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Bao Z, Xu M, Kan Y, Guo X, Li M, Wang J, Zhou Y, Zhang Z, Shao J, Zhang F, Chen L, Zheng S, Xuan J. Dihydroartemisinin requires NR1D1 mediated Rab7 ubiquitination to regulate hepatic stellate cells lipophagy in liver fibrosis. Int J Biol Macromol 2025; 305:141055. [PMID: 39956231 DOI: 10.1016/j.ijbiomac.2025.141055] [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: 10/16/2024] [Revised: 02/06/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
The activation of hepatic stellate cells (HSCs) is a core event in the pathogenesis of liver fibrosis, typically accompanied by the disappearance of lipid droplets (LDs). Reversing the disappearance of HSCs LDs is a strategy to inhibit HSCs activation and alleviate liver fibrosis. Previous studies have shown that nuclear receptor subfamily 1 group d member 1 (NR1D1), as an important component of the biological clock system, is closely related to lipid metabolism. Our previous evidence indicated that Dihydroartemisinin (DHA) can regulate the lipid droplet metabolism of activated HSCs. Moreover, in CCl4 induced liver fibrosis mice, the liver clock gene NR1D1 is dysregulated. On this basis we explored the potential molecular mechanism of DHA inhibiting liver fibrosis through NR1D1. We found that DHA can inhibit liver fibrosis by restoring activated LDs of HSCs through inhibiting HSCs lipophagy. In summary, our study emphasizes the importance of NR1D1 in liver fibrosis and the potential of DHA to regulate NR1D1 in the treatment of liver fibrosis, providing a new direction for the treatment of liver fibrosis.
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Affiliation(s)
- Zhengyang Bao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Min Xu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yifan Kan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaohan Guo
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Mengran Li
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Junrui Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ya Zhou
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zili Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiangjuan Shao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Feng Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Li Chen
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Shizhong Zheng
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ji Xuan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, 305 Zhongshan East Road, Xuanwu Avenue, Nanjing, Jiangsu 210002, China.
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Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2025; 45:e16117. [PMID: 39394864 PMCID: PMC11891384 DOI: 10.1111/liv.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
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Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
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Jin Z, Li Y, Yi H, Wang M, Wang C, Du S, Zeng W, Zong Z. Pathogenetic development, diagnosis and clinical therapeutic approaches for liver metastasis from colorectal cancer (Review). Int J Oncol 2025; 66:22. [PMID: 39950314 PMCID: PMC11844340 DOI: 10.3892/ijo.2025.5728] [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: 08/13/2024] [Accepted: 01/10/2025] [Indexed: 02/23/2025] Open
Abstract
Colorectal cancer (CRC) is a prevalent malignancy and a significant proportion of patients with CRC develop liver metastasis (CRLM), which is a major contributor to CRC‑related mortality. The present review aimed to comprehensively examine the pathogenetic development and diagnosis of CRLM and the clinical therapeutic approaches for treatment of this disease. The molecular mechanisms underlying CRLM were discussed, including the role of the tumour microenvironment and epithelial‑mesenchymal transition. The present review also highlighted the importance of early detection and the current challenges in predicting the development of CRLM. Various treatment strategies were reviewed, including surgical resection, chemotherapy and immunotherapy, and the potential of novel therapies, such as selective internal radiation therapy and Traditional Chinese Medicine. Despite recent advancements in treatment options, the treatment of CRLM remains a therapeutic challenge due to the complexity of the liver microenvironment and the heterogeneity of CRC. The present review emphasized the need for a multidisciplinary approach and the integration of emerging therapies to improve patient outcomes.
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Affiliation(s)
- Zhenhua Jin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yin Li
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hao Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Menghui Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chaofeng Wang
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shaokun Du
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wenjuan Zeng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Tetrick MG, Emon MAB, Doha U, Marcellus M, Symanski J, Ramanathan V, Saif MTA, Murphy CJ. Decoupling chemical and mechanical signaling in colorectal cancer cell migration. Sci Rep 2025; 15:4952. [PMID: 39929899 PMCID: PMC11811049 DOI: 10.1038/s41598-025-89152-4] [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: 10/13/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
Colorectal cancer metastasis is governed by a variety of chemical and mechanical signaling that are largely influenced by cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we deconvolute the chemical from mechanical signaling in the case of the colon cancer cell line HCT-116 and CAFs. We examined three chemoattractants (CXCL12, TGF-β, and activin A) which allegedly are secreted by CAFs and induce HCT-116 cell migration. None of the chemoattractants tested resulted in enhanced migration of HCT-116 in a 2D transwell assay, at low cell density. Similarly, CAF-conditioned media also did not lead to enhanced HCT-116 migration, while CAFs co-cultured in the transwell assay did lead to increased HCT-116 migration. This result suggests that either high cell densities are required for chemotaxis, and/or a reciprocal two-way signaling network between CAFs and HCT-116 is necessary to induce chemotaxis. Surprisingly, we find that HCT-116 cells exhibit enhanced migration along the axis of mechanical stress in a 3D collagen matrix, at very high cell densities. This migration is independent of whether the strain is induced mechanically or by CAFs. By comparing purely mechanical and purely chemical migration to a 3D co-culture of CAFs and HCT-116 containing both chemical and mechanical cues, it is concluded that HCT-116 migration is dominated by mechanical signaling, while chemical cues are less influential.
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Affiliation(s)
- Maxwell G Tetrick
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Md Abul Bashar Emon
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Umnia Doha
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Marsophia Marcellus
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Joseph Symanski
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Valli Ramanathan
- Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - M Taher A Saif
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Catherine J Murphy
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA.
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Liu Y, Sun X, Wei C, Guo S, Song C, Zhang J, Bai J. Targeted Drug Nanodelivery and Immunotherapy for Combating Tumor Resistance. Comb Chem High Throughput Screen 2025; 28:561-581. [PMID: 38676501 DOI: 10.2174/0113862073296206240416060154] [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: 12/27/2023] [Revised: 03/05/2024] [Accepted: 03/09/2024] [Indexed: 04/29/2024]
Abstract
Chemotherapy resistance is a common cause of tumor treatment failure. Various molecular responses, such as increased expression of efflux transporter proteins, including Pglycoprotein (P-gp), changes in the tumor microenvironment (TME), the role of platelets, and the effects of cancer stem cells (CSCs), can lead to drug resistance. Through extensive research on the mechanisms of drug resistance, more effective anti-resistance drugs and therapeutic approaches are being developed. This review explores drug resistance mechanisms and summarizes relevant anti-resistance drugs. In addition, due to the therapeutic limitations of the aforementioned treatments, new advances in nanocarrier-based combination immunotherapy to address the challenge of drug resistance have been described. Nanocarriers combined with immunotherapy can not only target tumor sites for targeted drug release but also modulate the autoimmune system and enhance immune efficacy, thereby overcoming tumor drug resistance. This review suggests new strategies for overcoming tumor drug resistance and is expected to inform tumor treatment and prognosis.
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Affiliation(s)
- Yun Liu
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, China
| | - Xinyu Sun
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Chen Wei
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Shoudong Guo
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China
| | - Chunxiao Song
- Anorectal Department, Weifang people's Hospital, Weifang, 261000, China
| | - Jiangyu Zhang
- school of Chemistry and Chemical Engineering, Xingtai University, Xingtai, 054001, China
| | - Jingkun Bai
- School of Bioscience and Technology, Shandong Second Medical University, Weifang, 261053, China
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Chen J, Yao Y, Mao X, Chen Y, Ni F. Liver-targeted delivery based on prodrug: passive and active approaches. J Drug Target 2024; 32:1155-1168. [PMID: 39072411 DOI: 10.1080/1061186x.2024.2386416] [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: 03/20/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND The liver, a central organ in human metabolism, is often the primary target for drugs. However, conditions such as viral hepatitis, cirrhosis, non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC) present substantial health challenges worldwide. Existing treatments, which suffer from the non-specific distribution of drugs, frequently fail to achieve desired efficacy and safety, risking unnecessary liver harm and systemic side effects. PURPOSE The aim of this review is to synthesise the latest progress in the design of liver-targeted prodrugs, with a focus on passive and active targeting strategies, providing new insights into the development of liver-targeted therapeutic approaches. METHODS This study conducted an extensive literature search through databases like Google Scholar, PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI), systematically collecting and selecting recent research on liver-targeted prodrugs. The focus was on targeting mechanisms, including the Enhanced Permeability and Retention (EPR) effect, the unique microenvironment of liver cancer, and active targeting through specific transporters and receptors. RESULTS Active targeting strategies achieve precise drug delivery by binding specific ligands to liver surface receptors. Passive targeting takes advantage of the EPR effect and tumour characteristics to enrich drugs in liver tumours. The review details successful cases of using small molecule ligands, peptides, antibodies and nanoparticles as drug carriers. CONCLUSION Liver-targeted prodrug strategies show great potential in enhancing the efficacy of drug treatment and reducing side effects for liver diseases. Future research should balance the advantages and limitations of both targeting strategies, focusing on optimising drug design and targeting efficiency, especially for clinical application. In-depth research on liver-specific receptors and the development of innovative targeting molecules are crucial for advancing the field of liver-targeted prodrugs.
