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1
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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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Lou YX, Gu J, Zhu L, Sun SQ, Hao XL, Chen JP, Han F, Wang DD, Jiang X, Liu JY. TC2N Promotes Cell Proliferation and Metastasis in Hepatocellular Carcinoma by Targeting the Wnt/β-Catenin Signaling Pathway. J Transl Med 2023; 103:100260. [PMID: 37839635 DOI: 10.1016/j.labinv.2023.100260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 09/14/2023] [Accepted: 10/07/2023] [Indexed: 10/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most prevalent types of cancer worldwide, has an exceedingly poor prognosis. Tandem C2 domain nuclear protein (TC2N) has been implicated in tumorigenesis and serves as an oncogene or tumor suppressor in different types of cancer. Here, we explore the possible regulatory activities and molecular mechanisms of TC2N in HCC progression. However, TC2N expression was significantly upregulated in HCC tissues and hepatoma cell lines, and this upregulation was positively correlated with tumor progression in HCC patients. The ectopic overexpression of TC2N accelerated the proliferation, migration, and invasion of HCC cells, whereas its knockdown showed the opposite effects. Bioinformatics analysis showed that TC2N participates in the regulation of the Wnt/β-catenin signaling pathway. Mechanistically, TC2N activated the Wnt/β-catenin signaling pathway by regulating the expression levels of β-catenin and its downstream targets CyclinD1, MMP7, c-Myc, c-Jun, AXIN2, and glutamine synthase. Furthermore, the deletion of β-catenin effectively neutralized the regulation of TC2N in HCC proliferation and metastasis. Overall, this study showed that TC2N promotes HCC proliferation and metastasis by activating the Wnt/β-catenin signaling pathway, indicating that TC2N might be a potential molecular target for the treatment of HCC.
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Affiliation(s)
- Yi-Xia Lou
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jing Gu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lei Zhu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Sheng-Qi Sun
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiang-Lin Hao
- Department of Pathology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jian-Ping Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Fei Han
- Department of Toxicology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Dan-Dan Wang
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China; Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, School of Basic Medicine, Henan University, Kaifeng, China
| | - Xiao Jiang
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jin-Yi Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China.
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Xing S, Zhu Y, You Y, Wang S, Wang H, Ning M, Jin H, Liu Z, Zhang X, Yu C, Lu ZJ. Cell-free RNA for the liquid biopsy of gastrointestinal cancer. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1791. [PMID: 37086051 DOI: 10.1002/wrna.1791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 03/22/2023] [Accepted: 04/03/2023] [Indexed: 04/23/2023]
Abstract
Gastrointestinal (GI) cancer includes many cancer types, such as esophageal, liver, gastric, pancreatic, and colorectal cancer. As the cornerstone of personalized medicine for GI cancer, liquid biopsy based on noninvasive biomarkers provides promising opportunities for early diagnosis and dynamic treatment management. Recently, a growing number of studies have demonstrated the potential of cell-free RNA (cfRNA) as a new type of noninvasive biomarker in body fluids, such as blood, saliva, and urine. Meanwhile, transcriptomes based on high-throughput RNA detection technologies keep discovering new cfRNA biomarkers. In this review, we introduce the origins and applications of cfRNA, describe its detection and qualification methods in liquid biopsy, and summarize a comprehensive list of cfRNA biomarkers in different GI cancer types. Moreover, we also discuss perspective studies of cfRNA to overcome its current limitations in clinical applications. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Shaozhen Xing
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
- Institute for Precision Medicine, Tsinghua University, Beijing, China
| | - Yumin Zhu
- MOE Key Laboratory of Population Health Across Life Cycle, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Department of Maternal & Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yaxian You
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Siqi Wang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Hongke Wang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Meng Ning
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Heyue Jin
- MOE Key Laboratory of Population Health Across Life Cycle, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Department of Maternal & Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Zhengxia Liu
- Department of General Surgery, SIR RUN RUN Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinhua Zhang
- Department of Health Care, Jiangsu Women and Children Health Hospital, the First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, China
| | - Chunzhao Yu
- Department of General Surgery, SIR RUN RUN Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhi John Lu
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
- Institute for Precision Medicine, Tsinghua University, Beijing, China
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4
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Zhao H, Chen C, Song H, Qin R, Wang X, He Q, Li F, Zhao H, Li Y. DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4277254. [PMID: 36299605 PMCID: PMC9592219 DOI: 10.1155/2022/4277254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/27/2022] [Indexed: 10/10/2023]
Abstract
DNA topoisomerases (TOPs) are dysregulated in various types of cancer. However, how TOP II-alpha (TOP2A) contributes to hepatocellular carcinoma (HCC) progression remains elusive. Cohort analysis revealed that the increased expression of TOP2A was associated with poor clinical outcomes and TOP2A was significantly upregulated in HCC tissues and cell lines. In vitro, TOP2A expression level is related to cell invasion and migration, which may be due to the alteration of epithelial-mesenchymal transition by the TOP2A. Moreover, we used verteporfin (a Hippo inhibitor) to test how the Hippo pathway promotes the effect of TOP2A on the HCC phenotype and found that TOP2A induces tumor progression through the Hippo pathway. Finally, miR-22-5p inhibited tumor progression by sponging TOP2A.
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Affiliation(s)
- Haichao Zhao
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 300032, China
| | - Changzhou Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 300032, China
| | - Huangqin Song
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Rongyi Qin
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Xiaoxiao Wang
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Qizu He
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Feng Li
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Haoliang Zhao
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
| | - Yanjun Li
- Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan 030032, China
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Kahraman DC, Bilget Guven E, Aytac PS, Aykut G, Tozkoparan B, Cetin Atalay R. A new triazolothiadiazine derivative inhibits stemness and induces cell death in HCC by oxidative stress dependent JNK pathway activation. Sci Rep 2022; 12:15139. [PMID: 36071119 PMCID: PMC9452548 DOI: 10.1038/s41598-022-17444-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 07/26/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and resistant to both conventional and targeted chemotherapy. Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the incidence and mortality of different types of cancers. Here, we investigated the cellular bioactivities of a series of triazolothiadiazine derivatives on HCC, which have been previously reported as potent analgesic/anti-inflammatory compounds. From the initially tested 32 triazolothiadiazine NSAID derivatives, 3 compounds were selected based on their IC50 values for further molecular assays on 9 different HCC cell lines. 7b, which was the most potent compound, induced G2/M phase cell cycle arrest and apoptosis in HCC cells. Cell death was due to oxidative stress-induced JNK protein activation, which involved the dynamic involvement of ASK1, MKK7, and c-Jun proteins. Moreover, 7b treated nude mice had a significantly decreased tumor volume and prolonged disease-free survival. 7b also inhibited the migration of HCC cells and enrichment of liver cancer stem cells (LCSCs) alone or in combination with sorafenib. With its ability to act on proliferation, stemness and the migration of HCC cells, 7b can be considered for the therapeutics of HCC, which has an increased incidence rate of ~ 3% annually.
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Affiliation(s)
- Deniz Cansen Kahraman
- Cancer Systems Biology Laboratory, Graduate School of Informatics, METU, 06800, Ankara, Turkey.
