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Zhang Y, Yue NN, Chen LY, Tian CM, Yao J, Wang LS, Liang YJ, Wei DR, Ma HL, Li DF. Exosomal biomarkers: A novel frontier in the diagnosis of gastrointestinal cancers. World J Gastrointest Oncol 2025; 17:103591. [DOI: 10.4251/wjgo.v17.i4.103591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/24/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
Gastrointestinal (GI) cancers, which predominantly manifest in the stomach, colorectum, liver, esophagus, and pancreas, accounting for approximately 35% of global cancer-related mortality. The advent of liquid biopsy has introduced a pivotal diagnostic modality for the early identification of premalignant GI lesions and incipient cancers. This non-invasive technique not only facilitates prompt therapeutic intervention, but also serves as a critical adjunct in prognosticating the likelihood of tumor recurrence. The wealth of circulating exosomes present in body fluids is often enriched with proteins, lipids, microRNAs, and other RNAs derived from tumor cells. These specific cargo components are reflective of processes involved in GI tumorigenesis, tumor progression, and response to treatment. As such, they represent a group of promising biomarkers for aiding in the diagnosis of GI cancer. In this review, we delivered an exhaustive overview of the composition of exosomes and the pathways for cargo sorting within these vesicles. We laid out some of the clinical evidence that supported the utilization of exosomes as diagnostic biomarkers for GI cancers and discussed their potential for clinical application. Furthermore, we addressed the challenges encountered when harnessing exosomes as diagnostic and predictive instruments in the realm of GI cancers.
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Affiliation(s)
- Yuan Zhang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
- Department of Medical Administration, Huizhou Institute for Occupational Health, Huizhou 516000, Guangdong Province, China
| | - Ning-Ning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen 518000, Guangdong Province, China
| | - Li-Yu Chen
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
| | - Cheng-Mei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (Jinan University of Second Clinical Medical Sciences), Shenzhen 518000, Guangdong Province, China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dao-Ru Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
| | - Hua-Lin Ma
- Department of Nephrology, The Second Clinical Medical College, Jinan University, Shenzhen 518020, Guangdong Province, China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, Guangdong Province, China
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Vafadar A, Younesi M, Babadi S, Alizadeh M, Movahedpour A, Savardashtaki A. Exosome biosensors for detection of liver cancer. Clin Chim Acta 2025; 570:120199. [PMID: 39961411 DOI: 10.1016/j.cca.2025.120199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 02/22/2025]
Abstract
Liver cancer is a significant global health concern due to its poor prognosis, often resulting from late-stage diagnosis and limited treatment options. While non-invasive methods such as ultrasound, blood tests (like AFP and PIVKA-II), CT scans, and MRIs are commonly employed in liver cancer diagnosis, they can occasionally be limited in sensitivity or associated with high costs. This has heightened the demand for innovative, non-invasive biomarkers that enable early and accurate diagnosis, leading to increased interest in the potential of exosomes. Exosomes are small vesicles released by cells and have the potential to serve as biomarkers for liver cancer. They contain a variety of biomolecules, including nucleic acids, proteins, and lipids, which can offer important information about cell health and disease progression. Developing fast, accurate, sensitive, and reliable techniques for detecting exosomes is essential. Biosensors, analytical tools for biological samples, have emerged as powerful instruments for analyzing exosomes. This review focuses on recent advancements in biosensor technology for exosome detection and explores future perspectives. The goal is to promote the development of innovative biosensor-based methods for detecting exosomes to enable earlier diagnosis and better clinical management of liver cancer.
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Affiliation(s)
- Asma Vafadar
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Younesi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Babadi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Alizadeh
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Movahedpour
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Bucurica S, Nancoff AS, Marin RI, Preda CM. Hepatocellular Carcinoma in Patients with Chronic Hepatitis C and Liver Cirrhosis Treated with DAA: A Focused Review. J Clin Med 2025; 14:1505. [PMID: 40095031 PMCID: PMC11900587 DOI: 10.3390/jcm14051505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/15/2025] [Accepted: 02/18/2025] [Indexed: 03/19/2025] Open
Abstract
Background/Objectives: The issue of HCC recurrence in patients with liver cirrhosis and chronic HCV infection after DAA treatment as well as the issue of de novo HCC in individuals with chronic HCV hepatitis treated with DAA is of great importance. In this review, the two important aspects are discussed and, finally, an algorithm for approaching the patient with HCC and chronic HCV infection is proposed. Methods: A literature search of the two databases (PubMed and Scopus) was conducted using the terms 'chronic hepatitis C' and/or 'liver cirrhosis' and 'hepatocellular carcinoma', from database inception to December 2024. Results: Thirty-one studies have examined the risk of HCC recurrence. Most of these studies conclude that DAA treatment reduces the risk of HCC recurrence compared to patients who did not receive DAA. There are considerable differences across various world regions. These variations may arise from: differences in genotypes, baseline characteristics of the populations, variability in DAA treatment protocols, and differences in follow-up intervals. Eleven studies that investigated the issue of de novo HCC after DAA were reviewed, of which two included historical cohorts of untreated patients. Conclusions: The conclusion is that these patients present a low or equal risk of HCC incidence compared to untreated patients, and the risk factors for HCC are: lower platelet number, impaired liver function, nonresponse to DAA. Most patients with chronic hepatitis C and HCC should receive DAAs, except for those in BCLC stage D, but we must emphasize that timing of intervention is crucial and it is very important to evaluate possible drug interactions.
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Affiliation(s)
- Sandica Bucurica
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (S.B.); (A.-S.N.)
- Department of Gastroenterology, University Emergency Central Military Hospital “Dr. Carol Davila”, 024185 Bucharest, Romania
| | - Andreea-Simona Nancoff
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (S.B.); (A.-S.N.)
| | - Raluca Ioana Marin
- Department of Gastroenterology, Fundeni Clinic Institute, 022328 Bucharest, Romania;
| | - Carmen Monica Preda
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (S.B.); (A.-S.N.)