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Affiliation(s)
- Jiaqi Chen
- Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yingrui Yao
- Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoran Mao
- Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuzhou Chen
- Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Feng Ni
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
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Li Q, Chen Q, Wang W, Xie R, Li Z, Chen D. KGF secreted from HSCs activates PAK4/BMI1, promotes HCC stemness through PI3K/AKT pathway. IUBMB Life 2024. [PMID: 39544166 DOI: 10.1002/iub.2929] [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: 07/31/2024] [Accepted: 09/29/2024] [Indexed: 11/17/2024]
Abstract
In our present study, we investigated the interaction between HSCs and HCC, also explored the molecular mechanism. Clinical samples were collected from HCC and adjacent tissue with different degree of liver fibrosis. HCC cells were co-cultured with LX-2 cell by Transwell system or cultured with conditioned medium (CM), which was collected from LX-2. The tumor spheroid growth and colony formation analyses were performed to evaluate the cell stemness. Flow cytometry analysis was conducted on cell apoptosis after 5-Fu treatment. Co-immunoprecipitation assay confirmed the interaction between BMI1 and PAK4. Our results showed that BMI1 was highly expressed in HCC and was correlated with HCC liver fibrosis. Both co-cultured with LX-2 and cultured with CM promoted HCC stemness, also increased KGF level and BMI1 expression. KGF treatment had a similar effect with co-culture with LX-2 on HCC. BMI1 overexpression promoted HCC stemness and activated PI3K/AKT pathway, which was reversed by PI3K inhibition. PAK4 was activated by KGF, then phosphorylated S315 site and promoted protein stability of BMI1, therefore enhanced HCC stemness. BMI1 also had a promote effect on liver fibrosis. In summary, we found that KGF secreted by HSCs activated PAK4, which phosphorylated S315 and promoted protein stability of BMI1, and further promoted liver fibrosis and HCC stemness through the PI3K/AKT signaling pathway. Our present study deeply studied the interaction and mechanism between HSCs and HCC, which might provide a new insight for HCC therapy.
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Affiliation(s)
- Qinghua Li
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, China
| | - Qiuyang Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, China
| | - Wenchao Wang
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, China
| | - Rongrong Xie
- Health Management, Shanghai Jianqiao University School, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, China
| | - Dawei Chen
- Department of Hepatopancreatobiliary Surgery, Jiangyin People's Hospital Affiliated to Nantong University, China
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Sato T, Shizu R, Baba R, Ooka A, Hosaka T, Kanno Y, Yoshinari K. Pregnane X receptor inhibits the transdifferentiation of hepatic stellate cells by down-regulating periostin expression. Biochem J 2024; 481:1173-1186. [PMID: 39171361 DOI: 10.1042/bcj20240172] [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: 04/14/2024] [Revised: 08/07/2024] [Accepted: 08/21/2024] [Indexed: 08/23/2024]
Abstract
Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR activation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-β1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key transdifferentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells.
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Affiliation(s)
- Takumi Sato
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Ryonosuke Baba
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Akira Ooka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Takuomi Hosaka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Yuichiro Kanno
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
| | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan
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Banerjee A, Farci P. Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression. Int J Mol Sci 2024; 25:8641. [PMID: 39201329 PMCID: PMC11354981 DOI: 10.3390/ijms25168641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.
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Affiliation(s)
- Anindita Banerjee
- Department of Transfusion Transmitted Diseases, ICMR-National Institute of Immunohaematology, Mumbai 400012, Maharashtra, India;
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Zhang D, Luo Q, Xiao L, Chen X, Yang S, Zhang S. Exosomes derived from gastric cancer cells promote phenotypic transformation of hepatic stellate cells and affect the malignant behavior of gastric cancer cells. J Cancer Res Ther 2024; 20:1157-1164. [PMID: 39206977 DOI: 10.4103/jcrt.jcrt_749_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 03/01/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE This study aimed to evaluate the effect of exosomes derived from gastric cancer cells on the phenotypic transformation of hepatic stellate cells (HSCs) and the effect of HSC activation on the malignant behavior of gastric cancer cells, including its molecular mechanism. METHODS Exosomes derived from the human gastric adenocarcinoma cell line AGS were extracted and purified by polymer precipitation and ultrafiltration, respectively. The exosomes' morphologic characteristics were observed using transmission electron microscopy, particle size was determined through nanoparticle-tracking analysis, and marker proteins were detected using western blotting. Exosome uptake by LX-2 HSCs was observed through fluorescence-based tracing. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the messenger RNA (mRNA) expression of alpha-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). Using functional assays, the effects of LX-2 HSC activation on the biological behavior of malignant gastric cancer cells were evaluated. The effects of LX-2 HSC activation on the protein expression of epithelial-mesenchymal transition (EMT)-related genes and β-catenin were evaluated via western blotting. RESULTS The extracted particles conformed to the definitions of exosomes and were thus considered gastric cancer cell-derived exosomes. Fluorescence-based tracing successfully demonstrated that exosomes were enriched in LX-2 HSCs. RT-qPCR revealed that the mRNA expression of the cancer-associated fibroblast markers α-SMA and FAP was significantly increased. LX-2 HSC activation considerably enhanced gastric cancer cell proliferation, invasion, and migration. Western blotting showed that the expression of the EMT-related epithelial marker E-cadherin was significantly downregulated, whereas the expression of interstitial markers (N-cadherin and vimentin) and β-catenin was remarkably upregulated in gastric cancer cells. CONCLUSION Exosomes derived from gastric cancer cells promoted phenotypic transformation of HSCs and activated HSCs to become tumor-associated fibroblasts. Gastric cancer cell-derived cells significantly enhanced gastric cancer cell proliferation, invasion, and migration after HSC activation, which may promote EMT of gastric cancer cells through the Wnt/β-catenin pathway.
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Affiliation(s)
- Donghuan Zhang
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Department of Oncology Medicine, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Qiong Luo
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Lirong Xiao
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Xiangqi Chen
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China
| | - Sheng Yang
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Suyun Zhang
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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Du YN, Zhao JW. GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications. J Hepatocell Carcinoma 2024; 11:1171-1183. [PMID: 38911292 PMCID: PMC11193986 DOI: 10.2147/jhc.s471239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/07/2024] [Indexed: 06/25/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.
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Affiliation(s)
- Yi-Ning Du
- Department of Medical Sciences, Li Ka-shing School of Medicine, University of Hong Kong, Hong Kong, People’s Republic of China
| | - Jin-Wei Zhao
- Department of Hepatopancreatobiliary Surgery, Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, People’s Republic of China
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12
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Liang X, Huang X, Cai Z, Deng Y, Liu D, Hu J, Jin Z, Zhou X, Zhou H, Wang L. The S100 family is a prognostic biomarker and correlated with immune cell infiltration in pan-cancer. Discov Oncol 2024; 15:137. [PMID: 38684596 PMCID: PMC11058162 DOI: 10.1007/s12672-024-00945-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/20/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND The S100 protein family is a group of small molecular EF-hand calcium-binding proteins that play critical roles in various biological processes, including promotion of growth, metastasis and immune evasion of tumor. However, the potential roles of S100 protein family expression in tumor microenvironment (TME) cell infiltration in pan-cancer remain elusive. METHODS Herein, we conducted a comprehensive assessment of the expression patterns of the S100 protein family in pan-cancer, meticulously examining their correlation with characteristics of TME cell infiltration. The S100 score was constructed to quantify S100 family expression patterns of individual tumors. RESULTS The S100 family was a potent risk factor in many cancers. Clustering analysis based on the transcriptome patterns of S100 protein family identified two cancer clusters with distinct immunophenotypes and clinical characteristics. Cluster A, with lower S100 expression, exhibited lower immune infiltration, whereas, Cluster B, with higher S100 expression, featured higher immune infiltration. Interestingly, Cluster B had a poorer prognosis, likely due to an immune-excluded phenotype resulting from stromal activation. The analysis revealed robust enrichment of the TGFb and EMT pathways in the cohort exhibiting high S100 score, alongside a positive correlation between the S100 score and Treg levels, suggesting the manifestation of an immune-excluded phenotype in this group. Moreover, S100 families were associated with the prognosis of 22 different cancers and a noteworthy association was observed between high S100 score and an unfavorable response to anti-PD-1/L1 immunotherapy. Consistent findings across two independent immunotherapy cohorts substantiated the advantageous therapeutic outcomes and clinical benefits in patients displaying lower S100score. CONCLUSION Our analysis demonstrated the role of S100 family in formation of TME diversity and complexity, enabling deeper cognition of TME infiltration characterization and the development of personalized immunotherapy strategies targeting S100 family for unique tumor types.