| | - Ebru Bilget Guven
- Department of Molecular Biology and Genetics, Bilkent University, 06800, Ankara, Turkey.,Department of Molecular Biology and Genetics, Kadir Has University, 34083, Istanbul, Turkey
| | - Peri S Aytac
- Department of Pharmaceutical Chemistry, Hacettepe University, 06800, Ankara, Turkey
| | - Gamze Aykut
- Department of Molecular Biology and Genetics, Bilkent University, 06800, Ankara, Turkey
| | - Birsen Tozkoparan
- Department of Pharmaceutical Chemistry, Hacettepe University, 06800, Ankara, Turkey
| | - Rengul Cetin Atalay
- Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, 60637, USA
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6
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Ke S, Wang C, Su Z, Lin S, Wu G. Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma. Front Genet 2022; 13:897683. [PMID: 35651950 PMCID: PMC9149379 DOI: 10.3389/fgene.2022.897683] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/13/2022] [Indexed: 12/21/2022] Open
Abstract
Background: The carcinogenesis and prognosis of hepatocellular carcinoma (HCC) involve complex molecular mechanisms, and ferroptosis is related to the development and therapeutic efficacy of HCC, but the specific mechanism and prognostic role of ferroptosis-related genes in HCC have not been elucidated. Methods: Differentially expressed gene analysis, Cox regression, and unsupervised consensus clustering were applied to identify crucial ferroptosis regulators and establish ferroptosis-related subtypes in HCC. Random forest analysis and survival analysis were adopted to confirm FTL as the hub prognostic and diagnostic ferroptosis regulator in HCC. Results: The ferroptosis-related subtypes based on the crucial prognostic ferroptosis regulators showed that patients in fescluster A had a higher survival probability (p < 0.001) and better clinical characteristics than patients in fescluster B in the TCGA-LIHC cohort. Patients with a high tumor mutation burden (TMB) in fescluster B presented a significantly poorer prognosis. FTL was the core ferroptosis regulator, and its low expression revealed a significant survival advantage compared with its high expression (p = 0.03). The expression and predictive value of FTL were both closely related to the clinical features (p < 0.05). Expression of FTL accurately distinguished HCC from normal tissues in the TCGA-LIHC cohort, ICGC cohort, and GSE14520 dataset. In addition, higher infiltrating fractions of immune cells, such as activated CD8+ T cells and Gamma delta T cells, mainly enriched immune-related signaling pathways, including the IL2-STAT3 signaling pathway and interferon-gamma response signaling pathway, and higher expression of immune checkpoints, including PDCD1, CTLA4, TIGIT, and CD83, were presented in patients with high FTL expression (p < 0.05). Patients with high FTL were more sensitive to some targeted drugs, such as cisplatin, dasatinib, and sorafenib, than those with low FTL (p < 0.05). A nomogram based on FTL accurately predicted the prognosis of HCC. Further knockdown of FTL was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion: Our study validated ferroptosis-related subtypes and FTL with effective prognostic value in HCC and was beneficial for identifying candidates suitable for targeted drug therapy and immunotherapy, thereby offering further insight into individual treatment strategies to improve disease outcomes in HCC patients.
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Affiliation(s)
- Shaoying Ke
- Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
| | - Congren Wang
- Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
| | - Zijian Su
- Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
| | - Shaoze Lin
- Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
| | - Gongle Wu
- Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
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7
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Li L, He K, Chen S, Wei W, Tian Z, Tang Y, Xiao C, Xiang G. Circ_0001175 Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis by Regulating miR-130a-5p. Onco Targets Ther 2020; 13:13315-13327. [PMID: 33408482 PMCID: PMC7781360 DOI: 10.2147/ott.s262408] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Objective Many aberrantly expressed circular RNAs (circRNAs) play important roles in the development and progression of hepatocellular carcinoma (HCC). However, the exact function of circ_0001175 in HCC cells is unknown. Our study aimed to investigate the expression characteristics of circ_0001175 in HCC and its effects on the proliferation, migration and invasion of HCC cells, and to explore the potential mechanism. Materials and Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to detect circ_0001175, microRNA-130a-5p (miR-130a-5p) and sorting nexin 5 (SNX5) expressions in HCC tissues and cells; cell counting kit-8 (CCK-8), BrdU and Transwell assays were conducted to detect the proliferation, migration and invasion of HCC cells. A lung metastasis model in nude mice was used to examine the effect of circ_0001175 on the metastasis of HCC cells in vivo. Bioinformatics prediction, luciferase reporter gene experiment, Ago2-RIP experiment and RNA pull-down assay were adopted to identify the binding relationships among circ_0001175, miR-130a-5p and SNX5. Results Circ_0001175 and SNX5 expressions were up-regulated in HCC tissues and cell lines, while miR-130a-5p expression was down-regulated. Abnormal expressions of circ_0001175, miR-130a-5p and SNX5 were associated with poor clinicopathological features of HCC patients; circ_0001175 facilitated HCC cell proliferation, migration and invasion in vitro and promoted lung metastasis in vivo; miR-130a-5p inhibited the above malignant biological behaviors of HCC cells, and it could reverse the function of circ_0001175. SNX5 was identified as a target gene of miR-130a-5p, and circ_0001175 could sponge miR-130a-5p and up-regulate the expression of SNX5 in HCC cells. Conclusion Circ_0001175 is highly expressed in HCC and facilitates HCC progression through regulating miR-130a-5p/SNX5 axis.
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Affiliation(s)
- Liheng Li
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Siliang Chen
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Wenjiang Wei
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Zuofu Tian
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Yinghong Tang
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Chengjiang Xiao
- Department of Interventional Radiology, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, People's Republic of China
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Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells. Int J Mol Sci 2020; 22:ijms22010224. [PMID: 33379356 PMCID: PMC7795419 DOI: 10.3390/ijms22010224] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance.
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9
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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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10
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Yasuda D, Ohe T, Takahashi K, Imamura R, Kojima H, Okabe T, Ichimura Y, Komatsu M, Yamamoto M, Nagano T, Mashino T. Inhibitors of the protein-protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line. Free Radic Res 2020; 54:859-871. [PMID: 32075457 DOI: 10.1080/10715762.2020.1732955] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein-protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.
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Affiliation(s)
- Daisuke Yasuda
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Tomoyuki Ohe
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kyoko Takahashi
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Riyo Imamura
- Drug Discovery Initiative, University of Tokyo, Tokyo, Japan
| | | | - Takayoshi Okabe
- Drug Discovery Initiative, University of Tokyo, Tokyo, Japan
| | - Yoshinobu Ichimura
- Department of Physiology, Juntendo University School of Medicine, Tokyo, Japan
| | - Masaaki Komatsu
- Department of Physiology, Juntendo University School of Medicine, Tokyo, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University School of Medicine, Sendai-shi, Japan
| | - Tetsuo Nagano
- Drug Discovery Initiative, University of Tokyo, Tokyo, Japan
| | - Tadahiko Mashino
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
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11
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Gu L, Zhu Y, Lin X, Tan X, Lu B, Li Y. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis. Oncogene 2020; 39:2437-2449. [PMID: 31974474 DOI: 10.1038/s41388-020-1156-0] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 12/24/2019] [Accepted: 01/10/2020] [Indexed: 11/09/2022]
Abstract
Metabolic alteration for adaptation of the local environment has been recognized as a hallmark of cancer. GNPAT dysregulation has been implicated in hepatocellular carcinoma (HCC). However, the precise posttranslational regulation of GNPAT is still undiscovered. Here we show that ACAT1 is upregulated in response to extra palmitic acid (PA). ACAT1 acetylates GNPAT at K128, which represses TRIM21-mediated GNPAT ubiquitination and degradation. Conversely, GNPAT deacetylation by SIRT4 antagonizes ACAT1's function. GNPAT represses TRIM21-mediated FASN degradation and promotes lipid metabolism. Furthermore, shRNA-mediated ACAT1 ablation and acetylation deficiency of GNPAT repress lipid metabolism and tumor progression in xenograft and DEN/CCl4-induced HCC. Otherwise, ACAT1 inhibitor combination with sorafenib enormously retards tumor formation in mice. Collectively, we demonstrate that stabilization of FASN by ACAT1-mediated GNPAT acetylation plays a critical role in hepatocarcinogenesis.
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Affiliation(s)
- Li Gu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China. .,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China.
| | - Yahui Zhu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Xi Lin
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Xingyu Tan
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Bingjun Lu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Youjun Li
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China. .,Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China.
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12
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Yang M, Liu X, Zhang C, Liao F, Li Z, Luo X, Sun Y, Chen C. A Study Of Efficacy And Safety With Apatinib Or Apatinib Combined With Chemotherapy In Recurrent/advanced Ovarian Cancer Patients. Cancer Manag Res 2019; 11:8869-8876. [PMID: 31632146 PMCID: PMC6790407 DOI: 10.2147/cmar.s223372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 09/23/2019] [Indexed: 12/26/2022] Open
Abstract
Objectives Despite recent advances in the treatment of advanced ovarian cancer, drug selection after second-line chemotherapy has not been well studied. In this study, we retrospectively evaluated the effect and safety of apatinib as monotherapy or in combination with chemotherapy for the treatment of advanced ovarian cancer after second-line treatment. Methods We reviewed the medical records of patients from April 2016 to October 2018 with advanced ovarian cancer who received apatinib after failed second-line chemotherapy. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method. Response rate (RR) and disease control rate (DCR) were evaluated using radiologic reports according to RECIST 1.1 criteria. Treatment-related adverse events were evaluated based on NCI-CTC version 4.0. Results Study concerned 22 evaluated cases; of them, 13 patients received apatinib combined with chemotherapy and 9 patients received apatinib monotherapy. The median PFS was 8.2 months (9.7 months in combined group and 4.4 months in monotherapy group, P value was 0.21). The median OS was 13.1 months (13.6 months in combined group and 11.6 months in monotherapy group, P value was 0.45). The RR was 20% and DCR was 85% (combined group: RR 33.3%, DCR 100%, monotherapy group: RR 0%, DCR 62.5%). The main side effect was hypertension (9/22), proteinuria (7/22), oral mucositis (5/22), hand and foot syndrome (6/22%), leukopenia (5/22), etc. Conclusion Apatinib showed good efficacy and safety for advanced ovarian cancer patients whether used alone or in combination with chemotherapy. In the meanwhile, this study is limited by the small cases number. Therefore, further research is needed to provide more data and ultimately apply it to guide clinical practice.