- Department of Gastroenterology, Fundeni Clinic Institute, 022328 Bucharest, Romania;
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Wang Y, Moh-Moh-Aung A, Wang T, Fujisawa M, Ohara T, Yamamoto KI, Sakaguchi M, Yoshimura T, Matsukawa A. Exosomal delivery of miR-200b-3p suppresses the growth of hepatocellular carcinoma cells by targeting ERG- and VEGF-mediated angiogenesis. Gene 2024; 931:148874. [PMID: 39159792 DOI: 10.1016/j.gene.2024.148874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/02/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited treatment options. Recent discoveries have highlighted the pivotal role of miRNAs in HCC progression. We previously reported that the expression of miR-200b-3p was decreased in HCC cells and exosomal miR-200b-3p from hepatocytes inhibited angiogenesis by suppressing the expression of the endothelial transcription factor ERG (erythroblast transformation-specific (ETS)-related gene), leading to the hypothesis that the delivery of this miRNA may inhibit angiogenesis and suppress HCC growth in vivo. Here, we tested this hypothesis by using human HCC inoculation models. First, we transfected the human HepG2 HCC cells and established a stable cell line that overexpressed a high level of miR-200b-3p. When miR-200b-3p-overexpressing cells were injected into severe combined immunedeficiency (SCID)-beige mice, tumor growth was significantly reduced compared to tumors of control cells, with a reduction in the expression of ERG and vascular endothelial growth factor (VEGF) and subsequent angiogenesis. Intra-tumoral injection of exosomes containing high levels of miR-200b-3p also reduced the growth of parental HepG2 tumors with reduced ERG and VEGF expression and angiogenesis. These results validate the inhibitory role of miR-200b-3p in tumor angiogenesis, thereby suppressing HCC tumor growth, and provide a novel insight into its potential therapeutic application.
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Affiliation(s)
- Yuze Wang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Aye Moh-Moh-Aung
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Tianyi Wang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Masayoshi Fujisawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Toshiaki Ohara
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Ken-Ichi Yamamoto
- Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan.
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Saleh RO, Hamad HA, Najim MA, Menon SV, Kaur M, Sivaprasad GV, Abohassan M, Juan WT, Husseen B, Mustafa YF. Exosome-mediated Transfer of lncRNA in Liver Associated Diseases; Uncovered Truths. Cell Biochem Biophys 2024:10.1007/s12013-024-01617-x. [PMID: 39567423 DOI: 10.1007/s12013-024-01617-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 11/22/2024]
Abstract
Exosomes are extracellular vesicles with a diameter ranging from 40 to 160 nm. They are produced by hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells in liver tissue. The secretion of exosomes might vary in quantity and composition in reaction to multiple triggers and various stages of disease. They transport various payloads, such as proteins, DNAs, and RNAs, and enable cell interaction to regulate myriad physiological and pathological processes in liver tissue. Long non-coding RNAs (lncRNAs) are a crucial component of exosomes with an excellent capability to regulate multiple cellular activities such as differentiation, development, metabolism, proliferation, apoptosis, and activation. With the advancements in transcriptomic and genomic study methods and database management technology, the functions and mechanisms of exosomal lncRNAs in liver diseases have been well-studied. This article delves into the detailed role of exosomal lncRNAs in liver disease onset and progression, ranging from hepatocellular carcinoma (HCC) to liver fibrosis drug-induced liver damage (DILI) and steatotic liver diseases.
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Affiliation(s)
- Raed Obaid Saleh
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al Maarif, Anbar, Iraq.
| | - Hamad Ali Hamad
- Department of Pathological Analysis, Collage of Applied Sciences, University of Fallujah, Fallujah, Iraq
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Malaysia
| | | | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - G V Sivaprasad
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Mohammad Abohassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Wen-Tau Juan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Beneen Husseen
- Medical Laboratory Technique college, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique college, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique college, The Islamic University of Babylon, Babylon, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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Chu YD, Chen MC, Yeh CT, Lai MW. Hijacking host extracellular vesicle machinery by hepatotropic viruses: current understandings and future prospects. J Biomed Sci 2024; 31:97. [PMID: 39369194 PMCID: PMC11453063 DOI: 10.1186/s12929-024-01063-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 06/25/2024] [Indexed: 10/07/2024] Open
Abstract
Recent advances in studies exploring the roles of extracellular vesicles (EVs) in viral transmission and replication have illuminated hepatotropic viruses, such as hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). While previous investigations have uncovered these viruses' ability to exploit cellular EV pathways for replication and transmission, most have focused on the impacts of exosomal pathways. With an improved understanding of EVs, four main subtypes, including exosomes, microvesicles, large oncosomes, and apoptotic bodies, have been categorized based on size and biogenic pathways. However, there remains a noticeable gap in comprehensive reviews summarizing recent findings and outlining future perspectives for EV studies related to hepatotropic viruses. This review aims to consolidate insights into EV pathways utilized by hepatotropic viruses, offering guidance for the future research direction in this field. By comprehending the diverse range of hepatotropic virus-associated EVs and their role in cellular communication during productive viral infections, this review may offer valuable insights for targeting therapeutics and devising strategies to combat virulent hepatotropic virus infections and the associated incidence of liver cancer.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Mi-Chi Chen
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan
- Department of Pediatric, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan.
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan.
- Department of Pediatric, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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8
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Fekry B, Ugartemendia L, Esnaola NF, Goetzl L. Extracellular Vesicles, Circadian Rhythms, and Cancer: A Comprehensive Review with Emphasis on Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2552. [PMID: 39061191 PMCID: PMC11274441 DOI: 10.3390/cancers16142552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/12/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
This review comprehensively explores the complex interplay between extracellular vesicles (ECVs)/exosomes and circadian rhythms, with a focus on the role of this interaction in hepatocellular carcinoma (HCC). Exosomes are nanovesicles derived from cells that facilitate intercellular communication by transporting bioactive molecules such as proteins, lipids, and RNA/DNA species. ECVs are implicated in a range of diseases, where they play crucial roles in signaling between cells and their surrounding environment. In the setting of cancer, ECVs are known to influence cancer initiation and progression. The scope of this review extends to all cancer types, synthesizing existing knowledge on the various roles of ECVs. A unique aspect of this review is the emphasis on the circadian-controlled release and composition of exosomes, highlighting their potential as biomarkers for early cancer detection and monitoring metastasis. We also discuss how circadian rhythms affect multiple cancer-related pathways, proposing that disruptions in the circadian clock can alter tumor development and treatment response. Additionally, this review delves into the influence of circadian clock components on ECV biogenesis and their impact on reshaping the tumor microenvironment, a key component driving HCC progression. Finally, we address the potential clinical applications of ECVs, particularly their use as diagnostic tools and drug delivery vehicles, while considering the challenges associated with clinical implementation.