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Affiliation(s)
- Xiaojie Liang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Xiaoshan Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zihong Cai
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yeling Deng
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524000, China
| | - Dan Liu
- Department of Radiology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Southern Medical University, Foshan, China
| | - Jiayi Hu
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524000, China
| | - Zhihao Jin
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524000, China
| | - Xinyu Zhou
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524000, China
| | - Hongsheng Zhou
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Liang Wang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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13
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Yang H, Mu W, Yuan S, Yang H, Chang L, Sang X, Gao T, Liang S, Liu X, Fu S, Zhang Z, Liu Y, Zhang N. Self-delivery photothermal-boosted-nanobike multi-overcoming immune escape by photothermal/chemical/immune synergistic therapy against HCC. J Nanobiotechnology 2024; 22:137. [PMID: 38553725 PMCID: PMC10981284 DOI: 10.1186/s12951-024-02399-3] [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: 07/17/2023] [Accepted: 03/18/2024] [Indexed: 04/01/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to "cold" tumors' immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC.
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Affiliation(s)
- Huizhen Yang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Weiwei Mu
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Shijun Yuan
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Han Yang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Lili Chang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xiao Sang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Tong Gao
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Shuang Liang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xiaoqing Liu
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Shunli Fu
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Zipeng Zhang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Yongjun Liu
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
| | - Na Zhang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
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14
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Wang P, Jie Y, Yao L, Sun YM, Jiang DP, Zhang SQ, Wang XY, Fan Y. Cells in the liver microenvironment regulate the process of liver metastasis. Cell Biochem Funct 2024; 42:e3969. [PMID: 38459746 DOI: 10.1002/cbf.3969] [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: 10/05/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 03/10/2024]
Abstract
The research of liver metastasis is a developing field. The ability of tumor cells to invade the liver depends on the complicated interactions between metastatic cells and local subpopulations in the liver (including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells, and immune-related cells). These interactions are mainly mediated by intercellular adhesion and the release of cytokines. Cell populations in the liver microenvironment can play a dual role in the progression of liver metastasis through different mechanisms. At the same time, we can see the participation of liver parenchymal cells and nonparenchymal cells in the process of liver metastasis of different tumors. Therefore, the purpose of this article is to summarize the relationship between cellular components of liver microenvironment and metastasis and emphasize the importance of different cells in the occurrence or potential regression of liver metastasis.
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Affiliation(s)
- Pei Wang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Jie
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lin Yao
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yi-Meng Sun
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Da-Peng Jiang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shi-Qi Zhang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Xiao-Yan Wang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Yu Fan
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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15
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Mou JY, Ma ZW, Zhang MY, Yuan Q, Wang ZY, Liu QH, Li F, Liu Z, Wang L. Structural abnormality of hepatic glycogen in rat liver with diethylnitrosamine-induced carcinogenic injury. Int J Biol Macromol 2024; 260:129432. [PMID: 38228208 DOI: 10.1016/j.ijbiomac.2024.129432] [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: 08/18/2023] [Revised: 01/01/2024] [Accepted: 01/09/2024] [Indexed: 01/18/2024]
Abstract
Growing evidence confirms associations between glycogen metabolic re-wiring and the development of liver cancer. Previous studies showed that glycogen structure changes abnormally in liver diseases such as cystic fibrosis, diabetes, etc. However, few studies focus on glycogen molecular structural characteristics during liver cancer development, which is worthy of further exploration. In this study, a rat model with carcinogenic liver injury induced by diethylnitrosamine (DEN) was successfully constructed, and hepatic glycogen structure was characterized. Compared with glycogen structure in the healthy rat liver, glycogen chain length distribution (CLD) shifts towards a short region. In contrast, glycogen particles were mainly present in small-sized β particles in DEN-damaged carcinogenic rat liver. Comparative transcriptomic analysis revealed significant expression changes of genes and pathways involved in carcinogenic liver injury. A combination of transcriptomic analysis, RT-qPCR, and western blot showed that the two genes, Gsy1 encoding glycogen synthase and Gbe1 encoding glycogen branching enzyme, were significantly altered and might be responsible for the structural abnormality of hepatic glycogen in carcinogenic liver injury. Taken together, this study confirmed that carcinogenic liver injury led to structural abnormality of hepatic glycogen, which provided clues to the future development of novel drug targets for potential therapeutics of carcinogenic liver injury.
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Affiliation(s)
- Jing-Yi Mou
- Department of Clinical Medicine, School of 1(st) Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Zhang-Wen Ma
- Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Meng-Ying Zhang
- School of Medical Informatics and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Quan Yuan
- School of Medical Informatics and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Zi-Yi Wang
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Qing-Hua Liu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau SAR, China
| | - Fen Li
- Laboratory Medicine, The Fifth People's Hospital of Huai'an, Huai'an, Jiangsu Province, China
| | - Zhao Liu
- Department of Clinical Medicine, School of 1(st) Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Liang Wang
- School of Medical Informatics and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China; School of Agriculture and Food Sciences, The University of Queensland, Brisbane, Queensland, Australia.
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16
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Mierke CT. Phenotypic Heterogeneity, Bidirectionality, Universal Cues, Plasticity, Mechanics, and the Tumor Microenvironment Drive Cancer Metastasis. Biomolecules 2024; 14:184. [PMID: 38397421 PMCID: PMC10887446 DOI: 10.3390/biom14020184] [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: 12/25/2023] [Revised: 01/19/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth System Science, Peter Debye Institute of Soft Matter Physics, Biological Physics Division, Leipzig University, 04103 Leipzig, Germany
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17
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Caon E, Forlano R, Mullish BH, Manousou P, Rombouts K. Liver sinusoidal cells in the diagnosis and treatment of liver diseases: Role of hepatic stellate cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:513-532. [DOI: 10.1016/b978-0-323-95262-0.00025-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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Nazeer B, Khawar MB, Khalid MU, Hamid SE, Rafiq M, Abbasi MH, Sheikh N, Ali A, Fatima H, Ahmad S. Emerging role of lipophagy in liver disorders. Mol Cell Biochem 2024; 479:1-11. [PMID: 36943663 DOI: 10.1007/s11010-023-04707-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/10/2023] [Indexed: 03/23/2023]
Abstract
Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.
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Affiliation(s)
- Bismillah Nazeer
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Muhammad Babar Khawar
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal, Pakistan.
| | - Muhammad Usman Khalid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Syeda Eisha Hamid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Mussarat Rafiq
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan
| | | | - Nadeem Sheikh
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan.
| | - Ahmad Ali
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Hooriya Fatima
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Sadia Ahmad
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
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19
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Liu S, Jia M, Dai R. Deciphering the tumour immune microenvironment of hepatocellular carcinoma. Scand J Immunol 2023; 98:e13327. [PMID: 38441331 DOI: 10.1111/sji.13327] [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: 06/06/2023] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 03/07/2024]
Abstract
Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross-talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi-omic research associated with HCC pathogenesis and therapy, and future perspectives on TME.
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Affiliation(s)
- Sha Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Pain, Daping Hospital, Army Medical University, Chongqing, China
| | - Man Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Rongyang Dai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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20
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Dekky B, Azar F, Bonnier D, Monseur C, Kalebić C, Arpigny E, Colige A, Legagneux V, Théret N. ADAMTS12 is a stromal modulator in chronic liver disease. FASEB J 2023; 37:e23237. [PMID: 37819632 DOI: 10.1096/fj.202200692rrrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/13/2023] [Accepted: 09/21/2023] [Indexed: 10/13/2023]
Abstract
Adamalysins, a family of metalloproteinases containing a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTSs), belong to the matrisome and play important roles in various biological and pathological processes, such as development, immunity and cancer. Using a liver cancer dataset from the International Cancer Genome Consortium, we developed an extensive in silico screening that identified a cluster of adamalysins co-expressed in livers from patients with hepatocellular carcinoma (HCC). Within this cluster, ADAMTS12 expression was highly associated with recurrence risk and poorly differentiated HCC signatures. We showed that ADAMTS12 was expressed in the stromal cells of the tumor and adjacent fibrotic tissues of HCC patients, and more specifically in activated stellate cells. Using a mouse model of carbon tetrachloride-induced liver injury, we showed that Adamts12 was strongly and transiently expressed after a 24 h acute treatment, and that fibrosis was exacerbated in Adamts12-null mice submitted to carbon tetrachloride-induced chronic liver injury. Using the HSC-derived LX-2 cell line, we showed that silencing of ADAMTS12 resulted in profound changes of the gene expression program. In particular, genes previously reported to be induced upon HSC activation, such as PAI-1, were mostly down-regulated following ADAMTS12 knock-down. The phenotype of these cells was changed to a less differentiated state, showing an altered actin network and decreased nuclear spreading. These phenotypic changes, together with the down-regulation of PAI-1, were offset by TGF-β treatment. The present study thus identifies ADAMTS12 as a modulator of HSC differentiation, and a new player in chronic liver disease.