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Affiliation(s)
- Mi Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, People's Republic of China.,Cancer Center of Nanjing Gaochun People's Hospital, Nanjing 211300, People's Republic of China
| | - Xiufeng Liu
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
| | - Cheng Zhang
- Department of Gynecology, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Feng Liao
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
| | - Zixiong Li
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
| | - Xianwen Luo
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
| | - Yiran Sun
- Department of Clinical Medicine, Xuzhou Medicine University, Xuzhou 221004, People's Republic of China
| | - Chao Chen
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
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13
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Sun P, Li Y, Chang L, Tian X. Prognostic and clinicopathological significance of Gamma-Glutamyltransferase in patients with hepatocellular carcinoma: A PRISMA-compliant meta-analysis. Medicine (Baltimore) 2019; 98:e15603. [PMID: 31083251 PMCID: PMC6531078 DOI: 10.1097/md.0000000000015603] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Many studies explored the prognostic and clinicopathological significance of pretreatment serum Gamma-Glutamyltransferase (GGT) level in hepatocellular carcinoma (HCC). However, there are inconsistent results in the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC. Thus, we conducted this meta-analysis to comprehensively assess the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC patients. METHODS We systematically searched PubMed, EMBASE and Web of Science for relevant studies (up to June 14, 2018). The estimated hazard ratios (HRs) were used to assess the association between pretreatment serum GGT level and survival in HCC patients. The estimated odds ratios (ORs) were applied to evaluate the correlation between pretreatment serum GGT and clinicopathological features in HCC. RESULTS Our results showed that high pretreatment serum GGT level was significantly correlated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.54-1.87; P < .01) and disease-free survival/relapse-free survival (DFS/RFS) (HR = 1.56, 95% CI: 1.42-1.71; P < .01). Additionally, our results also revealed that there was a close correlation between GGT level and several clinicopathological features in HCC patients, including vascular invasion, tumor size, tumor number and Alpha-fetoprotein (AFP) level. CONCLUSIONS This meta-analysis shows that high pretreatment serum GGT level is significantly correlated with poor survival and unfavorable clinicopathological features in HCC patients, suggesting that pretreatment serum GGT may be an economical and effective prognostic biomarker for HCC patients. However, more high-quality studies are still warranted to further validate our findings, considering there are several limitations in this meta-analysis.
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14
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Zhang XF, Wang J, Jia HL, Zhu WW, Lu L, Ye QH, Nelson PJ, Qin Y, Gao DM, Zhou HJ, Qin LX. Core fucosylated glycan-dependent inhibitory effect of QSOX1-S on invasion and metastasis of hepatocellular carcinoma. Cell Death Discov 2019; 5:84. [PMID: 30962950 PMCID: PMC6447561 DOI: 10.1038/s41420-019-0164-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/26/2019] [Accepted: 03/11/2019] [Indexed: 12/21/2022] Open
Abstract
The goal of the present study was to identify glycoproteins associated with the postoperative relapse of hepatocellular carcinoma (HCC) and to investigate their potential role in HCC metastasis. A method for quantitating N-glycoproteome was used to screen for, and identify, recurrence-related N-linked glycoproteins from 100 serum samples taken from patients with early-stage HCC. The prognostic significance of candidate glycoproteins was then validated in 193 HCC tissues using immunohistochemical staining. Serum core fucosylated quiescin sulfhydryl oxidase 1 (cf-QSOX1) was identified as a leading prognostic glycoprotein that significantly correlated with HCC recurrence. Patients with high serum cf-QSOX1 levels had a significantly longer time to recurrence (TTR) as compared with those with low serum cf-QSOX1. As was seen with serum cf-QSOX1, QSOX1 in HCC tissues was further shown to be significantly associated with good patient outcome. Gain-functional and loss-functional analyses of QSOX1-S were performed in vitro and in vivo. QSOX1-S overexpression significantly increased in vitro apoptosis, but decreased the invasive capacity of HCC cells, and reduced lung metastasis in nude mice models bearing human HCC. Furthermore, overexpression of a mutant version of QSOX1-S, which had eliminated the core-fucosylated glycan at Asn-130, showed no demonstrable effect on invasion or metastasis of HCC cells. Our study suggests that serum cf-QSOX1-S and tumor QSOX1 levels are helpful for predicting recurrence in HCC patients, and its core-fucosylated glycan at Asn-130 is critical for the inhibitory effects of QSOX1-S on invasion and metastasis of HCC
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Affiliation(s)
- Xiao-Fei Zhang
- 1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Ji Wang
- 2Department of General Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province China
| | - Hu-Liang Jia
- 1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Wen-Wei Zhu
- 1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Lu Lu
- 1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qing-Hai Ye
- 3Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,4Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, Shanghai, China
| | - Peter J Nelson
- 5Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany
| | - Yi Qin
- 6Pancreatic Cancer Institute, Fudan University, 200032 Shanghai, China
| | - Dong-Mei Gao
- 3Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,4Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, Shanghai, China
| | - Hai-Jun Zhou
- 3Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.,4Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, Shanghai, China
| | - Lun-Xiu Qin
- 1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China.,7Institute of Biomedical Sciences, Fudan University, Shanghai, China
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15
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Wang C, Luo X, Dong SL, Leng C, Zhang BX, Zhang BH. Small hepatocellular carcinoma suppressed by chemotherapy for synchronous gastric carcinoma after laparoscopy-assisted radical distal gastrectomy: A case report and literature review. Medicine (Baltimore) 2018; 97:e13190. [PMID: 30557968 PMCID: PMC6319982 DOI: 10.1097/md.0000000000013190] [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: 05/19/2018] [Accepted: 10/17/2018] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Synchronous gastric carcinoma and hepatocellular carcinoma (HCC) is rare. It is hard to distinguish synchronous HCC from metastatic liver cancer in this condition. The treatment and prognosis is quite different for synchronous HCC of gastric carcinoma and liver metastasis of gastric carcinoma. PATIENT CONCERNS A 68-year-old man with a chief complaint of epigastric pain for 1 year, accompanied by reflux and belching. The patient was diagnosed with gastric carcinoma (cT4NxM0) and laparoscopy-assisted radical distal gastrectomy was performed. This was followed by chemotherapy of FOLFOX regimen. However, a liver nodule growth was observed after postoperative systemic treatment. DIAGNOSIS The initial diagnosis was liver metastasis of gastric carcinoma. However after hepatectomy of segment VI and VII as well as thrombectomy of right hepatic vein, histology revealed intermediate to poor differentiated HCC. Hence this case was diagnosed as synchronous gastric carcinoma and HCC. INTERVENTIONS A preventive transcatheter arterial chemoembolization (TACE) was conducted at 4 weeks after hepatectomy. Another FOLFOX regimen was suggested, but was refused by the patient. OUTCOMES The patient survived without tumor recurrence for 9 months after the second surgery. LESSONS Synchronous HCC should be routinely distinguished from gastric carcinoma liver metastasis, especially for patients with hepatitis B virus (HBV) infection. The FOLFOX4 regimen for treating gastric carcinoma liver metastasis may have inhibited the progression of primary HCC in this case. This patient with HCC benefited from liver resection, inspite of hepatic vein tumor thrombosis.