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Affiliation(s)
- Baharan Fekry
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Lierni Ugartemendia
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Nestor F. Esnaola
- Division of Surgical Oncology and Gastrointestinal Surgery, Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA;
| | - Laura Goetzl
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
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Chen Z, Yue L, Guo Y, Huang H, Lin W. A fluorescence probe for imaging lipid droplet and visualization of diabetes-related polarity variations. Anal Chim Acta 2024; 1312:342748. [PMID: 38834262 DOI: 10.1016/j.aca.2024.342748] [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: 03/05/2024] [Revised: 05/14/2024] [Accepted: 05/19/2024] [Indexed: 06/06/2024]
Abstract
Diabetes mellitus is a disorder that affects lipid metabolism. Abnormalities in the lipid droplets (LDs) can lead to disturbances in lipid metabolism, which is a significant feature of diabetic patients. Nevertheless, the correlation between diabetes and the polarity of LDs has received little attention in the scientific literature. In order to detect LDs polarity changes in diabetes illness models, we created a new fluorescence probe LD-DCM. This probe has a stable structure, high selectivity, and minimal cytotoxicity. The probe formed a typical D-π-A molecular configuration with triphenylamine (TPA) and dicyanomethylene-4H-pyran (DCM) as electron donor and acceptor parts. The LD-DCM molecule has an immense solvatochromic effect (λem = 544-624 nm), fluorescence enhancement of around 150 times, and a high sensitivity to polarity changes within the linear range of Δf = 0.28 to 0.32, all due to its distinctive intramolecular charge transfer effect (ICT). In addition, LD-DCM was able to monitor the accumulation of LDs and the reduction of LDs polarity in living cells when stimulated by oleic acid, lipopolysaccharide, and high glucose. More importantly, LD-DCM has also been used effectively to detect polarity differences in organs from diabetic, drug-treated, and normal mice. The results showed that the liver polarity of diabetic mice was lower than that of normal mice, while the liver polarity of drug-treated mice was higher than that of diabetic mice. We believe that LD-DCM has the potential to serve as an efficient instrument for the diagnosis of disorders that are associated with the polarity of LDs.
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Affiliation(s)
- Zehua Chen
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nan-ning, Guangxi, 530004, PR China
| | - Lizhou Yue
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nan-ning, Guangxi, 530004, PR China
| | - Yingxin Guo
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nan-ning, Guangxi, 530004, PR China
| | - Huawei Huang
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nan-ning, Guangxi, 530004, PR China
| | - Weiying Lin
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nan-ning, Guangxi, 530004, PR China.
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Abdelbaset R, Shawky SM, Abdullah MAA, Morsy OE, Yahia YA, Ghallab YH, Matboli M, Ismail Y. A new label free spiral sensor using impedance spectroscopy to characterize hepatocellular carcinoma in tissue and serum samples. Sci Rep 2024; 14:13155. [PMID: 38849386 PMCID: PMC11161506 DOI: 10.1038/s41598-024-63141-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/24/2024] [Indexed: 06/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer, predominantly affecting patients with chronic liver diseases such as hepatitis B or C-induced cirrhosis. Diagnosis typically involves blood tests (assessing liver functions and HCC biomarkers), imaging procedures such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), and liver biopsies requiring the removal of liver tissue for laboratory analysis. However, these diagnostic methods either entail lengthy lab processes, require expensive imaging equipment, or involve invasive techniques like liver biopsies. Hence, there exists a crucial need for rapid, cost-effective, and noninvasive techniques to characterize HCC, whether in serum or tissue samples. In this study, we developed a spiral sensor implemented on a printed circuit board (PCB) technology that utilizes impedance spectroscopy and applied it to 24 tissues and sera samples as proof of concept. This newly devised circuit has successfully characterized HCC and normal tissue and serum samples. Utilizing the distinct dielectric properties between HCC cells and serum samples versus the normal samples across a specific frequency range, the differentiation between normal and HCC samples is achieved. Moreover, the sensor effectively characterizes two HCC grades and distinguishes cirrhotic/non-cirrhotic samples from tissue specimens. In addition, the sensor distinguishes cirrhotic/non-cirrhotic samples from serum specimens. This pioneering study introduces Electrical Impedance Spectroscopy (EIS) spiral sensor for diagnosing HCC and liver cirrhosis in clinical serum-an innovative, low-cost, rapid (< 2 min), and precise PCB-based technology without elaborate sample preparation, offering a novel non-labeled screening approach for disease staging and liver conditions.
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Affiliation(s)
- Reda Abdelbaset
- Biomedical Engineering Department, Helwan University, Cairo, 11795, Egypt
- Centre of Nanoelectronics and Devices (CND), The American University in Cairo (AUC), New Cairo, 11835, Egypt
- Centre of Nanoelectronics and Devices (CND), Zewail City of Science and Technology, Giza, 12588, Egypt
| | - Sherif M Shawky
- Biochemistry Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, 12566, Egypt
- Center of Genomics, Helmy Institute, Zewail City of Science and Technology, Giza, 12588, Egypt
| | - Mohammed A A Abdullah
- Centre of Nanoelectronics and Devices (CND), The American University in Cairo (AUC), New Cairo, 11835, Egypt.