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Affiliation(s)
- Bassil Dekky
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
| | - Fida Azar
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
| | - Dominique Bonnier
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
| | - Christine Monseur
- Laboratory of Connective Tissues Biology, GIGA-R, University of Liege, Liege, Belgium
| | - Chiara Kalebić
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
| | - Esther Arpigny
- Laboratory of Connective Tissues Biology, GIGA-R, University of Liege, Liege, Belgium
| | - Alain Colige
- Laboratory of Connective Tissues Biology, GIGA-R, University of Liege, Liege, Belgium
| | - Vincent Legagneux
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
| | - Nathalie Théret
- University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France
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21
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Zhang Y, Huang J, Gan L, Wu R, Jin J, Wang T, Sun S, Zhang Z, Li L, Zheng X, Zhang K, Sun L, Ma H, Li D. Hepatoprotective effects of Niudali ( Callerya speciosa) root aqueous extracts against tetrachloromethane-induced acute liver injury and inflammation. Food Sci Nutr 2023; 11:7026-7038. [PMID: 37970412 PMCID: PMC10630805 DOI: 10.1002/fsn3.3626] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 08/02/2023] [Accepted: 08/05/2023] [Indexed: 11/17/2023] Open
Abstract
Niudali (Callerya speciosa) is commonly grown in southeastern regions of China and consumed as a food ingredient. Although Niudali root extracts showed various biological activities, the hepatoprotective effects of Niudali root phytochemicals are not fully studied. Herein, we prepared two Niudali root aqueous extracts, namely, c and Niudali polysaccharides-enriched extract (NPE), and identified an alkaloid, (hypaphorine) in NEW. The hepatoprotective effects of NWE, NPE, and hypaphorine were evaluated in an acute liver injury model induced by carbon tetrachloride (CCl4) in mice. Pathohistological examination and blood chemistry assays showed that treatment of NWE, NPE, and hypaphorine alleviated CCl4-induced liver damage by lowering the liver injury score (by 75.51%, 80.01%, and 41.22%) and serum aspartate and alanine transaminases level (by 63.24%, 85.22%, and 49.74% and by 78.73%, 80.08%, and 81.70%), respectively. NWE, NPE, and hypaphorine also reduced CCl4-induced hepatic oxidative stresses in the liver tissue by decreasing the levels of malondialdehyde (by 40.00%, 51.25%, and 28.75%) and reactive oxygen species (by 30.22%, 36.14%, and 33.54%) while increasing the levels of antioxidant enzymes including superoxide dismutase (by 21.36%, 21.64%, and 8.90%), catalase (by 22.13%, 33.33%, and 5.39%), and glutathione (by 84.87%, 90.65%, and 80.53%), respectively. Mechanistic assays showed that NWE, NPE, and hypaphorine alleviated liver damage by mediating inflammatory biomarkers (e.g., pro-inflammatory cytokines) via the signaling pathways of mitogen-activated protein kinases and nuclear factor-κB. Findings from our study extend the understanding of Niudali's hepatoprotective effects, which is useful for its development as a dietary intervention for liver inflammation.
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Affiliation(s)
- Yizi Zhang
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
| | - Jinwen Huang
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
| | - Lishe Gan
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
- International Healthcare Innovation Institute (Jiangmen)JiangmenChina
| | - Rihui Wu
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
- International Healthcare Innovation Institute (Jiangmen)JiangmenChina
| | - Jingwei Jin
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
- International Healthcare Innovation Institute (Jiangmen)JiangmenChina
| | - Tinghan Wang
- Bioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of PharmacyUniversity of Rhode IslandKingstonRhode IslandUSA
| | - Shili Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & UtilizationGuangzhouChina
| | - Zhenbiao Zhang
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & UtilizationGuangzhouChina
| | - Liya Li
- Institute of Microbial Pharmaceuticals, College of Life and Health SciencesNortheastern UniversityShenyangChina
| | - Xi Zheng
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
| | - Kun Zhang
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
| | - Lingli Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & UtilizationGuangzhouChina
| | - Hang Ma
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
- International Healthcare Innovation Institute (Jiangmen)JiangmenChina
- Bioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of PharmacyUniversity of Rhode IslandKingstonRhode IslandUSA
| | - Dongli Li
- School of Biotechnology and Health SciencesWuyi UniversityJiangmenChina
- International Healthcare Innovation Institute (Jiangmen)JiangmenChina
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Batudeligen, Han Z, Chen H, Narisu, Xu Y, Anda, Han G. Luteolin Alleviates Liver Fibrosis in Rat Hepatic Stellate Cell HSC-T6: A Proteomic Analysis. Drug Des Devel Ther 2023; 17:1819-1829. [PMID: 37360572 PMCID: PMC10285022 DOI: 10.2147/dddt.s402864] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 05/23/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) with single or compound materials is an effective cure for liver fibrosis. Hepatic stellate cells (HSCs) play a key role in liver fibrosis pathology and have become a novel drug target for this condition. METHODS CCK-8 assay was used to determine the cytotoxicity of four components, SYPA, HSYPA, Apigenin, and Luteolin, from Deduhonghua-7 powder on HSC-T6 cells. Transforming Growth Factor β 1 (TGFβ1)-induced fibrotic cell model and CCI4-induced fibrotic rat model were constructed, the expression of fibrosis-related genes, the pathological changes and serum biochemical markers were evaluated. Proteomic analysis was performed to determine the mechanism by which luteolin attenuated liver fibrosis, which were further confirmed by Western blot. RESULTS Luteolin attenuates liver fibrosis in HSC-T6 cells and luteolin decreases the liver fibrosis index level in vivo. A total of 5000 differentially expressed proteins (DEPs) were obtained using proteomic analysis. KEGG analysis found that DEPs were concentrated in various metabolic pathways, including DNA replication and repair and lysosomal signaling. GO analysis showed that molecular functions included the activity and binding of various enzymes, related cellular components included the extracellular space, lysosomal lumen, mitochondrial matrix, and nucleus, and biological processes included collagen organization and biosynthesis and the positive regulation of cell migration. Western blot results showed that CCR1, CD59, and NAGA were downregulated in TGFβ1 treatment, while upregulated both in Lut2 and Lut10 treatment. Meanwhile, eight proteins, ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, FBLN2, that were upregulated in TGFβ1 treatment, while downregulated both in Lut2 and Lut10 treatment. CONCLUSION Luteolin was shown to have a strong protective effect on liver fibrosis. CCR1, CD59, and NAGA may promote liver fibrosis while ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, and FBLN2 may facilitate protection against fibrosis.
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Affiliation(s)
- Batudeligen
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Zhiqiang Han
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Hongmei Chen
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Narisu
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Yanhua Xu
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Anda
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Gegentaoli Han
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
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Shao M, Wang Y, Dong H, Wang L, Zhang X, Han X, Sang X, Bao Y, Peng M, Cao G. From liver fibrosis to hepatocarcinogenesis: Role of excessive liver H2O2 and targeting nanotherapeutics. Bioact Mater 2023; 23:187-205. [PMID: 36406254 PMCID: PMC9663332 DOI: 10.1016/j.bioactmat.2022.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/23/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H2O2 is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H2O2 accumulation is associated with overproduction of superoxide anion (O2•−) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H2O2 have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H2O2 accumulation, and the role of H2O2 in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H2O2 were summarized for further consideration of antifibrotic or antitumor therapy.
Liver fibrosis and HCC are closely related because ROS induced liver damage and inflammation, especially over-cumulated H2O2. Excess H2O2 diffusion in pathological liver was due to increased metabolic rate and diminished cellular antioxidant systems. Freely diffused H2O2 damaged liver-specific cells, thereby leading to fibrogenesis and hepatocarcinogenesis. Nanotherapeutics targeting H2O2 are summarized for treatment of liver fibrosis and HCC, and also challenges are proposed.
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Han XY, Li X, Zhao RY, Ma HZ, Yu M, Niu XD, Jin HJ, Wang YF, Liu DM, Cai H. Comprehensive analysis of prognostic value and immunotherapy prospect of brain cytoplasmic RNA1 in hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:644-664. [PMID: 37123057 PMCID: PMC10134208 DOI: 10.4251/wjgo.v15.i4.644] [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: 11/24/2022] [Revised: 02/18/2023] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND The expression of brain cytoplasmic RNA1 (BCYRN1) is linked to the clinicopathology and prognosis of several types of cancers, among which hepatocellular carcinoma (HCC) is one of the most frequent types of cancer worldwide.
AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.