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Affiliation(s)
- Chao Wang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Luo
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shui-Lin Dong
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Leng
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin-Hao Zhang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital of Tongji Medical College
- Division of General Surgery, Sino-French Branch of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Li Y, Guo M, Lin Z, Zhao M, Xia Y, Wang C, Xu T, Zhu B. Multifunctional selenium nanoparticles with Galangin-induced HepG2 cell apoptosis through p38 and AKT signalling pathway. ROYAL SOCIETY OPEN SCIENCE 2018; 5:180509. [PMID: 30564384 PMCID: PMC6281927 DOI: 10.1098/rsos.180509] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 10/23/2018] [Indexed: 05/24/2023]
Abstract
The morbidity and mortality of hepatocellular carcinoma, the most common cancer, are increasing continuously worldwide. Galangin (Ga) has been demonstrated to possess anti-cancer effect, but the efficacy of Ga was limited by its low permeability and poor solubility. To develop aqueous formulation and improve the anti-cancer activity of Ga, surface decoration of functionalized selenium nanoparticles with Ga (Se@Ga) was synthesized in the present study. The aim of this study was to evaluate the anti-cancer effect of Se@Ga and the mechanism on HepG2 cells. Se@Ga-induced HepG2 cell apoptosis was confirmed by depletion of mitochondrial membrane potential, translocation of phosphatidylserine and caspase-3 activation. Furthermore, Se@Ga enhanced the anti-cancer activity of HepG2 cells through ROS-mediated AKT and p38 signalling pathways. In summary, these results suggest that Se@Ga might be potential candidate chemotherapy for cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Bing Zhu
- Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510120, People's Republic of China
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17
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Rogalska A, Gajek A, Łukawska M, Oszczapowicz I, Marczak A. Novel oxazolinoanthracyclines as tumor cell growth inhibitors-Contribution of autophagy and apoptosis in solid tumor cells death. PLoS One 2018; 13:e0201296. [PMID: 30040861 PMCID: PMC6057680 DOI: 10.1371/journal.pone.0201296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 07/12/2018] [Indexed: 12/11/2022] Open
Abstract
Chemical modification of known, effective drugs are one method to improve the chemotherapy of tumors. We reported ability of oxazoline analogs of doxorubicin (O-DOX) and daunorubicin (O-DAU) to induce apoptosis and autophagy in ovarian and liver cancer cells. Reactive oxygen and nitrogen species (ROS and RNS, respectively), together with intracellular calcium-mediated downstream signaling, are essential for the anticancer effect of these new anthracycline analogs. The changes of mitochondrial membrane potential and induction of the ceramide pathway suggests that these compounds induce cell death by apoptosis. In addition, a significant increase of autophagosome formation was observed by fluorescence assay and acridine orange staining, indicating that the new analogs also induce autophagic cell death. Compared to free DOX- and DAU-treated cells, we observed inhibition of colony formation and migration, a time-dependency between ROS/RNS levels and a greater fall in mitochondrial membrane potential. Altogether, our research broadens the base of molecular oxazolinoanthracyclines targets and reveals that derivatives mediated oxidative stress, ceramide production and increase in intracellular calcium level by mitochondria. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator of autophagy and apoptosis signals.
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Affiliation(s)
- Aneta Rogalska
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Arkadiusz Gajek
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Małgorzata Łukawska
- Department of Modified Antibiotics, Institute of Biotechnology and Antibiotics, Warsaw, Poland
| | - Irena Oszczapowicz
- Department of Modified Antibiotics, Institute of Biotechnology and Antibiotics, Warsaw, Poland
| | - Agnieszka Marczak
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
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18
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Zheng X, Chen K, Liu X, Jiang G, Liu H. High expression of ERCC5 predicts a poor prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:3664-3670. [PMID: 31949747 PMCID: PMC6962895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 04/24/2018] [Indexed: 06/10/2023]
Abstract
Human cells exposed to environmental or endogenous carcinogens can develop DNA damage. This DNA damage may contribute to a susceptibility to cancer; therefore, it is important to repair these defects. The nucleotide excision repair pathway (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions induced by environmental or endogenous carcinogenic sources. The excision repair cross-complementation group 5 (ERCC5) gene is a central component of NER. Ectopic expression of ERCC5 has been linked to different types of cancers, including hepatocellular carcinoma (HCC). However, previous reports, mainly based on mRNA level and the role of ERCC5 in cancer, remain conflicting and unclear. In this study, we examined 104 cases of HCC for immunohistochemistry to explore the role of ERCC5 protein in HCC. We found the expression of ERCC5 protein was significantly increased in tumor tissues compared to paracancerous ones (P<0.01). The percentage of positive staining of ERCC5 in tumor tissues was 28.8% (30/104), while only 4.8% (5/104) in paracancerous tissues. Patients with low ERCC5 expression levels had a better overall survival rate and remained disease-free longer (both P<0.01). In addition, univariate and multivariate analysis showed a high expression of ERCC5 protein and large tumor size predict a poor prognosis for patients with HCC (P<0.05).
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Affiliation(s)
- Xueyong Zheng
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityNo. 3, Qingchun Road, Hangzhou 310016, China
| | - Ke Chen
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityNo. 3, Qingchun Road, Hangzhou 310016, China
| | - Xiaolong Liu
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityNo. 3, Qingchun Road, Hangzhou 310016, China
| | - Guangyi Jiang
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityNo. 3, Qingchun Road, Hangzhou 310016, China
| | - Hui Liu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang UniversityHangzhou, Zhejiang, China
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A Phase I Study of Combination Therapy with Sorafenib and 5-Fluorouracil in Patients with Advanced Hepatocellular Carcinoma. Drugs R D 2018; 17:381-388. [PMID: 28573606 PMCID: PMC5629128 DOI: 10.1007/s40268-017-0187-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background and aims Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. Methods This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. Results Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. Conclusions Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.
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20
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Chen X, Zhang S, Wang Z, Wang F, Cao X, Wu Q, Zhao C, Ma H, Ye F, Wang H, Fang Z. Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:128. [PMID: 29954442 PMCID: PMC6025706 DOI: 10.1186/s13046-018-0787-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 06/07/2018] [Indexed: 01/27/2023]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear. Methods Tissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down. Results Hypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo. Conclusions Hypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0787-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xueran Chen
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China
| | - Shangrong Zhang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China
| | - Zhen Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.,University of Science and Technology of China, No. 96, Jin Zhai Road, Hefei, 230026, Anhui, China
| | - Fengsong Wang
- School of Life Science, Anhui Medical University, No. 81, Mei Shan Road, Hefei, 230032, Anhui, China
| | - Xinwang Cao
- School of Life Science, Anhui Medical University, No. 81, Mei Shan Road, Hefei, 230032, Anhui, China
| | - Quan Wu
- Central Laboratory of Medical Research Center, Anhui Provincial Hospital, No. 17, Lu Jiang Road, Hefei, 230001, Anhui, China
| | - Chenggang Zhao
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.,University of Science and Technology of China, No. 96, Jin Zhai Road, Hefei, 230026, Anhui, China
| | - Huihui Ma
- University of Science and Technology of China, No. 96, Jin Zhai Road, Hefei, 230026, Anhui, China.,Department of Radiation Oncology, First Affiliated Hospital, Anhui Medical University, No. 81, Mei Shan Road, Hefei, 230032, Anhui, China
| | - Fang Ye
- Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China
| | - Zhiyou Fang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China. .,Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, 230031, Anhui, China.
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Liang C, Zhao J, Ge H, Li G, Wu J. Clinicopathological and prognostic significance of FoxM1 in hepatocellular carcinoma patients: a meta-analysis. Onco Targets Ther 2018; 11:3561-3571. [PMID: 29950861 PMCID: PMC6016270 DOI: 10.2147/ott.s155541] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background and aims Recently, the abnormal expression of FoxM1 has been found in many malignant tumors. However, the clinicopathological and prognostic value of FoxM1 expression in hepatocellular carcinoma (HCC) patients remains controversial. We conducted a meta-analysis to establish the relationship between FoxM1 expression and the clinicopathological features and prognostic value in patients with HCC. Methods An electronic search for relevant articles was conducted according to a set of criteria in the PubMed, Cochrane Library, Web of Science, EMBASE, Chinese CNKI and Chinese WanFang databases. The correlation data between FoxM1 expression and clinicopathological features and survival outcomes were analyzed. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% CIs were calculated using STATA14.2. Results A total of 14 studies comprising of 2,036 patients were enrolled in this meta-analysis. The results showed that FoxM1 expression was related to the incidence, tumor size (>5 cm), vascular invasion, differentiation and TNM stage. Moreover, overexpression of FoxM1 indicated a poor 3- and 5-year overall survival rate (OS) and recurrence-free survival rate (disease-free survival rate). Conclusion Our meta-analysis indicated that FoxM1 expression was associated with incidence, tumor size (>5 cm), vascular invasion, differentiation and TNM stage. Accordingly, FoxM1 may be a reliable prognostic biomarker for patients with HCC. However, additional high-quality studies are still needed to further support these findings.