- Centre of Nanoelectronics and Devices (CND), Zewail City of Science and Technology, Giza, 12588, Egypt.
| | - Omar E Morsy
- Centre of Nanoelectronics and Devices (CND), The American University in Cairo (AUC), New Cairo, 11835, Egypt
- Centre of Nanoelectronics and Devices (CND), Zewail City of Science and Technology, Giza, 12588, Egypt
| | - Yahia A Yahia
- Biochemistry Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, 12566, Egypt
| | - Yehya H Ghallab
- Biomedical Engineering Department, Helwan University, Cairo, 11795, Egypt
- Centre of Nanoelectronics and Devices (CND), The American University in Cairo (AUC), New Cairo, 11835, Egypt
- Centre of Nanoelectronics and Devices (CND), Zewail City of Science and Technology, Giza, 12588, Egypt
| | - Marwa Matboli
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, 11591, Egypt
| | - Yehea Ismail
- Centre of Nanoelectronics and Devices (CND), The American University in Cairo (AUC), New Cairo, 11835, Egypt
- Centre of Nanoelectronics and Devices (CND), Zewail City of Science and Technology, Giza, 12588, Egypt
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11
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Ju T, Dong J, Wang B, Qu K, Cheng C, He X, Tian Y, Crabbe MJC, Wang Z, Chen Y. Cancer Development in Hepatocytes by Long-Term Induction of Hypoxic Hepatocellular Carcinoma Cell (HCC)-Derived Exosomes In Vivo and In Vitro. Mol Pharm 2023; 20:5579-5592. [PMID: 37844208 DOI: 10.1021/acs.molpharmaceut.3c00488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
Hypoxic tumor cell-derived exosomes play a key role in the occurrence, development, and metastasis of tumors. However, the mechanism of hypoxia-mediated metastasis remains unclear. In this study, hypoxic hepatocellular carcinoma cell (HCC-LM3)-derived exosomes (H-LM3-exos) were used to induce hepatocytes (HL-7702) over a long term (40 passages in 120 days). A nude mouse experiment further verified the effect of H-LM3-exos on tumor growth and metastasis. The process of cancer development in hepatocytes induced by H-LM3-exos was analyzed using both biological and physical techniques, and the results showed that the proliferation and soft agar growth abilities of the transformed cells were enhanced. The concentration of tumor markers secreted by transformed cells was increased, the cytoskeleton was disordered, and the migration ability was enhanced and was accompanied by epithelial-mesenchymal transition (EMT). Transcriptome results showed that differentially expressed genes between transformed cells and hepatocytes were enriched in cancer-related signaling pathways. The degree of cancer development in transformed cells was enhanced by an increase in H-LM3-exos-induced passages. Nude mice treated with different concentrations of H-LM3-exos showed different degrees of tumor growth and liver lesions. The physical properties of the cells were characterized by atomic force microscopy. Compared with the hepatocytes, the height and roughness of the transformed cells were increased, while the adhesion and elastic modulus were decreased. The changes in physical properties of primary tumor cells and hepatocytes in nude mice were consistent with this trend. Our study linking omics with the physical properties of cells provides a new direction for studying the mechanisms of cancer development and metastasis.
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Affiliation(s)
- Tuoyu Ju
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Jianjun Dong
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Bowei Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Kaige Qu
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Can Cheng
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Xiuxia He
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Yanling Tian
- School of Engineering, University of Warwick, Coventry CF4 7AL, U.K
| | - M James C Crabbe
- Wolfson College, University of Oxford, Oxford OX2 6UD, U.K
- Institute of Biomedical and Environmental Science & Technology, and Institute for Research in Applicable Computing, University of Bedfordshire, Luton LU1 3JU, U.K
| | - Zuobin Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
- Institute of Biomedical and Environmental Science & Technology, and Institute for Research in Applicable Computing, University of Bedfordshire, Luton LU1 3JU, U.K
| | - Yujuan Chen
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
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12
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ElBadre HM, El-Deek SEM, Ramadan HKA, Elbadr MM, Sabry D, Ahmed NM, Ahmed AM, El-Mahdy RI. Potential role of human umbilical cord stem cells-derived exosomes as novel molecular inhibitors of hepatocellular carcinoma growth. Apoptosis 2023; 28:1346-1356. [PMID: 37338718 PMCID: PMC10425301 DOI: 10.1007/s10495-023-01863-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2023] [Indexed: 06/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most critical cancers; thus, novel therapeutical regimens are of great need. In this study, we investigated the effects of umbilical cord mesenchymal stem cells (UC-MSCs) derived exosomes on HepG2 cell line, and the underlying mechanism to control HCC proliferation, to identify the potential clinical role of exosomes as a novel molecular therapeutic target. Proliferation, apoptosis, and angiogenesis effects were assessed together with the cell viability evaluation by MTT assay in HepG2 cells at 24/48 h. with or without UC-MSCs-derived exosomes. Gene expressions of TNF-α, caspase-3, VEGF, stromal cell-derived factor-1 (SDF-1), and CX chemokine receptor-4 (CXCR-4) were measured by quantitative real-time PCR technique. Expression of sirtuin-1 (SIRT-1) protein was detected by western blot. Treatment of HepG2 cells with UC-MSCs-derived exosomes for 24 and 48 h. demonstrated a significant reduction of cells survival compared to the control group (p < 0.05). The SIRT-1 protein, and VEGF, SDF-1, CXCR-4 expression levels were significantly lower, TNF-α and caspase-3 expression levels were significantly higher in exosomal-treated HepG2 cells for 24 and 48 h. than those in the control group. Moreover, our findings documented that the anti-proliferative, apoptotic, and anti-angiogenic effects were achieved in a time-dependent manner in which more effects were determined after 48 h supplementation compared to 24 h (p < 0.05). UC-MSCs-derived exosomes exert anticarcinogenic molecular effects on HepG2 cells through the involvement of SIRT-1, SDF-1, and CXCR-4. Hence, exosomes would be a potential novel therapy regimen against HCC. Large-scale studies are recommended to verify this conclusion.
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Affiliation(s)
- Hala M ElBadre
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sahar E M El-Deek
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed M Elbadr
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Badr City, Egypt
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noran M Ahmed
- Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amr M Ahmed
- Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Reham I El-Mahdy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt.