METHODS Information was obtained from the Cancer Genome Atlas database. First, the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored. Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis. Secondly, potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes. The relationships between BCYRN1 expression and tumor microenvironment, immune cell infiltration, immune checkpoint, drug sensitivity and immunotherapy effect were also investigated. Finally, three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.
RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics. Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules, participates in the metabolism of nutrients, such as proteins, and participates in tumor-related pathways. BCYRN1 expression was linked to the tumor microenvironment, immune cell infiltration, drug sensitivity and the efficacy of immunotherapy. Furthermore, the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.
CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.
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Affiliation(s)
- Xiao-Yong Han
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiong Li
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Rang-Yin Zhao
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hai-Zhong Ma
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Miao Yu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiang-Dong Niu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hao-Jie Jin
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yong-Feng Wang
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - De-Ming Liu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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25
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Oh HR, Ko MK, Son D, Ki YW, Kim SI, Lee SY, Kang KW, Cheon GJ, Hwang DW, Youn H. Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model. Biomedicines 2023; 11:1090. [PMID: 37189708 PMCID: PMC10135902 DOI: 10.3390/biomedicines11041090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 05/17/2023] Open
Abstract
Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeutic strategy for liver cirrhosis. In this study, we examined the therapeutic effects of NK cells in the carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model. NK cells were isolated from the mouse spleen and expanded in the cytokine-stimulated culture medium. Natural killer group 2, member D (NKG2D)-positive NK cells were significantly increased after a week of expansion in culture. The intravenous injection of NK cells significantly alleviated liver cirrhosis by reducing collagen deposition, HSC marker activation, and macrophage infiltration. For in vivo imaging, NK cells were isolated from codon-optimized luciferase-expressing transgenic mice. Luciferase-expressing NK cells were expanded, activated and administrated to the mouse model to track them. Bioluminescence images showed increased accumulation of the intravenously inoculated NK cells in the cirrhotic liver of the recipient mouse. In addition, we conducted QuantSeq 3' mRNA sequencing-based transcriptomic analysis. From the transcriptomic analysis, 33 downregulated genes in the extracellular matrix (ECM) and 41 downregulated genes involved in the inflammatory response were observed in the NK cell-treated cirrhotic liver tissues from the 1532 differentially expressed genes (DEGs). This result indicated that the repetitive administration of NK cells alleviated the pathology of liver fibrosis in the CCl4-induced liver cirrhosis mouse model via anti-fibrotic and anti-inflammatory mechanisms. Taken together, our research demonstrated that NK cells could have therapeutic effects in a CCl4-induced liver cirrhosis mouse model. In particular, it was elucidated that extracellular matrix genes and inflammatory response genes, which were mainly affected after NK cell treatment, could be potential targets.
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Affiliation(s)
- Ho Rim Oh
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Min Kyung Ko
- Research & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of Korea
| | - Daehee Son
- Research & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of Korea
| | - Young Wook Ki
- Research & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of Korea
| | - Shin-Il Kim
- Research & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of Korea
| | - Seok-Yong Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Imaging Center, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Keon Wook Kang
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Gi Jeong Cheon
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Do Won Hwang
- Research & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of Korea
| | - Hyewon Youn
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Imaging Center, Seoul National University Hospital, Seoul 03080, Republic of Korea
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Wei L, Liu Z, Qin L, Xian L, Chen K, Zhou S, Hu L, Xiong Y, Li B, Qin Y. BORIS variant SF2(C2/A4) promotes the malignant development of liver cancer by activating epithelial-mesenchymal transition and hepatic stellate cells. Mol Carcinog 2023; 62:731-742. [PMID: 36929051 DOI: 10.1002/mc.23520] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/31/2022] [Accepted: 01/31/2023] [Indexed: 03/18/2023]
Abstract
The underlying mechanisms of metastasis and recurrence of liver cancer remain largely unknown. Here, we found that Brother of the Regulator of Imprinted Sites (BORIS) variant SF2(C2/A4) was highly expressed in high metastatic potential hepatocellular carcinoma (HCC) cells and clinical tumor samples, related to the formation of satellite nodules. Its over expression promoted self-renewal, the expression of tumor stem cell markers, chemoresistance, wound healing rate, invasion and metastasis of HepG2 and Hep3B cells; reinforced epithelial-mesenchymal transition (EMT), decreased the expression of E-cadherin and increased N-cadherin and Vimentin. Subcellular localization experiment showed that BORIS SF2(C2/A4) was localized in nucleus and cytoplasm. Further double luciferase reporter gene experiment confirmed that it bound to TWIST1 gene promoter and significantly increased latter expression. BORIS SF2(C2/A4) knock down induced apoptosis of HCCLM3 and PLC/PRF/5 cells, and increased the protein content of cleaved caspase 3. Additionally, BORIS SF2(C2/A4) over expression increased the expression of fibroblast growth factor 2 (FGF2) in HepG2 and Hep3B cells. FGF2 expressed higher in HCC tumor tissues than in paired peri-tumor tissues, and its expression was positively correlated with BORIS SF2(C2/A4). Interestingly, high expression of FGF2 is also associated with the formation of satellite nodules. Moreover, using the medium from BORIS SF2(C2/A4) overexpressed cell lines to coculture hepatic stellate cell (HSCs) line LX-2, the latter could be activated and increased the expression of CD90 and PIGF, which is consistent with the effect of adding bFGF alone. These results indicate that BORIS SF2(C2/A4) plays a role in deterioration of liver cancer by regulating TWIST1 to induce EMT, and by FGF2 to activate HSCs.
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Affiliation(s)
- Ling Wei
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhongjian Liu
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
| | - Lu Qin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
| | - Longjun Xian
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Chen
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Siqi Zhou
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Lei Hu
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yimei Xiong
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
| | - Bo Li
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yang Qin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan Province, China
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Ali E, Trailin A, Ambrozkiewicz F, Liška V, Hemminki K. Activated Hepatic Stellate Cells in Hepatocellular Carcinoma: Their Role as a Potential Target for Future Therapies. Int J Mol Sci 2022; 23:ijms232315292. [PMID: 36499616 PMCID: PMC9741299 DOI: 10.3390/ijms232315292] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a global healthcare challenge, which affects more than 815,000 new cases every year. Activated hepatic stellate cells (aHSCs) remain the principal cells that drive HCC onset and growth. aHSCs suppress the anti-tumor immune response through interaction with different immune cells. They also increase the deposition of the extracellular matrix proteins, challenging the reversion of fibrosis and increasing HCC growth and metastasis. Therapy for HCC was reported to activate HSCs, which could explain the low efficacy of current treatments. Conversely, recent studies aimed at the deactivation of HSCs show that they have been able to inhibit HCC growth. In this review article, we discuss the role of aHSCs in HCC pathophysiology and therapy. Finally, we provide suggestions for the experimental implementation of HSCs in HCC therapies.
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Affiliation(s)
- Esraa Ali
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
| | - Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Correspondence: ; Tel.: +420-377-593-862
| | - Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
| | - Václav Liška
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Department of Surgery University Hospital and Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, 32300 Pilsen, Czech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 32300 Pilsen, Czech Republic
- Department of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Zhao C, Liu S, Gao F, Zou Y, Ren Z, Yu Z. The role of tumor microenvironment reprogramming in primary liver cancer chemotherapy resistance. Front Oncol 2022; 12:1008902. [PMID: 36505831 PMCID: PMC9731808 DOI: 10.3389/fonc.2022.1008902] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/01/2022] [Indexed: 11/25/2022] Open
Abstract
Primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and other rare tumours, is the second leading cause of cancer-related mortality. It has been a major contributor to the cancer burden worldwide. Of all primary liver cancer, HCC is the most common type. Over the past few decades, chemotherapy, immunotherapy and other therapies have been identified as applicable to the treatment of HCC. However, evidence suggests that chemotherapy resistance is associated with higher mortality rates in liver cancer. The tumour microenvironment (TME), which includes molecular, cellular, extracellular matrix(ECM), and vascular signalling pathways, is a complex ecosystem. It is now increasingly recognized that the tumour microenvironment plays a pivotal role in PLC prognosis, progression and treatment response. Cancer cells reprogram the tumour microenvironment to develop resistance to chemotherapy drugs distinct from normal differentiated tissues. Chemotherapy resistance mechanisms are reshaped during TME reprogramming. For this reason, TME reprogramming can provide a powerful tool to understand better both cancer-fate processes and regenerative, with the potential to develop a new treatment. This review discusses the recent progress of tumour drug resistance, particularly tumour microenvironment reprogramming in tumour chemotherapy resistance, and focuses on its potential application prospects.
