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Kawakami Y, Okada H, Nio K, Hayashi T, Seki A, Nakagawa H, Yamada S, Iida N, Shimakami T, Takatori H, Honda M, Kaneko S, Yamashita T. Transcription factor JUNB is required for transformation of EpCAM-positive hepatocellular carcinoma (HCC) cells into CD90-positive HCC cells in vitro. Cell Death Dis 2025; 16:319. [PMID: 40253402 PMCID: PMC12009367 DOI: 10.1038/s41419-025-07602-3] [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: 09/22/2024] [Revised: 02/22/2025] [Accepted: 03/27/2025] [Indexed: 04/21/2025]
Abstract
Hepatocellular carcinoma (HCC) harbors two types of stem cells-epithelial and mesenchymal stem cells. The mechanism by which epithelial EpCAM-positive HCC cells transform into mesenchymal CD90-positive HCC cells remains unclear. On peritumoral fibrotic nodules, epithelial HCC cells form communities with stromal cells, driving tumor growth and malignancy. We aimed to clarify the mechanism by which epithelial cell adhesion molecule (EpCAM)-positive HCC cells contribute to the phenotype of mesenchymal CD90-positive HCC cells that metastasize to distant sites by elucidating the interaction between EpCAM-positive HCC cells and fibroblasts. EpCAM-positive CD90-negative epithelial HCC cells (Huh1, Huh7, and HCC cells) were converted into metastasis-prone CD90-positive HCC cells by co-culture with fibroblasts (Lx-2 and Tig3-20). We identified the transcription factor JUNB as responsible for this altered phenotype. We found that the overexpression of JUNB in CD90-negative epithelial HCC cells resulted in significant transformation to mesenchymal CD90-positive HCC in vitro and in vivo, showing metastatic potential to the lungs. In addition, the JUNB expression in EpCAM-positive hepatoma cells was increased by paracrine stimulation with fibroblast-derived TGFb1. This study unravels the mechanism by which fibroblasts aggravate the malignancy of liver cancer, and the results suggest that JUNB may be a target for treating liver cancer metastasis.
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Affiliation(s)
- Yutaro Kawakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Hikari Okada
- Information-Based Medicine Development, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Tomoyuki Hayashi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Hidetoshi Nakagawa
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Shinya Yamada
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
| | - Shuichi Kaneko
- Information-Based Medicine Development, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
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Giron-Michel J, Padelli M, Oberlin E, Guenou H, Duclos-Vallée JC. State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment. BioDrugs 2025; 39:237-260. [PMID: 39826071 PMCID: PMC11906529 DOI: 10.1007/s40259-024-00702-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2024] [Indexed: 01/20/2025]
Abstract
Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.
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Affiliation(s)
- Julien Giron-Michel
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France.
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France.
| | - Maël Padelli
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- Department of Biochemistry and Oncogenetics, Paul Brousse Hospital, AP-HP, Villejuif, France
| | - Estelle Oberlin
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Hind Guenou
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Jean-Charles Duclos-Vallée
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- INSERM UMR-S 1193, Paul Brousse Hospital, Villejuif, France
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, Villejuif, France
- Fédération Hospitalo-Universitaire (FHU) Hepatinov, Villejuif, France
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Yang C, Wang R, Hardy P. The Multifaceted Roles of MicroRNA-181 in Stem Cell Differentiation and Cancer Stem Cell Plasticity. Cells 2025; 14:132. [PMID: 39851559 PMCID: PMC11763446 DOI: 10.3390/cells14020132] [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: 12/12/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025] Open
Abstract
Stem cells are undifferentiated or partially differentiated cells with an extraordinary ability to self-renew and differentiate into various cell types during growth and development. The epithelial-mesenchymal transition (EMT), a critical developmental process, enhances stem cell-like properties in cells, and is associated with both normal stem cell function and the formation of cancer stem cells. Cell stemness and the EMT often coexist and are interconnected in various contexts. Cancer stem cells are a critical tumor cell population that drives tumorigenesis, cancer progression, drug resistance, and metastasis. Stem cell differentiation and the generation of cancer stem cells are regulated by numerous molecules, including microRNAs (miRNAs). These miRNAs, particularly through the modulation of EMT-associated factors, play major roles in controlling the stemness of cancer stem cells. This review presents an up-to-date summary of the regulatory roles of miR-181 in human stem cell differentiation and cancer cell stemness. We outline studies from the current literature and summarize the miR-181-controlled signaling pathways responsible for driving human stem cell differentiation or the emergence of cancer stem cells. Given its critical role in regulating cell stemness, miR-181 is a promising target for influencing human cell fate. Modulation of miR-181 expression has been found to be altered in cancer stem cells' biological behaviors and to significantly improve cancer treatment outcomes. Additionally, we discuss challenges in miRNA-based therapies and targeted delivery with nanotechnology-based systems.