- Department of Basic medical science, Badr University, west of Assiut, New Naser City, Assiut, Egypt.
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13
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Zeng Y, Hu S, Luo Y, He K. Exosome Cargos as Biomarkers for Diagnosis and Prognosis of Hepatocellular Carcinoma. Pharmaceutics 2023; 15:2365. [PMID: 37765333 PMCID: PMC10537613 DOI: 10.3390/pharmaceutics15092365] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Due to the insidiousness of HCC onset and the lack of specific early-stage markers, the early diagnosis and treatment of HCC are still unsatisfactory, leading to a poor prognosis. Exosomes are a type of extracellular vesicle containing various components, which play an essential part in the development, progression, and metastasis of HCC. A large number of studies have demonstrated that exosomes could serve as novel biomarkers for the diagnosis of HCC. These diagnostic components mainly include proteins, microRNAs, long noncoding RNAs, and circular RNAs. The exosome biomarkers showed high sensitivity and high specificity in distinguishing HCC from health controls and other liver diseases, such as chronic HBV and liver cirrhosis. The expression of these biomarkers also exhibits correlations with various clinical factors such as tumor size, TMN stage, overall survival, and recurrence rate. In this review, we summarize the function of exosomes in the development of HCC and highlight their application as HCC biomarkers for diagnosis and prognosis prediction.
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Affiliation(s)
- Yulai Zeng
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Shuyu Hu
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Yi Luo
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Kang He
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
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14
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Mahmoodpour M, Kiasari BA, Karimi M, Abroshan A, Shamshirian D, Hosseinalizadeh H, Delavari A, Mirzei H. Paper-based biosensors as point-of-care diagnostic devices for the detection of cancers: a review of innovative techniques and clinical applications. Front Oncol 2023; 13:1131435. [PMID: 37456253 PMCID: PMC10348714 DOI: 10.3389/fonc.2023.1131435] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
The development and rapid progression of cancer are major social problems. Medical diagnostic techniques and smooth clinical care of cancer are new necessities that must be supported by innovative diagnostic methods and technologies. Current molecular diagnostic tools based on the detection of blood protein markers are the most common tools for cancer diagnosis. Biosensors have already proven to be a cost-effective and accessible diagnostic tool that can be used where conventional laboratory methods are not readily available. Paper-based biosensors offer a new look at the world of analytical techniques by overcoming limitations through the creation of a simple device with significant advantages such as adaptability, biocompatibility, biodegradability, ease of use, large surface-to-volume ratio, and cost-effectiveness. In this review, we covered the characteristics of exosomes and their role in tumor growth and clinical diagnosis, followed by a discussion of various paper-based biosensors for exosome detection, such as dipsticks, lateral flow assays (LFA), and microfluidic paper-based devices (µPADs). We also discussed the various clinical studies on paper-based biosensors for exosome detection.
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Affiliation(s)
- Mehrdad Mahmoodpour
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary, The University of Tehran, Tehran, Iran
| | - Merat Karimi
- Institute of Nanoscience and Nanotechnology, University of Kashan, Kashan, Iran
| | - Arezou Abroshan
- Student Research Committee, Faculty of Veterinary Medicine, Shahid Bahonar University, Kerman, Iran
| | - Danial Shamshirian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Hosseinalizadeh
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Alireza Delavari
- Student's Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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15
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Pei S, Li H, Li J, Liu Y, Zhang G, Shi L, Liang W, Zhang C, Shuang S, Dong C. Synthesis of a Red-Emitting Polarity-Sensitive Fluorescent Probe Based on ICT and Visualization for Lipid Droplet Dynamic Processes. ACS Biomater Sci Eng 2023. [PMID: 37243606 DOI: 10.1021/acsbiomaterials.3c00409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Abnormal lipid droplets (LDs) have been recognized as critical factors in many diseases because they are metabolically active and dynamic organelles. Visualization for LD dynamic processes is fundamental for elucidating the relationship of LDs and related diseases. Herein, a red-emitting polarity-sensitive fluorescent probe (TPA-CYP) based on intramolecular charge transfer (ICT) was proposed, which was constructed by employing triphenylamine (TPA) and 2-(5,5-dimethyl-2-cyclohex-1-ylidene)propanedinitrile (CYP) as electron donor and acceptor moiety, respectively. The spectra results underlined the excellent characteristics of TPA-CYP, such as high polarity sensitivity (Δf = 0.209 to 0.312), strong solvatochromic effect (λem 595-699 nm), and the large Stokes shifts (174 nm). Moreover, TPA-CYP exhibited a specific ability to target LDs and effectively differentiated cancer cells and normal cells. Surprisingly, TPA-CYP had been successfully applied to dynamic tracking of LDs, not only in inflammation induced by lipopolysaccharide (LPS), the process of oxidative stress, but also in live zebrafish. We believe that TPA-CYP could serve as a powerful tool to gain insight into the dynamics of LDs and to understand and diagnose LD-associated diseases.
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Affiliation(s)
- Shizeng Pei
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Haoyang Li
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Jiale Li
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Ying Liu
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Guomei Zhang
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Lihong Shi
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Wenting Liang
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, China
| | - Caihong Zhang
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Shaomin Shuang
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Chuan Dong
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, China
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16
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Parvin R, Zhang L, Zu Y, Ye F. Photothermal Responsive Digital Polymerase Chain Reaction Resolving Exosomal microRNAs Expression in Liver Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023:e2207672. [PMID: 36942691 DOI: 10.1002/smll.202207672] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/05/2023] [Indexed: 06/18/2023]
Abstract
Exosomal microRNAs have been studied as a good source of noninvasive biomarkers due to their functions in genetic exchange between cells and have been already well documented in many biological activities; however, inaccuracy remains a key challenge for liver cancer surveillance. Herein, a versatile duplex photothermal digital polymerase chain reaction (PCR) strategy combined with a lipid nanoparticle-based exosome capture approach is proposed to profile microRNAs expression through a 3-h easy-to-operate process. The microfluidically-generated molybdenum disulfide-nanocomposite-doped gelatin microcarriers display attractive properties as a 2-4 °C s-1 ramping-up rate triggered by near-infrared and reversible sol-gel transforming in step with PCR activation. To achieve PCR thermocycling, the corresponding irradiation coordinating with fan cooling are automatically performed via a homemade control module with programs. Thus, taking the multiplexing capability of dual-color labeling, 19-31 folds higher in exosomal microRNA-200b-3p and microRNA-21-5p, and tenfold lower in microRNA-22-3p expressions relative to the control microRNA-26a-5p are quantified in two liver cancer cells (Huh7 and HepG2) than in those from the healthy cells. It is believed that this exosomal microRNA genotyping method would be highly applicable for liver cancer diagnostics.