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Affiliation(s)
- Chunyu Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shanshuo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yawen Zou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wu S, Li Z, Yao C, Dong S, Gao J, Ke S, Zhu R, Huang S, Wang S, Xu L, Ye C, Kong J, Sun W. Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research. Front Oncol 2022; 12:1032746. [PMID: 36483051 PMCID: PMC9723167 DOI: 10.3389/fonc.2022.1032746] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/04/2022] [Indexed: 05/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains an important disease for health care systems in view of its high morbidity, mortality, and increasing incidence worldwide. Radiofrequency ablation (RFA) is preferred to surgery as a local treatment for HCC because it is safer, less traumatic, less painful, better tolerated, causes fewer adverse reactions, and allows more rapid postoperative recovery. The biggest shortcoming of RFA when used to treat HCC is the high incidence of residual tumor, which is often attributed to the vascular thermal deposition effect, the wide infiltration zone of peripheral venules, and the distance between satellite foci and the main focus of the cancer. Recurrence and progression of the residual tumor is the most important determinant of the prognosis. Therefore, it is important to be aware of the risk of recurrence and to improve the efficacy of RFA. This review summarizes the relevant literature and the possible mechanisms involved in progression of HCC after RFA. Current studies have demonstrated that multimodal treatments which RFA combined with other anti-cancer approaches can prevent progression of HCC after RFA.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jian Kong
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Wenbing Sun
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
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Alqudah A, AbuDalo R, Qnais E, Wedyan M, Oqal M, McClements L. The emerging importance of immunophilins in fibrosis development. Mol Cell Biochem 2022; 478:1281-1291. [PMID: 36302992 PMCID: PMC10164022 DOI: 10.1007/s11010-022-04591-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/13/2022] [Indexed: 10/31/2022]
Abstract
AbstractImmunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates diverse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins’ pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-β pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.
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Wang PW, Lin TY, Yang PM, Yeh CT, Pan TL. Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms231810777. [PMID: 36142683 PMCID: PMC9503407 DOI: 10.3390/ijms231810777] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/29/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.
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Affiliation(s)
- Pei-Wen Wang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan
| | - Tung-Yi Lin
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung 20401, Taiwan
| | - Pei-Ming Yang
- TMU Research Center of Cancer Translational Medicine, Taipei 11042, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11042, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan
| | - Tai-Long Pan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Cosmetic Science, Research Center for Food and Cosmetic Safety, and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
- Correspondence: ; Tel.: +886-3-211-8800 (ext. 5105); Fax: +886-3-211-8700
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Chen L, Zhang D, Zheng S, Li X, Gao P. Stemness analysis in hepatocellular carcinoma identifies an extracellular matrix gene–related signature associated with prognosis and therapy response. Front Genet 2022; 13:959834. [PMID: 36110210 PMCID: PMC9468756 DOI: 10.3389/fgene.2022.959834] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Tumor stemness is the stem-like phenotype of cancer cells, as a hallmark for multiple processes in the development of hepatocellular carcinoma (HCC). However, comprehensive functions of the regulators of tumor cell’s stemness in HCC remain unclear.Methods: Gene expression data and clinical information of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) dataset as the training set, and three validation datasets were derived from Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC). Patients were dichotomized according to median mRNA expression–based stemness index (mRNAsi) scores, and differentially expressed genes were further screened out. Functional enrichment analysis of these DEGs was performed to identify candidate extracellular matrix (ECM)–related genes in key pathways. A prognostic signature was constructed by applying least absolute shrinkage and selection operator (LASSO) to the candidate ECM genes. The Kaplan–Meier curve and receiver operating characteristic (ROC) curve were used to evaluate the prognostic value of the signature. Correlations between signatures and genomic profiles, tumor immune microenvironment, and treatment response were also explored using multiple bioinformatic methods.Results: A prognostic prediction signature was established based on 10 ECM genes, including TRAPPC4, RSU1, ILK, LAMA1, LAMB1, FLNC, ITGAV, AGRN, ARHGEF6, and LIMS2, which could effectively distinguish patients with different outcomes in the training and validation sets, showing a good prognostic prediction ability. Across different clinicopathological parameter stratifications, the ECMs signature still retains its robust efficacy in discriminating patient with different outcomes. Based on the risk score, vascular invasion, α-fetoprotein (AFP), T stage, and N stage, we further constructed a nomogram (C-index = 0.70; AUCs at 1-, 3-, and 5-year survival = 0.71, 0.75, and 0.78), which is more practical for clinical prognostic risk stratification. The infiltration abundance of macrophages M0, mast cells, and Treg cells was significantly higher in the high-risk group, which also had upregulated levels of immune checkpoints PD-1 and CTLA-4. More importantly, the ECMs signature was able to distinguish patients with superior responses to immunotherapy, transarterial chemoembolization, and sorafenib.Conclusion: In this study, we constructed an ECM signature, which is an independent prognostic biomarker for HCC patients and has a potential guiding role in treatment selection.
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Affiliation(s)
- Lei Chen
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Dafang Zhang
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Shengmin Zheng
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Xinyu Li
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Pengji Gao
- Department of General Surgery, Beijing Jishuitan Hospital, Beijing, China
- *Correspondence: Pengji Gao,
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Lu Y, Feng N, Du Y, Yu R. Nanoparticle-Based Therapeutics to Overcome Obstacles in the Tumor Microenvironment of Hepatocellular Carcinoma. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:nano12162832. [PMID: 36014696 PMCID: PMC9414814 DOI: 10.3390/nano12162832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 05/09/2023]
Abstract
Hepatocellular carcinoma (HCC) is still a main health concern around the world, with a rising incidence and high mortality rate. The tumor-promoting components of the tumor microenvironment (TME) play a vital role in the development and metastasis of HCC. TME-targeted therapies have recently drawn increasing interest in the treatment of HCC. However, the short medication retention time in TME limits the efficiency of TME modulating strategies. The nanoparticles can be elaborately designed as needed to specifically target the tumor-promoting components in TME. In this regard, the use of nanomedicine to modulate TME components by delivering drugs with protection and prolonged circulation time in a spatiotemporal manner has shown promising potential. In this review, we briefly introduce the obstacles of TME and highlight the updated information on nanoparticles that modulate these obstacles. Furthermore, the present challenges and future prospects of TME modulating nanomedicines will be briefly discussed.
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Affiliation(s)
- Yuanfei Lu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
| | - Na Feng
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
| | - Yongzhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
- Correspondence: (Y.D.); (R.Y.); Tel.: +86-571-88208435 (Y.D.); +86-571-87783925 (R.Y.)
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
- Correspondence: (Y.D.); (R.Y.); Tel.: +86-571-88208435 (Y.D.); +86-571-87783925 (R.Y.)
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Dios-Barbeito S, González R, Cadenas M, García LF, Victor VM, Padillo FJ, Muntané J. Impact of nitric oxide in liver cancer microenvironment. Nitric Oxide 2022; 128:1-11. [DOI: 10.1016/j.niox.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022]
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Khafaga AF, Mousa SA, Aleya L, Abdel-Daim MM. Three-dimensional (3D) cell culture: a valuable step in advancing treatments for human hepatocellular carcinoma. Cancer Cell Int 2022; 22:243. [PMID: 35908054 PMCID: PMC9339175 DOI: 10.1186/s12935-022-02662-3] [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: 04/14/2022] [Accepted: 07/18/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the third most frequent cause of tumour-related mortality worldwide. Currently, several surgical and medical therapeutic strategies are available for HCCs; however, the interaction between neoplastic cells and non-neoplastic stromal cells within the tumour microenvironment (TME) results in strong therapeutic resistance of HCCs to conventional treatment. Therefore, the development of novel treatments is urgently needed to improve the survival of patients with HCC. The first step in developing efficient chemotherapeutic drugs is the establishment of an appropriate system for studying complex tumour culture and microenvironment interactions. Three-dimensional (3D) culture model might be a crucial bridge between in vivo and in vitro due to its ability to mimic the naturally complicated in vivo TME compared to conventional two-dimensional (2D) cultures. In this review, we shed light on various established 3D culture models of HCC and their role in the investigation of tumour-TME interactions and HCC-related therapeutic resistance.