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Affiliation(s)
- Chaojie Liang
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jingyang Zhao
- Department of Tumor Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Hua Ge
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Guangming Li
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jixiang Wu
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
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22
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Zhan N, Michael AA, Wu K, Zeng G, Bell A, Tao J, Monga SP. The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, β-Catenin-Mutated Mouse Model. Gene Expr 2018; 18:135-147. [PMID: 29409568 PMCID: PMC5954626 DOI: 10.3727/105221618x15174108894682] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Simultaneous mutations in CTNNB1 and activation of c-MET occur in 9%-12.5% of patients with hepatocellular carcinoma (HCC). Coexpression of c-MET-V5 and mutant β-catenin-Myc in mouse liver by sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HTVI) led to the development of HCC with 70% molecular identity to the clinical subset. Using this model, we investigated the effect of EMD1214063, a highly selective c-MET inhibitor. Five weeks after SB-HTVI when tumors were established, EMD1214063 (10 mg/kg) was administered by gastric gavage as a single agent on 5-day-on/3-day-off schedule, compared to vehicle only control. Mice were harvested at 8 or 11 weeks posttreatment. Decreased p-MET, p-AKT, p-STAT3, and p-ERK proved in vivo efficacy of EMD1214063. We observed lower Ki-67, PCNA, V5-tag, and cyclin D1 after EMD1214063 treatment only at 8 weeks. Overall, no significant differences were observed in tumor burden between the groups, although EMD1214063 marginally but significantly improved overall survival by 1.5-2 weeks. Tumors remained α-fetoprotein+, did not show any differences in inflammation, and lacked fibrosis in either group. In conclusion, c-MET inhibition alone had a minor effect on Met-β-catenin HCC at the early stages of HCC development. Thus, a single therapy with the c-MET inhibitor will be insufficient for sustained response in Met-β-catenin HCC requiring assessment of additional combinations.
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Affiliation(s)
- Na Zhan
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- †Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
- ‡Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Adeola Adebayo Michael
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kaiyuan Wu
- †Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
| | - Gang Zeng
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron Bell
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Junyan Tao
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Satdarshan P. Monga
- *Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- §Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Zheng X, Chen K, Liu X, Pan Y, Liu H. High RNF40 expression indicates poor prognosis of hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2901-2906. [PMID: 31938414 PMCID: PMC6958262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 03/28/2018] [Indexed: 06/10/2023]
Abstract
Human RING-finger protein 40 (RNF40) is reported as an E3 ligase of H2B ubiquitination. RNF40 needs to couple with its homolog RNF20 to format a complex to regulate DNA double strand break (DSB) response and chromatin stability. Deficient expression of RNF40 might cause incorrect DNA repair and contribute to genomic instability, leading to an abnormal transcriptional program. Incorrect DSB repair and aberrant gene transcription play important roles in tumorigenesis. The role in primary hepatocellular carcinoma (HCC), however, remains unclear. In this study, we selected 103 cases of HCC for immunohistochemistry to explore the role of RNF40 in HCC. The relationship between RNF40 expression and clinicopathological features of HCC was evaluated. RNF40 was mainly localized in the nucleus, where the percentage of low and high staining of RNF40 in tumor tissues was 50.4% (53/103) and 49.6% (50/103), respectively. By contrast, in para-normal tissues the percentage was 92.2% (95/103) and 7.8% (8/103) respectively. Expression of RNF40 in tumor tissues was significantly higher than that in para-normal tissues (P>0.01). Expression of RNF40 had significant association with AFP and TNM tumor stage (both P>0.01). However, age, gender, Hepatitis B Virus infection, liver cirrhosis, tumor size, tumor number, differential stage, and tumor thrombosis were not associated with RNF40 expression. Meanwhile, HCC patients with high expression of RNF40 had lower 5 year overall survival rates and disease-free survival rates (P>0.05). RNF40 is, potentially, an independent prognostic factor for survival in HCC.
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Affiliation(s)
- Xueyong Zheng
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityHangzhou, China
| | - Ke Chen
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityHangzhou, China
| | - Xiaolong Liu
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityHangzhou, China
| | - Yu Pan
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityHangzhou, China
| | - Hui Liu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang UniversityHangzhou, Zhejiang, China
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Liang C, Li W, Ge H, Zhang K, Li G, Wu J. Role of Beclin1 expression in patients with hepatocellular carcinoma: a meta-analysis. Onco Targets Ther 2018; 11:2387-2397. [PMID: 29740214 PMCID: PMC5931235 DOI: 10.2147/ott.s151751] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background and aim Beclin1 has been reported as a vital marker for a number of malignant tumors. However, the role of Beclin1 in hepatocellular carcinoma (HCC) remains inconclusive. Thus, we conducted a meta-analysis to assess the correlation between Beclin1 and its clinicopathological and prognostic values in HCC. Methods PubMed, Cochrane Library, Web of Science, EMBASE, Chinese CNKI, and Chinese WanFang databases were searched for published articles on Beclin1 expression in hepatocellular tissues. Standard-compliant articles were screened using the Newcastle–Ottawa Scale for strict quality control of the literature. The correlation of Beclin1 expression with the clinicopathological features and survival outcomes was analyzed. Pooled odds ratios and hazard ratios with 95% confidence intervals were calculated using STATA14.2. Results Eleven articles with 1,279 patients were included in this meta-analysis. Positive Beclin1 expression was found to be correlated with alpha fetoprotein, liver cirrhosis, and vascular invasion, but not with gender, age, HBsAg, size of tumor, number of tumors, differentiation, and TNM stage. Positive Beclin1 expression was also associated with favorable 5-year overall survival and disease-free survival rates. Conclusion Our meta-analysis indicated that positive Beclin1 expression was negatively related to alpha fetoprotein, liver cirrhosis, and vascular invasion in HCC. Beclin1 could be used as a prognostic biomarker for HCC.
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Affiliation(s)
- Chaojie Liang
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Wei Li
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hua Ge
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Kaitong Zhang
- Department of Tumor Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Guangming Li
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Jixiang Wu
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
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25
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Lucà MG, Nani R, Schranz M, De Giorgio M, Iegri C, Agazzi R, Sala F, Virotta G, Sarti D, Conte G, Pinelli D, Nicora C, Colledan M, Sironi S, Fagiuoli S. Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib. Future Oncol 2018; 14:727-735. [DOI: 10.2217/fon-2017-0566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: The aim was to evaluate cost–effectiveness of yttrium-90 transarterial radioembolization (TARE) in comparison to sorafenib treatment. Patients & methods: A single-center, retrospective, observational study was performed, 166 patients with intermediate-/advanced-stage hepatocellular carcinoma were treated with sorafenib and 19 with TARE. The patients out of the sorafenib group matching the inclusion criteria for TARE, were reassigned to a subgroup SOR3. Results: Mean costs for SOR3 patients amounted to €27,992 per patient, instead for TARE treatment, mean expense per patient was €17,761 (p = 0.028). Overall survival was similar between the two groups, while midterm survival rates (p = 0.012) were significantly higher with TARE treatment. Conclusion: TARE causes significantly lower treatment costs than sorafenib with better outcome in midterm survival.