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Affiliation(s)
- Rokshana Parvin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, P. R. China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, P. R. China
| | - Lexiang Zhang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, P. R. China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, P. R. China
| | - Yan Zu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, P. R. China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, P. R. China
| | - Fangfu Ye
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, P. R. China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, P. R. China
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, 100190, P. R. China
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17
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Dezhakam E, Khalilzadeh B, Mahdipour M, Isildak I, Yousefi H, Ahmadi M, Naseri A, Rahbarghazi R. Electrochemical biosensors in exosome analysis; a short journey to the present and future trends in early-stage evaluation of cancers. Biosens Bioelectron 2023; 222:114980. [PMID: 36521207 DOI: 10.1016/j.bios.2022.114980] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/15/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022]
Abstract
The tumor microenvironment consists of a multiplicity of cells such as cancer cells, fibroblasts, endothelial cells, and immune cells within the specific parenchyma. It has been indicated that cancer cells can educate other cells within the tumor niche in a paracrine manner by the release of nano-sized extracellular vesicles namely exosomes (Exo), resulting in accelerated tumor mass growth. It is suggested that exosomal cargo with remarkable information can reflect any changes in metabolic and proteomic profiles in parent tumor cells. Therefore, exosomes can be touted as prognostic, diagnostic, and therapeutic elements with specific biomarkers in patients with different tumor types. Despite the advantages, conventional exosome separation and purification protocols are time-consuming and laborious with low abnormal morphology and purity rate. During the last decades, biosensor-based modalities, as emerging instruments, have been used to detect and analyze Exo in biofluids. Due to suitable specificity, sensitivity, and real-time readout, biosensors became promising approaches for the analysis of Exo in in vitro and in vivo settings. The inherent advantages and superiority of electrochemical biosensors in the determination of tumor grade based on exosomal cargo and profile were also debated. Present and future challenges were also discussed related to the application of electrochemical biosensors in the clinical setting. In this review, the early detection of several cancer types associated with ovaries, breast, brain, colon, lungs, T and B lymphocytes, liver and rare types of cancers were debated in association with released exosomes.
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Affiliation(s)
- Ehsan Dezhakam
- Department of Analytical Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran
| | - Balal Khalilzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ibrahim Isildak
- Department of Bioengineering, Faculty of Chemistry-Metallurgy, Yildiz Technical University, 34220, Istanbul, Turkey
| | - Hadi Yousefi
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Mahdi Ahmadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abdolhossein Naseri
- Department of Analytical Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran.
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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Wu ZQ, Zhu YX, Jin Y, Zhan YC. Exosomal miRNA in early-stage hepatocellular carcinoma. World J Clin Cases 2023; 11:528-533. [PMID: 36793641 PMCID: PMC9923864 DOI: 10.12998/wjcc.v11.i3.528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/26/2022] [Accepted: 01/05/2023] [Indexed: 01/23/2023] Open
Abstract
The incidence and mortality of hepatic carcinoma (HCC) remain high, and early diagnosis of HCC is seen as a key approach in improving clinical outcomes. However, the sensitivity and specificity of current early screening methods for HCC are not satisfactory. In recent years, research around exosomal miRNA has gradually increased, and these molecules have emerged as attractive candidates for early diagnosis and treatment of HCC. This review summarizes the feasibility of using miRNAs in peripheral blood exosomes as early diagnostic tools for HCC.
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Affiliation(s)
- Zhi-Qiang Wu
- Department of Surgery, The Second People's Hosptal of Quzhou, Quzhou 324000, Zhejiang Province, China
| | - Yi-Xin Zhu
- Department of Surgery, The Second People's Hosptal of Quzhou, Quzhou 324000, Zhejiang Province, China
| | - Yun Jin
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Yin-Chu Zhan
- Department of Surgery, The Second People's Hosptal of Quzhou, Quzhou 324000, Zhejiang Province, China
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Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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20
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Ding J, Zhao W. The Application of Liquid Biopsy Techniques in High-Risk Population for Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:2735-2748. [PMID: 36133739 PMCID: PMC9484767 DOI: 10.2147/cmar.s373165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/27/2022] [Indexed: 12/01/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.
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Affiliation(s)
- Jingnuo Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People's Republic of China
| | - Weifeng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People's Republic of China
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21
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Choi EJ, Kim YJ. Liquid biopsy for early detection and therapeutic monitoring of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2022; 22:103-114. [PMID: 37383403 PMCID: PMC10035729 DOI: 10.17998/jlc.2022.09.08] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 06/30/2023]
Abstract
Advances in our knowledge of the molecular characteristics of hepatocellular carcinoma (HCC) have enabled significant progress in the detection and therapeutic prediction of HCC. As a non-invasive alternative to tissue biopsy, liquid biopsy examines circulating cellular components such as exosomes, nucleic acids, and cell-free DNA found in body fluids (e.g., urine, saliva, ascites, and pleural effusions) and provides information about tumor characteristics. Technical advances in liquid biopsy have led to the increasing adoption of diagnostic and monitoring applications for HCC. This review summarizes the various analytes, ongoing clinical trials, and case studies of United States Food and Drug Administrationapproved in vitro diagnostic applications for liquid biopsy, and provides insight into its implementation in managing HCC.