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Affiliation(s)
- Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt.
| | - Shaker A Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, 12144, USA
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, 25030, Besançon Cedex, France
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt.,Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
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Jie L, Hong RT, Zhang YJ, Sha LL, Chen W, Ren XF. Melatonin Alleviates Liver Fibrosis by Inhibiting Autophagy. Curr Med Sci 2022; 42:498-504. [PMID: 35583587 DOI: 10.1007/s11596-022-2530-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 06/18/2021] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Melatonin has been reported to suppress inflammation and alleviate liver fibrosis, but its effect on autophagy in liver fibrosis has not been studied. This study investigated the effect of melatonin on autophagy in an animal model of liver fibrosis and the hepatic stellate cell (HSC)-T6 cell line. METHODS The model was established in rats through carbon tetrachloride treatment, and melatonin was administered at three doses (2.5, 5.0, and 10.0 mg/kg). Haematoxylin and eosin staining and Van Gieson's staining were performed to examine the pathological changes of liver. The expression of alpha-smooth muscle actin (α-SMA) and Beclin1 in liver tissues was detected by immunohistochemical staining. The protein levels of α-SMA, Beclin1 and LC3 in the animal model were detected by Western blot analysis, and gene levels of Beclin1 and LC3 were detected by quantitative real-time PCR (qRT-PCR) in the animal model. HSC-T6 cells were activated by platelet-derived growth factor-BB (PDGF-BB). The expression of α-SMA, Beclin1 and collagen I was detected by Western blot analysis, and the gene expression of Beclin1 and LC3 was detected by qRT-PCR. RESULTS Melatonin reduced the expression of α-SMA, Beclin1 and LC3 in liver tissues. In addition, melatonin inhibited the activation of HSC-T6 cells and the expression of α-SMA, Beclin1 and LC3 in these cells. These results revealed that melatonin could inhibit autophagy and HSC activation. CONCLUSION Melatonin might ameliorate liver fibrosis by regulating autophagy, suggesting that melatonin is a potential therapeutic agent for liver fibrosis.
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Affiliation(s)
- Lei Jie
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Ru-Tao Hong
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China.
| | - Yu-Jie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Lu-Lin Sha
- Department of Critical Care Medicine of Cardiothoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Wei Chen
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Xiao-Fei Ren
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
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Yang S, Cai C, Wang H, Ma X, Shao A, Sheng J, Yu C. Drug delivery strategy in hepatocellular carcinoma therapy. Cell Commun Signal 2022; 20:26. [PMID: 35248060 PMCID: PMC8898478 DOI: 10.1186/s12964-021-00796-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
AbstractHepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with high rates of recurrence and death. Surgical resection and ablation therapy have limited efficacy for patients with advanced HCC and poor liver function, so pharmacotherapy is the first-line option for those patients. Traditional antitumor drugs have the disadvantages of poor biological distribution and pharmacokinetics, poor target selectivity, high resistance, and high toxicity to nontargeted tissues. Recently, the development of nanotechnology has significantly improved drug delivery to tumor sites by changing the physical and biological characteristics of drugs and nanocarriers to improve their pharmacokinetics and biological distribution and to selectively accumulate cytotoxic agents at tumor sites. Here, we systematically review the tumor microenvironment of HCC and the recent application of nanotechnology in HCC.
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Cucarull B, Tutusaus A, Rider P, Hernáez-Alsina T, Cuño C, García de Frutos P, Colell A, Marí M, Morales A. Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances. Cancers (Basel) 2022; 14:cancers14030621. [PMID: 35158892 PMCID: PMC8833604 DOI: 10.3390/cancers14030621] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.
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Affiliation(s)
- Blanca Cucarull
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | | | - Carlos Cuño
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Unidad Asociada (IMIM), IIBB-CSIC, CIBERCV, IDIBAPS, 08036 Barcelona, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08036 Barcelona, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, IDIBAPS, 08036 Barcelona, Spain
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
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Ayvaz I, Sunay D, Sariyar E, Erdal E, Karagonlar ZF. Three-Dimensional Cell Culture Models of Hepatocellular Carcinoma - a Review. J Gastrointest Cancer 2021; 52:1294-1308. [PMID: 34927218 DOI: 10.1007/s12029-021-00772-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2021] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Three-dimensional (3D) cell culture studies are becoming extremely common because of their capability to mimic tumor architecture, such as cell-cell and cell-ECM interactions, more efficiently than 2D monolayer systems. These interactions have important roles in defining the tumor cell behaviors, such as proliferation, differentiation, and most importantly, tumor drug response. OBJECTIVE This review aims to provide an overview of the methods for 3D tumor spheroid formation to model human tumors, specifically concentrated on studies using hepatocellular carcinoma (HCC) cells. METHOD We obtained information from previously published articles. In this review, there is discussion of the scaffold and non-scaffold-based approaches, including hanging drop, bioreactors and 3D bioprinting. RESULTS AND CONCLUSION The mimicking of the tumor microenvironment (TME) as tumor spheroids could provide a valuable platform for studying tumor biology. Multicellular tumor spheroids are self-assembled cultures of mixed cells (tumor and stromal cells) organized in a 3D arrangement. These spheroids closely mimic the main features of human solid tumors, such as structural organization, central hypoxia, and overall oxygen and nutrient gradients. Hepatocellular carcinoma (HCC) is the most common liver malignancy, and most difficult to overcome because of its drug resistance and tumor heterogeneity. In order to mimic this highly heterogeneous environment, 3D cell culture systems are needed.
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Affiliation(s)
- Irmak Ayvaz
- Genetics and Bioengineering Department, Izmir University of Economics, Izmir, 35330, Turkey
| | - Dilara Sunay
- Genetics and Bioengineering Department, Izmir University of Economics, Izmir, 35330, Turkey
| | - Ece Sariyar
- Genetics and Bioengineering Department, Izmir University of Economics, Izmir, 35330, Turkey
| | - Esra Erdal
- Department of Medical Biology and Genetics, FacultyofMedicine, Dokuz Eylul University, Izmir, 35340, Turkey.,Izmir Biomedicine and Genome Center, Izmir, 35340, Turkey
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Li T, Liu J, Wang Y, Zhou C, Shi Q, Huang S, Yang C, Chen Y, Bai Y, Xiong B. Liver fibrosis promotes immunity escape but limits the size of liver tumor in a rat orthotopic transplantation model. Sci Rep 2021; 11:22846. [PMID: 34819565 PMCID: PMC8613241 DOI: 10.1038/s41598-021-02155-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/10/2021] [Indexed: 11/09/2022] Open
Abstract
Liver fibrosis plays a crucial role in promoting tumor immune escape and tumor aggressiveness for liver cancer. However, an interesting phenomenon is that the tumor size of liver cancer patients with liver fibrosis is smaller than that of patients without liver fibrosis. In this study, 16 SD rats were used to establish orthotopic liver tumor transplantation models with Walker-256 cell lines, respectively on the fibrotic liver (n = 8, LF group) and normal liver (n = 8, control group). MRI (magnetic resonance imaging) was used to monitor the size of the tumors. All rats were executed at the third week after modeling, and the immunohistochemical staining was used to reflect the changes in the tumor microenvironment. The results showed that, compared to the control group, the PD-L1 (programmed cell death protein receptor-L1) expression was higher, and the neutrophil infiltration increased while the effector (CD8+) T cell infiltration decreased in the LF group. Additionally, the expression of MMP-9 (matrix metalloproteinase-9) of tumor tissue in the LF group increased. Three weeks after modeling, the size of tumors in the LF group was significantly smaller than that in the control group (382.47 ± 195.06 mm3 vs. 1736.21 ± 657.25 mm3, P < 0.001). Taken together, we concluded that liver fibrosis facilitated tumor immunity escape but limited the expansion of tumor size.
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Affiliation(s)
- Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Qin Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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41
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Lu Q, Zhou Y, Xu M, Liang X, Jing H, Wang X, Li N. Sequential delivery for hepatic fibrosis treatment based on carvedilol loaded star-like nanozyme. J Control Release 2021; 341:247-260. [PMID: 34826531 DOI: 10.1016/j.jconrel.2021.11.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 11/30/2022]
Abstract
Hepatic fibrosis, characterized by excessive reactive oxygen species (ROS) generation, hepatic stellate cells (HSCs) activation, and enormous extracellular matrix (ECM) production, can further cause liver cirrhosis, liver failure and liver cancer. However, the combination of limited solubility, low targeting, uncontrolled release and the sophisticated physiological barriers are tremendous challenges for therapeutic effect. In this study, we engineered a sequential delivery strategy based on autophagy inhibitor carvedilol (CAR) loaded and hyaluronic acid (HA) modified star-like Au nanozyme (Au NS@CAR-HA) for targeted HSCs suppression. In hepatic fibrosis acidic environment, CAR-HA can be firstly detached from Au NS@CAR-HA. Then, CAR would be released from CAR-HA conjugation by chemical bond breakage which triggered by intracellular acid potential, thus could suppressing autolysosome generation by up-regulation of autosome and lysosome pH value to inhibit HSCs activation. Meanwhile, Au NS exhibited enhanced ROS scavenging efficiency of hydrogen peroxides and superoxide, which was helpful to restrain the activity of peroxisome proliferators-activated receptors β (PPARβ) and c-Jun N-terminal kinase (JNK), thereby reducing HSCs proliferation to enhance HSCs inactivation efficacy. In conclusion, Au NS@CAR-HA can attenuate hepatic fibrosis via regulating the proliferation and activation of hepatic stellate cells, which provides a new strategy for hepatic fibrosis treatment.
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Affiliation(s)
- Qiang Lu
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Yue Zhou
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Min Xu
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Xiaoyang Liang
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Huaqing Jing
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Xinxing Wang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, PR China.
| | - Nan Li
- Tianjin Key Laboratory of Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China.
