HCC-cell lines (HepG2, Huh7) and a hepatocyte cell line (AML 12). Cells were either treated with Glo-I inhibitors, ethyl pyruvate (EP, 1-20 mM) and BrBzGSHCp2 (1-10 μM), or sorafenib (2.5-10 μM) and protein expression (Western Blot), proliferation (WST-assay), migration (scratch assay), and colony formation (clonogenic assay) were assessed. Results: High expression of Glo-I was detected in human HCC tissue samples. Huh7 showed highest expression and activity of Glo-I and revealed highest proliferation compared to AML 12 and HepG2. Targeting Glo-I by EP or BrBzGSHCp2 led to significantly reduced proliferation (20 mM EP 24 h: 57 ± 12%), migration and colony formation. Glo-I inhibition by 20 mM EP resulted in reduced expression of PDGFR-β (18 ± 10%), VEGFR2 (46 ± 11%), VEGF (61 ± 10%), pERK/ERK (62 ± 6%), NF-κB (44 ± 12%) as well as stimulation of Nrf2 (243 ± 36%). Similar results were seen with BrBzGSHCp2. Sorafenib treatment revealed elevation of Glo-I (10 μM: 209 ± 25%) and MGO. Co-treatment of EP and sorafenib led to an additional reduction of proliferation compared to sorafenib alone. Conclusion: Glo-I is positively correlated with HCC proliferation. Inhibition of Glo-I reduced proliferation, migration, and colony formation. In turn, sorafenib increases Glo-I. Co-treatment using Glo-I inhibitors could enhance susceptibility of HCC to sorafenib.
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Affiliation(s)
- Maurice Michel
- Laboratory of Molecular Hepatology, Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Marcus Hollenbach
- Laboratory of Molecular Hepatology, Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Sabine Pohl
- Laboratory of Molecular Hepatology, Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Cristina Ripoll
- Laboratory of Molecular Hepatology, Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Alexander Zipprich
- Laboratory of Molecular Hepatology, Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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