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Affiliation(s)
| | - Young-Joon Kim
- LepiDyne Co., Ltd., Seoul, Korea
- Department of Biochemistry, Yonsei University, Seoul, Korea
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22
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Intercellular communication in the tumour microecosystem: Mediators and therapeutic approaches for hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166528. [PMID: 36007784 DOI: 10.1016/j.bbadis.2022.166528] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.
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23
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Yang S, Wang J, Wang S, Zhou A, Zhao G, Li P. Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review). Int J Oncol 2022; 61:91. [PMID: 35674180 PMCID: PMC9262158 DOI: 10.3892/ijo.2022.5381] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 11/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy of hepatocytes accounting for 75-85% of primary hepatic carcinoma cases. Small extracellular vesicles (sEVs), previously known as exosomes with a diameter of 30-200 nm, can transport a variety of biological molecules between cells, and have been proposed to function in physiological and pathological processes. Recent studies have indicated that the cargos of sEVs are implicated in intercellular crosstalk among HCC cells, paratumor cells and the tumor microenvironment. sEV-encapsulated substances (including DNA, RNA, proteins and lipids) regulate signal transduction pathways in recipient cells and contribute to cancer initiation and progression in HCC. In addition, the differential expression of sEV cargos between patients facilitates the potential utility of sEVs in the diagnosis and prognosis of patients with HCC. Furthermore, the intrinsic properties of low immunogenicity and high stability render sEVs ideal vehicles for targeted drug delivery in the treatment of HCC. The present review article summarizes the carcinogenic and anti-neoplastic capacities of sEVs and discusses the potential and prospective diagnostic and therapeutic applications of sEVs in HCC.
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Affiliation(s)
- Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Jiaxin Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Anni Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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24
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Sadrkhanloo M, Entezari M, Orouei S, Ghollasi M, Fathi N, Rezaei S, Hejazi ES, Kakavand A, Saebfar H, Hashemi M, Goharrizi MASB, Salimimoghadam S, Rashidi M, Taheriazam A, Samarghandian S. STAT3-EMT axis in tumors: modulation of cancer metastasis, stemness and therapy response. Pharmacol Res 2022; 182:106311. [PMID: 35716914 DOI: 10.1016/j.phrs.2022.106311] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 02/07/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-β, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis.
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Affiliation(s)
- Mehrdokht Sadrkhanloo
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Nikoo Fathi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shamin Rezaei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elahe Sadat Hejazi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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25
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Fan Q, Yu Y, Zhou Y, Zhang S, Wu C. An emerging role of radiation‑induced exosomes in hepatocellular carcinoma progression and radioresistance (Review). Int J Oncol 2022; 60:46. [PMID: 35266016 PMCID: PMC8923655 DOI: 10.3892/ijo.2022.5336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/01/2022] [Indexed: 11/20/2022] Open
Abstract
The incidence rates of hepatocellular carcinoma (HCC) worldwide are increasing, and the role of radiotherapy is currently under discussion. Radioresistance is one of the most important challenges in the therapy of HCC compared with other local advanced, recurrent and metastatic cancers. The mechanisms of radioresistance are complex and remain to be fully understood; however, extracellular vesicles have been investigated in recent studies. Exosomes, which are 40- to 150-nm extracellular vesicles released by cancer cells, contain multiple pathogenic components, including proteins, nucleic acids and lipids, and play critical functions in cancer progression. Emerging data indicate a diagnosis potential for exosomes in HCC, since radiation-derived exosomes promote radioresistance. Radiation-based therapy alters the contents and components of exosomes, suggesting that exosomes and their components may serve as prognostic and predictive biomarkers to monitor radiation response. Therefore, understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase our knowledge concerning the roles of exosomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment. The current review summarizes recent studies on exosome involvement in HCC and the molecular changes in exosome components during HCC progression. It also discusses the functions of exosomes in HCC therapy, and highlights the importance of exosomes in HCC progression and resistance for the development of novel therapies.
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Affiliation(s)
- Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yue Yu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yueling Zhou
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Sheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chunli Wu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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26
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Pusta A, Tertis M, Graur F, Cristea C, Al Hajjar N. Aptamers and New Bioreceptors for the Electrochemical Detection of Biomarkers Expressed in Hepatocellular Carcinoma. Curr Med Chem 2022; 29:4363-4390. [PMID: 35196969 DOI: 10.2174/0929867329666220222113707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/11/2021] [Accepted: 12/18/2021] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma is a malignancy associated with high mortality and increasing incidence. Early detection of this disease could help increase survival and overall patient benefit. Non-invasive strategies for the diagnosis of this medical condition are of utmost importance. In this scope, the detection of hepatocellular carcinoma biomarkers could provide a useful diagnostic tool. Aptamers represent as short, single-stranded DNAs or RNAs that can specifically bind selected analytes, and also as pseudo-biorecognition elements that can be employed for electrode functionalization. Also, other types of DNA sequences can be used for the construction of DNA-based biosensors applied for the quantification of hepatocellular carcinoma biomarkers. Herein, we will be analyzing recent examples of aptasensors and DNA biosensors for the detection of hepatocellular carcinoma biomarkers like micro-RNAs, long non-coding RNAs, exosomes, circulating tumor cells and proteins. The literature data is discussed comparatively in a critical manner highlighting the advantages of using electrochemical biosensors in diagnosis, as well as the use of nanomaterials and biocomponents in the functionalization of electrodes for improved sensitivity and selectivity.