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42
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Sükei T, Palma E, Urbani L. Interplay between Cellular and Non-Cellular Components of the Tumour Microenvironment in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5586. [PMID: 34771746 PMCID: PMC8583132 DOI: 10.3390/cancers13215586] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Currently, treatments available for advanced HCC provide dismal chances of survival, thus there is an urgent need to develop more effective therapeutic strategies. While much of the focus of recent decades has been on targeting malignant cells, promising results have emerged from targeting the tumour microenvironment (TME). The extracellular matrix (ECM) is the main non-cellular component of the TME and it profoundly changes during tumorigenesis to promote the growth and survival of malignant cells. Despite this, many in vitro models for drug testing fail to consider the TME leading to a high failure rate in clinical trials. Here, we present an overview of the function and properties of the ECM in the liver and how these change during malignant transformation. We also discuss the relationship between immune cells and ECM in the TME in HCC. Lastly, we present advanced, 3D culture techniques of cancer modelling and argue that the incorporation of TME components into these is essential to better recapitulate the complex interactions within the TME.
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Affiliation(s)
- Tamás Sükei
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK; (T.S.); (E.P.)
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Elena Palma
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK; (T.S.); (E.P.)
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Luca Urbani
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK; (T.S.); (E.P.)
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
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43
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Kalasekar SM, VanSant-Webb CH, Evason KJ. Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities. Cancers (Basel) 2021; 13:5524. [PMID: 34771685 PMCID: PMC8582820 DOI: 10.3390/cancers13215524] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: β-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions.
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Affiliation(s)
| | | | - Kimberley J. Evason
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (S.M.K.); (C.H.V.-W.)
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44
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Passi M, Zahler S. Mechano-Signaling Aspects of Hepatocellular Carcinoma. J Cancer 2021; 12:6411-6421. [PMID: 34659531 PMCID: PMC8489129 DOI: 10.7150/jca.60102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/11/2021] [Indexed: 12/13/2022] Open
Abstract
HCC is one of the leading causes of cancer related death worldwide and comprises about 90% of the cases of primary liver cancer. It is generally accompanied by chronic liver fibrosis characterised by deposition of collagen fibres, which, in turn, causes enhanced stiffness of the liver tissue. Changes of tissue stiffness give rise to alterations of signalling pathways that are associated to mechanical properties of the cells and the extracellular matrix, and that can be subsumed as "mechano-signaling pathways", like, e.g., the YAP/TAZ pathway, or the SRF pathway. Stiffness of the liver tissue modulates mechanical regulation of many genes involved in HCC progression. However, mechano-signaling is still rather underrepresented in our concepts of cancer in comparison to "classical" biochemical signalling pathways. This review aims to give an overview of various stiffness induced mechano-biological aspects of HCC.
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Affiliation(s)
- Mehak Passi
- Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr. 5-13, 81377 Munich, Germany
| | - Stefan Zahler
- Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr. 5-13, 81377 Munich, Germany
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45
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Lam M, Reales-Calderon JA, Ow JR, Adriani G, Pavesi A. In vitro 3D liver tumor microenvironment models for immune cell therapy optimization. APL Bioeng 2021; 5:041502. [PMID: 34632251 PMCID: PMC8492081 DOI: 10.1063/5.0057773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Despite diagnostic and therapeutic advances, liver cancer kills more than 18 million people every year worldwide, urging new strategies to model the disease and to improve the current therapeutic options. In vitro tumor models of human cancer continue to evolve, and they represent an important screening tool. However, there is a tremendous need to improve the physiological relevance and reliability of these in vitro models to fulfill today's research requirements for better understanding of cancer progression and treatment options at different stages of the disease. This review describes the hepatocellular carcinoma microenvironmental characteristics and illustrates the current immunotherapy strategy to fight the disease. Moreover, we present a recent collection of 2D and 3D in vitro liver cancer models and address the next generation of in vitro systems recapitulating the tumor microenvironment complexity in more detail.
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Affiliation(s)
- Maxine Lam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jose Antonio Reales-Calderon
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
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46
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Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, Rosenberg N, Pappo O, Elgavish S, Nevo Y, Safadi R, Peled A, Rose-John S, Galun E, Axelrod JH. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis. Cancer Res 2021; 81:4766-4777. [PMID: 34117031 DOI: 10.1158/0008-5472.can-21-0321] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/05/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
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Affiliation(s)
- Anat Shriki
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Tali Lanton
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orr Levkovitch-Siany
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dana Eidelshtein
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- The Wohl Institute for Translational Medicine, Human Biology Research Center, Hadassah University Medical Center, Jerusalem, Israel
| | - Nofar Rosenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Orit Pappo
- Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Rifaat Safadi
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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47
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Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 2021; 21:541-557. [PMID: 34326518 DOI: 10.1038/s41568-021-00383-9] [Citation(s) in RCA: 330] [Impact Index Per Article: 82.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
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Affiliation(s)
- Xin Li
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Seehawer
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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48
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Esmail MM, Saeed NM, Michel HE, El-Naga RN. The ameliorative effect of niclosamide on bile duct ligation induced liver fibrosis via suppression of NOTCH and Wnt pathways. Toxicol Lett 2021; 347:23-35. [PMID: 33961984 DOI: 10.1016/j.toxlet.2021.04.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/07/2021] [Accepted: 04/29/2021] [Indexed: 12/14/2022]
Abstract
Liver fibrosis is the conjoint consequence of almost all chronic liver diseases. Cholestatic liver injury is a significant stimulus for fibrotic liver. This study was conducted to investigate the hepatoprotective effect of niclosamide as a NOTCH inhibitor and on the Wnt pathway against cholestatic liver fibrosis (CLF) which was experimentally induced by bile duct ligation (BDL). Rats were randomly divided into five main groups (6 per group): sham, BDL, BDL/niclosamide 5, BDL/niclosamide 10 and niclosamide 10 only group. Niclosamide was administered intraperitoneally (i.p.) for 4 weeks starting at the same day of surgery at doses 5 and 10 mg/kg. Liver function, cholestasis, oxidative stress, inflammation, liver fibrosis, NOTCH signaling pathway and Wnt pathway markers were assessed. Niclosamide (5 and 10 mg/kg) significantly reduced liver enzymes levels, oxidative stress, inflammation and phosphorylated signal transducer and activator of transcription3 (p-STAT3). Niclosamide (5 and 10 mg/kg) also significantly reduced NOTCH pathway (Jagged1, NOTCH2, NOTCH3, HES1, SOX9), Wnt pathway (Wnt5B, and Wnt10A), and fibrosis (transforming growth factor-beta1 (TGF-β1), alpha smooth muscle actin (α-SMA) and collagen deposition with more prominent effect of the higher dose 10 mg/kg. So, this study presents nicloamide as a promising antifibrotic agent in CLF through inhibition of NOTCH and Wnt pathways.
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Affiliation(s)
- Manar M Esmail
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Noha M Saeed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
| | - Haidy E Michel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Reem N El-Naga
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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49
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Zhu H, Liu X. Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies. Front Oncol 2021; 11:666340. [PMID: 34434889 PMCID: PMC8381364 DOI: 10.3389/fonc.2021.666340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023] Open
Abstract
Globally, in 2018, 4.8 million new patients have a diagnosis of gastrointestinal (GI) cancers, while 3.4 million people died of such disorders. GI malignancies are tightly relevant to 26% of the world-wide cancer incidence and occupies 35% of all cancer-associated deaths. In this article, we principally investigated molecular and cellular mechanisms of tumorigenesis in five major GI cancers occurring at esophagus, stomach, liver, pancreas, and colorectal region that illustrate high morbidity in Eastern and Western countries. Moreover, through this investigation, we not only emphasize importance of the tumor microenvironment in development and treatment of malignant tumors but also identify significance of M2PK, miRNAs, ctDNAs, circRNAs, and CTCs in early detection of GI cancers, as well as systematically evaluate contribution of personalized precision medicine including cellular immunotherapy, new antigen and vaccine therapy, and oncolytic virotherapy in treatment of GI cancers.
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Affiliation(s)
- Haipeng Zhu
- Precision and Personalized Cancer Treatment Center, Division of Cancer Diagnosis & Therapy, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China.,Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical College, Xinxiang, China
| | - Xiaojun Liu
- Division of Cellular & Biomedical Science, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China
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50
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Wu M, Miao H, Fu R, Zhang J, Zheng W. Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma. Curr Mol Pharmacol 2021; 13:261-272. [PMID: 32091349 DOI: 10.2174/1874467213666200224102820] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/24/2022]
Abstract
Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Huajie Miao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Rong Fu
- Department of Pathology, Affiliated Haian Hospital of Nantong University, 17 Zhongba Road, 226600, Haian, Jiangsu, China
| | - Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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