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Affiliation(s)
- Maria Grazia Lucà
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Roberto Nani
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Melanie Schranz
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Massimo De Giorgio
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Claudia Iegri
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Roberto Agazzi
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Francesco Sala
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Giorgio Virotta
- Nuclear Medicine, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Donatella Sarti
- Onco-Hematology Department, Azienda Ospedaliera Ospedali Riuniti Marche Nord, via Lombroso 1, 61122 Pesaro, Italy
| | - Grazia Conte
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Domenico Pinelli
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Carlo Nicora
- General Management, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Michele Colledan
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Sandro Sironi
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Stefano Fagiuoli
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
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26
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He RQ, Yang X, Liang L, Chen G, Ma J. MicroRNA-124-3p expression and its prospective functional pathways in hepatocellular carcinoma: A quantitative polymerase chain reaction, gene expression omnibus and bioinformatics study. Oncol Lett 2018; 15:5517-5532. [PMID: 29552191 PMCID: PMC5840674 DOI: 10.3892/ol.2018.8045] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 12/14/2017] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to explore the potential clinical significance of microRNA (miR)-124-3p expression in the hepatocarcinogenesis and development of hepatocellular carcinoma (HCC), as well as the potential target genes of functional HCC pathways. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate the expression of miR-124-3p in 101 HCC and adjacent non-cancerous tissue samples. Additionally, the association between miR-124-3p expression and clinical parameters was also analyzed. Differentially expressed genes identified following miR-124-3p transfection, the prospective target genes predicted in silico and the key genes of HCC obtained from Natural Language Processing (NLP) were integrated to obtain potential target genes of miR-124-3p in HCC. Relevant signaling pathways were assessed with protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein Annotation Through Evolutionary Relationships (PANTHER) pathway enrichment analysis. miR-124-3p expression was significantly reduced in HCC tissues compared with expression in adjacent non-cancerous liver tissues. In HCC, miR-124-3p was demonstrated to be associated with clinical stage. The mean survival time of the low miR-124-3p expression group was reduced compared with that of the high expression group. A total of 132 genes overlapped from differentially expressed genes, miR-124-3p predicted target genes and NLP identified genes. PPI network construction revealed a total of 109 nodes and 386 edges, and 20 key genes were identified. The major enriched terms of three GO categories included regulation of cell proliferation, positive regulation of cellular biosynthetic processes, cell leading edge, cytosol and cell projection, protein kinase activity, transcription activator activity and enzyme binding. KEGG analysis revealed pancreatic cancer, prostate cancer and non-small cell lung cancer as the top three terms. Angiogenesis, the endothelial growth factor receptor signaling pathway and the fibroblast growth factor signaling pathway were identified as the most significant terms in the PANTHER pathway analysis. The present study confirmed that miR-124-3p acts as a tumor suppressor in HCC. miR-124-3p may target multiple genes, exerting its effect spatiotemporally, or in combination with a diverse range of processes in HCC. Functional characterization of miR-124-3p targets will offer novel insight into the molecular changes that occur in HCC progression.
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Affiliation(s)
- Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xia Yang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Liang Liang
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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27
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Prognostic and clinicopathological value of Nanog in hepatocellular carcinoma: A meta-analysis. Clin Chim Acta 2018; 477:24-31. [DOI: 10.1016/j.cca.2017.11.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 11/26/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023]
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28
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Ali MM, H Borai I, Ghanem HM, H Abdel-Halim A, Mousa FM. The prophylactic and therapeutic effects of Momordica charantia methanol extract through controlling different hallmarks of the hepatocarcinogenesis. Biomed Pharmacother 2017; 98:491-498. [PMID: 29287196 DOI: 10.1016/j.biopha.2017.12.096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti-angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl4) subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,-8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent.
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Affiliation(s)
- Mamdouh M Ali
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt.
| | - Ibrahim H Borai
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Abeer H Abdel-Halim
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Fatma M Mousa
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
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29
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Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells. Toxicol In Vitro 2017; 47:48-62. [PMID: 29117515 DOI: 10.1016/j.tiv.2017.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/20/2017] [Accepted: 11/03/2017] [Indexed: 02/07/2023]
Abstract
High mortality rates in ovarian and liver cancer are largely a result of resistance to currently used chemotherapy. Here, we investigated genotoxic and pro-oxidant effects of metformin (MET) and epothilone A (A) in combination with respect to apoptosis in HepG2 and SKOV-3 cancer cells. Reactive oxygen species (ROS) was studied using 2',7'-dichlorodihydrofluoresein diacetate, and samples were analyzed for the presence and absence of the N-acetylcysteine (NAC). Expression of genes involved in programmed cell death, oxidative and alkylating DNA damage was measured. Probes were analyzed in the presence of Akt or nuclear factor-κB inhibitor. Compared to either drug alone, combination of epothilone A and metformin was more potent; decreased Akt level; and elevated percentage of apoptotic cells, induced cell cycle arrest at G1 phase and elevated the sub-G1 cell population by increasing the mRNA level of caspase-3, poly (ADP-ribose) polymerase-1 and H2AX. The anticancer effect of the drug combination was partially reversed by NAC supplementation, suggesting that ROS generation is required to induce apoptosis. The present study demonstrates that novel combination such as epothilone A and MET show promise in expanding ovarian and liver cancer therapy.
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30
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Wang W, Zhang M, Peng Y, He J. Ubiquitin Associated Protein 2-Like (UBAP2L) Overexpression in Patients with Hepatocellular Carcinoma and its Clinical Significance. Med Sci Monit 2017; 23:4779-4788. [PMID: 28981479 PMCID: PMC5639951 DOI: 10.12659/msm.907071] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recently, accumulating studies have shown that ubiquitin associated protein 2-like (UBAP2L) is overexpressed in many kinds of malignant tumors, which is closely associated to tumor growth and metastasis. However, the correlations of UBAP2L expression with clinicopathological factors and prognosis of hepatocellular carcinoma (HCC) patients still remain unclear. MATERIAL AND METHODS Bioinformatics database (GEO and TCGA) and our own experimental results (including immunohistochemical staining, western blotting and real-time PCR) were analyzed to validate the expression levels of UBAP2L in HCC. Furthermore, Kaplan-Meier survival analysis and Cox multivariate regression model were used to demonstrate the associations of UBAP2L expression with clinicopathological factors and prognosis of HCC patients. Additionally, the potential underlying mechanisms associated to angiogenesis were preliminarily explored. RESULTS Compared to the normal group, UBAP2L was significantly highly expressed in HCC cell lines and tissues. Kaplan-Meier survival analysis revealed that patients with high UBAP2L expression level had dramatically less survival time than those with low UBAP2L expression level (p=0.000). Moreover, multivariate Cox regression analysis showed that UBAP2L high expression was an independently unfavorable prognostic parameter for OS of HCC patients (p=0.000). Additionally, Pearson correlation analysis showed that the relationship between UBAP2L expression and VEGF or MVD was significantly positive, respectively (r=0.460, p=0.000 and r=0.387, p=0.000). CONCLUSIONS UBAP2L was overexpressed in HCC, and patients with high UBAP2L expression had unfavorable prognosis. UBAP2L could be a new potential therapeutic target for HCC in the future.
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Affiliation(s)
- Wei Wang
- Medical College of Shandong University, Jinan, Shandong, China (mainland).,Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Min Zhang
- Department of Pathology, Anhui Provincial Cancer Hospital, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Yan Peng
- Department of Pathology, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Jie He
- Department of Pathology, Anhui Provincial Cancer Hospital, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
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31
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Aliberti C, Carandina R, Sarti D, Pizzirani E, Ramondo G, Cillo U, Guadagni S, Fiorentini G. Transarterial chemoembolization with DC Bead LUMI™ radiopaque beads for primary liver cancer treatment: preliminary experience. Future Oncol 2017; 13:2243-2252. [DOI: 10.2217/fon-2017-0364] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Aim: Primary objectives of the study were to assess the safety of transarterial chemoembolization (TACE) using DC Bead LUMI™ for the treatment of hepatocellular carcinoma and beads distribution after TACE. Patients/methods: This was a prospective observational cohort study. The study included 44 hepatocellular carcinoma patients who were treated with TACE using DC Bead LUMI. Beads distribution was monitored 1 h after TACE by CT scan. Results: TACE had no intraprocedural complications. Observed side effects were of mild intensity and included pain in 5 (11%), fever in 4 (9%) and vomiting in 2 (5%) patients. Most patients (89%) reported no adverse event. Non-target distribution was observed in only two cases (5%). Conclusion: DC Bead LUMI allowed assessing in real time their distribution. This could prevent non-target infusion and reduce toxicity.