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Affiliation(s)
- Alexandra Pusta
- Department of Analytical Chemistry, Faculty of Pharmacy,"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Medical Devices, Faculty of Pharmacy,"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca,Romania
| | - Mihaela Tertis
- Department of Analytical Chemistry, Faculty of Pharmacy,"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Florin Graur
- Department of Surgery, Iuliu Hațieganu University of Medicine and Pharmacy Romania
| | - Cecilia Cristea
- Department of Medical Devices, Faculty of Pharmacy,"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca,Romania
| | - Nadim Al Hajjar
- Department of Surgery, Iuliu Hațieganu University of Medicine and Pharmacy Romania
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27
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Liu YM, Cao Y, Zhao PS, Wu LY, Lu YM, Wang YL, Zhao JF, Liu XG. CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway. Int J Biol Sci 2022; 18:637-651. [PMID: 35002514 PMCID: PMC8741844 DOI: 10.7150/ijbs.66915] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/31/2021] [Indexed: 02/07/2023] Open
Abstract
Background: Circular RNAs (circRNAs), which generally act as microRNA (miRNA) sponges to competitively regulate the downstream target genes of miRNA, play an essential role in cancer biology. However, few studies have been reported on the role of circRNA based competitive endogenous RNA (ceRNA) network in hepatocellular carcinoma (HCC). Herein, we aimed to screen and establish the circRNA/miRNA/mRNA networks related to the prognosis and progression of HCC and further explore the underlying mechanisms of tumorigenesis. Methods: GEO datasets GSE97332, GSE108724, and GSE101728 were utilized to screen the differentially expressed circRNAs (DE-circRNAs), DE-miRNAs, and DEmRNAs between HCC and matched para-carcinoma tissues. After six RNA-RNA predictions and five intersections between DE-RNAs and predicted RNAs, the survival-related RNAs were screened by the ENCORI analysis tool. The ceRNA networks were constructed using Cytoscape software, based on two models of up-regulated circRNA/down-regulated miRNA/up-regulated mRNA and down-regulated circRNA/up-regulated miRNA/down-regulated mRNA. The qRT-PCR assay was utilized for detecting the RNA expression levels in HCC cells and tissues. The apoptosis, Edu, wound healing, and transwell assays were performed to evaluate the effect of miR-106b-5p productions on the proliferation, invasion, and metastasis of HCC cells. In addition, the clone formation, cell cycle, and nude mice xenograft tumor assays were used to investigate the influence of hsa_circ_0001495 (circCCNB1) silencing and overexpression on the proliferation of HCC cells in vitro and in vivo. Furthermore, the mechanism of downstream gene DYNC1I1 and AKT/ERK signaling pathway via the circCCNB1/miR-106b-5p/GPM6A network in regulating the cell cycle was also explored. Results: Twenty DE-circRNAs with a genomic length less than 2000bp, 11 survival-related DE-miRNAs, and 61 survival-related DE-mRNAs were screened out and used to construct five HCC related ceRNA networks. Then, the circCCNB1/miR-106b-5p/GPM6A network was randomly selected for subsequent experimental verification and mechanism exploration at in vitro and in vivo levels. The expression of circCCNB1 and GPM6A were significantly down-regulated in HCC cells and cancer tissues, while miR-106b-5p expression was up-regulated. After transfections, miR-106b-5p mimics notably enhanced the proliferation, invasion, and metastasis of HCC cells, while the opposite was seen with miR-105b-5p inhibitor. In addition, circCCNB1 silencing promoted the clone formation ability, the cell cycle G1-S transition, and the growth of xenograft tumors of HCC cells via GPM6A downregulation. Subsequently, under-expression of GPM6A increased DYNC1I1 expression and activated the phosphorylation of the AKT/ERK pathway to regulate the HCC cell cycle. Conclusions: We demonstrated that circCCNB1 silencing promoted cell proliferation and metastasis of HCC cells by weakening sponging of oncogenic miR-106b-5p to induce GPM6A underexpression. DYNC1I1 gene expression was up-regulated and further led to activation of the AKT/ERK signaling pathway.
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Affiliation(s)
- Yan-Ming Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan, Guangdong, China.,Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Yue Cao
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Department of Medical Technology, Medical College of Shaoguan University, Shaogguan, Guangdong, China
| | - Ping-Sen Zhao
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Liang-Yin Wu
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Ya-Min Lu
- Department of Clinical Laboratory, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Yu-Long Wang
- Department of Anesthesiology, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Jia-Feng Zhao
- Department of Hepatobiliary Surgery, YueBei People's Hospital, Shaoguan, Guangdong, China
| | - Xin-Guang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan, Guangdong, China
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28
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Zamora-León SP. Hepatocellular carcinoma biomarkers, an imminent need. World J Gastrointest Oncol 2021; 13:1847-1849. [PMID: 34853655 PMCID: PMC8603452 DOI: 10.4251/wjgo.v13.i11.1847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/05/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignant neoplasm of the liver and one of the deadliest cancers worldwide. The identification of novel, highly specific and more sensitive biomarkers for HCC is crucial because existing ones are deficient and non-confirmatory without histological biopsy or imaging techniques.
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Affiliation(s)
- S Pilar Zamora-León
- Department of Preclinical Sciences, Faculty of Medicine, Universidad Católica del Maule, Talca 3460000, Chile
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29
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Role of Exosomal MicroRNAs and Their Crosstalk with Oxidative Stress in the Pathogenesis of Osteoporosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6301433. [PMID: 34336108 PMCID: PMC8315851 DOI: 10.1155/2021/6301433] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022]
Abstract
Osteoporosis (OP) is an aging-related disease involving permanent bone tissue atrophy. Most patients with OP show high levels of oxidative stress (OS), which destroys the microstructure of bone tissue and promotes disease progression. Exosomes (exos) help in the delivery of microRNAs (miRNAs) and allow intercellular communication. In OP, exosomal miRNAs modulate several physiological processes, including the OS response. In the present review, we aim to describe how exosomal miRNAs and OS contribute to OP. We first summarize the relationship of OS with OP and then detail the features of exos along with the functions of exo-related miRNAs. Further, we explore the interplay between exosomal miRNAs and OS in OP and summarize the functional role of exos in OP. Finally, we identify the advantages of exo-based miRNA delivery in treatment strategies for OP. Our review seeks to improve the current understanding of the mechanism underlying OP pathogenesis and lay the foundation for the development of novel theranostic approaches for OP.
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30
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Moon H, Ro SW. MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3026. [PMID: 34204242 PMCID: PMC8234271 DOI: 10.3390/cancers13123026] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.
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Affiliation(s)
| | - Simon Weonsang Ro
- Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Korea;
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