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Affiliation(s)
- Camillo Aliberti
- Oncology Radiodiagnostics Department, Oncology Institute of Veneto, Institute for the Research & Treatment of Cancer (IRCC), 35128 Padova, Italy
| | - Riccardo Carandina
- Oncology Radiodiagnostics Department, Oncology Institute of Veneto, Institute for the Research & Treatment of Cancer (IRCC), 35128 Padova, Italy
| | - Donatella Sarti
- Onco-Ematology Department, Azienda Ospedaliera ‘Ospedali Riuniti Marche Nord’, 61122 Pesaro, Italy
| | - Enrico Pizzirani
- Oncology Radiodiagnostics Department, Oncology Institute of Veneto, Institute for the Research & Treatment of Cancer (IRCC), 35128 Padova, Italy
| | - Gaetano Ramondo
- Oncology Radiodiagnostics Department, Oncology Institute of Veneto, Institute for the Research & Treatment of Cancer (IRCC), 35128 Padova, Italy
| | - Umberto Cillo
- Surgical and Gastroenterological Sciences Dept, University of Padova, 35128 Padova, Italy
| | - Stefano Guadagni
- Department of Applied Clinical Sciences & Biotechnology, University of L'Aquila, 7100 L'Aquila, AQ, Italy, and Alma Mater Europaea – ECM, Slovenska ulica 17, Maribor, Slovenja
| | - Giammaria Fiorentini
- Onco-Ematology Department, Azienda Ospedaliera ‘Ospedali Riuniti Marche Nord’, 61122 Pesaro, Italy
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Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinoma. Gene Ther 2017; 25:54-65. [PMID: 28925992 PMCID: PMC5817393 DOI: 10.1038/gt.2017.86] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 08/31/2017] [Accepted: 09/11/2017] [Indexed: 12/12/2022]
Abstract
Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.
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Cao Y, Ding Y, Zhang L, Shi G, Sang X, Ni C. Preparation of surface-modified, micrometer-sized carboxymethyl chitosan drug-loaded microspheres. J Appl Polym Sci 2017. [DOI: 10.1002/app.45731] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Yuanlong Cao
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
| | - Yuanyuan Ding
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
| | - Liping Zhang
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
| | - Gang Shi
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
| | - Xinxin Sang
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
| | - Caihua Ni
- Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering; Jiangnan University; Wuxi 214122 China
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Zhu Q, Luo M, Zhou C, Zhou Z, He Z, Yu X, Zhou S. A proteomics-based investigation on the anticancer activity of alisertib, an Aurora kinase A inhibitor, in hepatocellular carcinoma Hep3B cells. Am J Transl Res 2017; 9:3558-3572. [PMID: 28861148 PMCID: PMC5575171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 06/16/2017] [Indexed: 06/07/2023]
Abstract
Targeted therapy may provide survival benefit for advanced hepatocellular carcinoma (HCC) and Aurora A kinase (AURKA) represents a feasible target in cancer treatment. The purpose of this study is to investigate the anticancer activity of alisertib (ALS) on Hep3B cells based on a proteomic study conducted with the stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic response to ALS was obtained with SILAC-based proteomic study. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. ALS inhibited the proliferation of Hep3B cells, with IC50 values for 24- and 48-h exposure of 46.8 and 28.0 μM, respectively. Our SILAC study demonstrated that there were at least 565 proteins responding to ALS treatment, with 256 upregulated, 275 downregulated and 35 stable. Ninety-four signaling pathways, majority of which involved cell proliferation and survival, programmed cell death, and nutrition and energy metabolism, were regulated by ALS. ALS significantly inhibited the phosphorylation of AURKA at Thr288 in a concentration-dependent manner. Subsequent study showed that ALS remarkably arrested Hep3B cells in G2/M phase via regulating the expression of key cell cycle regulators, and induced a marked autophagy via the PI3K/Akt/mTOR axis. Inhibition of autophagy enhanced the anticancer activity of ALS in Hep3B cells. Overall, ALS leads to comprehensive proteomic response, inhibits cellular proliferation, and induces cell cycle arrest and autophagy in Hep3B cells. Further studies are warranted to explore the role of ALS in the treatment of HCC.
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Affiliation(s)
- Qiaohua Zhu
- Department of Oncology and Interventional Radiology, Shunde Hospital, Southern Medical UniversityShunde 528300, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South FloridaTampa, FL, USA
| | - Meihua Luo
- Department of Oncology and Interventional Radiology, Shunde Hospital, Southern Medical UniversityShunde 528300, Guangdong, China
| | - Chengyu Zhou
- Department of Oncology and Interventional Radiology, Shunde Hospital, Southern Medical UniversityShunde 528300, Guangdong, China
| | - Zhiwei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South FloridaTampa, FL, USA
| | - Zhixu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical UniversityGuiyang 550004, China
| | - Xinfa Yu
- Department of Oncology and Interventional Radiology, Shunde Hospital, Southern Medical UniversityShunde 528300, Guangdong, China
| | - Shufeng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South FloridaTampa, FL, USA
- Department of Bioengineering and Biotechnology, College of Chemical Engineering, Huaqiao UniversityXiamen 361021, Fujian, China
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Takahashi K, Putchakayala KG, Safwan M, Kim DY. Extrahepatic metastasis of hepatocellular carcinoma to the paravertebral muscle: A case report. World J Hepatol 2017; 9:973-978. [PMID: 28839518 PMCID: PMC5550763 DOI: 10.4254/wjh.v9.i22.973] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/29/2017] [Accepted: 05/18/2017] [Indexed: 02/06/2023] Open
Abstract
Identification of extrahepatic metastases (EHM) of hepatocellular carcinoma (HCC) has been paradoxically increasing due to an increase in the survival of HCC patients. However, metastasis of HCC to the skeletal muscle tissue is extremely rare. We describe a unique case of HCC metastasizing to the paravertebral muscle. A 55-year-old man with a history of hepatitis B cirrhosis underwent partial liver resection with complete removal of HCC. Three months later, a computed tomography (CT) scan showed intrahepatic recurrence. The tumors were treated with yttrium-90 microspheres, trans-catheter arterial chemoembolization, and sorafenib. Six months later, a CT scan showed an enhancing lesion of the left paravertebral muscle that on biopsy were consistent with metastatic HCC. The tumor was treated with stereotactic hypo-fractionated image-guided radiation therapy (SHFRT). A follow-up scan 3 mo post-radiotherapy revealed a stable appearance of the paravertebral muscle metastasis. Because of the progression in the intrahepatic tumors, the patient was treated with capecitabine, which was changed to dasatinib 6 mo later. The patient passed away three years after the primary surgical resection. Management of EHM poses an extreme challenge. This is the first case of HCC with EHM to the paravertebral muscle in which stability of disease was achieved using SHFRT. This case highlights the importance of early detection of hepatitis B viral infection and initiation of anti-viral therapy to decrease recurrence of HCC and prevent EHM.
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Affiliation(s)
- Kazuhiro Takahashi
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Krishna G Putchakayala
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Mohamed Safwan
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Dean Y Kim
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI 48202, United States.
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Pei Y, Sun X, Guo X, Yin H, Wang L, Tian F, Jing H, Liang X, Xu J, Shi P. FGF8 promotes cell proliferation and resistance to EGFR inhibitors via upregulation of EGFR in human hepatocellular carcinoma cells. Oncol Rep 2017; 38:2205-2210. [PMID: 28791365 DOI: 10.3892/or.2017.5887] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 06/13/2017] [Indexed: 11/06/2022] Open
Abstract
Fibroblast growth factor 8 (FGF8), a member of the fibroblast growth factor (FGF) family, is upregulated in several human cancers, including HCC (HCC). Previous studies have demonstrated that FGF8 increased cell growth and invasion of tumor cells. In the present study we investigated whether FGF8 is involved in the cell proliferation and resistance to several drugs in human HCC cells. We stably overexpressed FGF8 by lentiviral transfection. In addition, we also added recombinant FGF8 instead of stably overexpressing FGF8 in human HCC cells. Stable overexpression of FGF8 or exogenous recombinant FGF8 resulted in significantly enhanced cell proliferation in human HCC cells. With the use of CellTiter-Glo assay for the determination of cell viability, we found that FGF8 increased the resistance to epidermal growth factor receptor (EGFR) inhibitors in human HCC cells. Additionally, the expression of EGFR was also upregulated by stably overexpressing FGF8 or exogenous recombinant FGF8. Yes-associated protein 1 (YAP1) was reported to upregulate the expression of EGFR. Moreover, we also found that FGF8 increased the expression of YAP1 and knockdown of YAP1 eliminated the upregulation of EGFR and the resistance to EGFR inhibition induced by FGF8. Our study provides evidence that FGF8 plays an important role in the resistance to EGFR inhibition of human HCC cells.
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Affiliation(s)
- Yuanmin Pei
- Department of General Surgery, Yidu Central Hospital of Weifang, Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Xueling Sun
- Department of General Surgery, Yidu Central Hospital of Weifang, Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Xiwei Guo
- Department of General Surgery, Yidu Central Hospital of Weifang, Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Huashan Yin
- Department of General Surgery, Yidu Central Hospital of Weifang, Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Le Wang
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Fugu Tian
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Hongxi Jing
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Xiaobo Liang
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jun Xu
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Pengcheng Shi
- Shanxi Breast Cancer Center, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
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Gong Y, Zhang J, Wu X, Wang T, Zhao J, Yao Z, Zhang Q, Liu X, Jian X. Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy. Oncol Lett 2017; 14:4158-4166. [PMID: 28943923 PMCID: PMC5592876 DOI: 10.3892/ol.2017.6724] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 05/16/2017] [Indexed: 12/13/2022] Open
Abstract
Proton-coupled oligopeptide transporter 1 (PEPT1) is a membrane protein which expressed predominantly in intestine and recognized as the target of dietary nutrients (di/tripeptide) or peptidomimetic drug for delivery. The information on the existence of PEPT1 in carcinomas were limited. Our study aimed to investigate the expression profile and transport activity of PEPT1 both in human hepatocarcinoma tissues and cell lines. Western blotting and an immunofluorescence assay revealed the high level of PEPT1 protein expression in hepatocarcinoma Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cell lines. Quantitative real time PCR showed the mRNA expression of PEPT1 in Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cells. High level PEPT1 expression in hepatocarcinoma patient samples were observed by Immunohistology and showed a significant correlation between protein level and pathological grade. Functional activities were also studied using D-Ala-Lys-AMCA (a substrate of peptide transporter) in above five hepatocarcinoma cell lines. The uptake tests performed by fluorescent microscopy suggested that PEPT1 can transport both D-Ala-Lys-AMCA into the hepatocarcinoma cells and the uptake can be competitively inhibited by three PEPT1 substrates (Gly-sar, Gly-gln and Glyglygly). In conclusion, our findings provided the novel information on the expression and function of PEPT1 in human hepatocarcinoma and expanded the potential values for tumor specific drug delivery.
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Affiliation(s)
- Yanxia Gong
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.,Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, P.R. China
| | - Jie Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xiang Wu
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Tao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jia Zhao
- Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhi Yao
- Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Qingyu Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xu Jian
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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38
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Cidon EU. Systemic treatment of hepatocellular carcinoma: Past, present and future. World J Hepatol 2017; 9:797-807. [PMID: 28706578 PMCID: PMC5491402 DOI: 10.4254/wjh.v9.i18.797] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 05/07/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common neoplasia which represents the second leading cause of cancer related death. Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C. Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment. HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc. Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients. This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.
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Affiliation(s)
- Esther Una Cidon
- Esther Una Cidon, Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom
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39
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Re-programming pullulan for targeting and controlled release of doxorubicin to the hepatocellular carcinoma cells. Eur J Pharm Sci 2017; 103:104-115. [DOI: 10.1016/j.ejps.2017.02.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/03/2017] [Accepted: 02/08/2017] [Indexed: 02/07/2023]
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40
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Rimassa L, Reig M, Abbadessa G, Peck-Radosavljevic M, Harris W, Zagonel V, Pastorelli D, Rota Caremoli E, Porta C, Damjanov N, Patel H, Daniele B, Lamar M, Schwartz B, Goldberg T, Santoro A, Bruix J. Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma. World J Gastroenterol 2017; 23:2448-2452. [PMID: 28428725 PMCID: PMC5385412 DOI: 10.3748/wjg.v23.i13.2448] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 02/24/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.
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Xu M, Zhao Z, Song J, Lan X, Lu S, Chen M, Wang Z, Chen W, Fan X, Wu F, Chen L, Tu J, Ji J. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res 2017; 351:142-149. [PMID: 28109867 DOI: 10.1016/j.yexcr.2017.01.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/12/2017] [Accepted: 01/17/2017] [Indexed: 02/08/2023]
Abstract
Emerging evidence implicates an important role for myeloid-derived suppressor cells (MDSCs) in tumor growth, angiogenesis and metastasis. However, limited knowledge is known about the function of MDSCs in response to chemotherapies. In this study, we find that drug-resistant hepatocellular cancer (HCC) cells-derived conditioned medium significantly enhances the expansion and immunosuppressive function of MDSCs compared to their parental sensitive cells, which is demonstrated by increased level of arginase, nitric oxide (NO), and reactive oxygen species (ROS). Next, we reveal that drug-resistant HCC cells-derived IL-6 activated MDSCs, which is demonstrated by using an anti-IL-6 neutralizing antibody that caused a reduced MDSC immunosuppressive activity. More importantly, the depletion of MDSC via the administration of anti-Gr-1 antibody or the blockade of IL-6 signaling sensitized 5-FU-resistant H22 hepatoma to chemotherapy in the immunocompetent C57BL/6N mice. In primary human HCC, IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients. In conclusion, these results describe a role of IL-6 in the drug resistance in HCC chemotherapy and suggest that MDSC-targeting treatments may be potential therapeutic strategy for HCC chemoresistance.
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Affiliation(s)
- Min Xu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Zhongwei Zhao
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Jingjing Song
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Xilin Lan
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Siming Lu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Minjiang Chen
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Zufei Wang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Weiqian Chen
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Xiaoxi Fan
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Fazong Wu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Li Chen
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Jianfei Tu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China
| | - Jiansong Ji
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
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Soares do Amaral N, Cruz E Melo N, de Melo Maia B, Malagoli Rocha R. Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases. Genes (Basel) 2016; 8:genes8010006. [PMID: 28025544 PMCID: PMC5295001 DOI: 10.3390/genes8010006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 11/20/2016] [Accepted: 12/14/2016] [Indexed: 12/12/2022] Open
Abstract
Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways—primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases.
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Affiliation(s)
| | - Natalia Cruz E Melo
- Molecular Gynecology Laboratory, Gynecologic Department, Federal University of São Paulo, São Paulo, Brazil.
| | - Beatriz de Melo Maia
- Molecular Morphology Laboratory, AC Camargo Cancer Center, São Paulo 01508-010, Brazil.
| | - Rafael Malagoli Rocha
- Molecular Gynecology Laboratory, Gynecologic Department, Federal University of São Paulo, São Paulo, Brazil.
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Li Y, Guo M, Lin Z, Zhao M, Xiao M, Wang C, Xu T, Chen T, Zhu B. Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis. Int J Nanomedicine 2016; 11:6693-6702. [PMID: 27994465 PMCID: PMC5154725 DOI: 10.2147/ijn.s122666] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hepatocarcinoma is the third leading cause of cancer-related deaths around the world. Recently, a novel emerging nanosystem as anticancer therapeutic agents with intrinsic therapeutic properties has been widely used in various medical applications. In this study, surface decoration of functionalized silver nanoparticles (AgNPs) by polyethylenimine (PEI) and paclitaxel (PTX) was synthesized. The purpose of this study was to evaluate the effect of Ag@ PEI@PTX on cytotoxic and anticancer mechanism on HepG2 cells. The transmission electron microscope image and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that Ag@PEI@PTX had satisfactory size distribution and high stability and selectivity between cancer and normal cells. Ag@PEI@PTX-induced HepG2 cell apoptosis was confirmed by accumulation of the sub-G1 cells population, translocation of phosphatidylserine, depletion of mitochondrial membrane potential, DNA fragmentation, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. Furthermore, Ag@PEI@PTX enhanced cytotoxic effects on HepG2 cells and triggered intracellular reactive oxygen species; the signaling pathways of AKT, p53, and MAPK were activated to advance cell apoptosis. In conclusion, the results reveal that Ag@ PEI@PTX may provide useful information on Ag@PEI@PTX-induced HepG2 cell apoptosis and as appropriate candidate for chemotherapy of cancer.
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Affiliation(s)
- Yinghua Li
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Min Guo
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Zhengfang Lin
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Mingqi Zhao
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Misi Xiao
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Changbing Wang
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Tiantian Xu
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
| | - Tianfeng Chen
- Department of Chemistry, Jinan University, Guangzhou, People’s Republic of China
| | - Bing Zhu
- Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
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