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Affiliation(s)
- Chun Yang
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Rui Wang
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Pierre Hardy
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada
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Zhang J, Cui T, Xu J, Wang P, Lv C, Pan G. The potential of cancer stem cells for personalized risk assessment and therapeutic intervention in individuals with intrahepatic cholangiocarcinoma. Discov Oncol 2024; 15:306. [PMID: 39048806 PMCID: PMC11269542 DOI: 10.1007/s12672-024-01179-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Accumulating evidence suggests that intrahepatic cholangiocarcinoma (ICC) is a stem cell-based disease, but information on the biology of cancer stem cells (CSC) in ICC is very limited. METHODS ICC RNA-seq cohorts from three different public databases were integrated and the protein-coding genes were divided into different modules using "WGCNA" to screen the most relevant modules with CSC scores. Least Absolute Shrinkage and Selection Operator (LASSO) regression were introduced to construct prognostic classification models. In addition, the extent of immune cell infiltration in patients in different risk groups was assessed based on the ESTIMATE, CIBERSORT, MCP-Counter, and single sample gene set enrichment analysis (ssGSEA) algorithms. Finally, the correlation between different risk scores and common drugs was analyzed by pRRophetic package and Spearman method. RESULTS In the present study, we found that a high CSC score was associated with a poorer prognosis in patients with ICC. The yellow module obtained by WGCNA was significantly positively correlated with the CSCs score, in which 8 genes were served to build a prognostic classification model, and the obtained risk score was negatively correlated with CSCs score and prognosis. The low-risk score was more suitable for immunotherapy, and the high-risk score was more suitable for treatment with 11 antitumor drugs. CONCLUSION This study revealed the regulatory role of CSC-mediated EMT, angiogenesis, and immunomodulatory biological processes in ICC, and applied a prognostic classification model to highlight the great potential of CSC for personalized risk assessment, chemotherapy, and immunotherapy intervention in ICC individuals.
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Affiliation(s)
- Jian Zhang
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China
| | - Tao Cui
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China
| | - Jiaobang Xu
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China
| | - Peng Wang
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China
| | - Chongqing Lv
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China
| | - Guozheng Pan
- Hepatobiliary Surgery, Shengli Oilfield Central Hospital, Dongying, 257093, China.
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Liu R, Liu Y, Zhang W, Zhang G, Zhang Z, Huang L, Tang N, Wang K. PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma. Genes Dis 2024; 11:101114. [PMID: 38560500 PMCID: PMC10978540 DOI: 10.1016/j.gendis.2023.101114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 06/19/2023] [Accepted: 08/04/2023] [Indexed: 04/04/2024] Open
Abstract
Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.
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Affiliation(s)
- Rui Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Yi Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Guiji Zhang
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, China
| | - Zhirong Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Luyi Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
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Li H, Liu J, Lai J, Su X, Wang X, Cao J, Mao S, Zhang T, Gu Q. The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC. J Transl Med 2024; 22:537. [PMID: 38844969 PMCID: PMC11155165 DOI: 10.1186/s12967-024-05324-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/20/2024] [Indexed: 06/10/2024] Open
Abstract
Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Huizi Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Jin Liu
- Department of Radiology, University of California, San Diego, The, USA
| | - Jie Lai
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xinyao Su
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xiaofeng Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiaqing Cao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Shengxun Mao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Tong Zhang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Actuated Hospital of Sun Yat-sen University, Guangzhou, 510000, Guangdong, China.
- Department of General Surgery, School of Medicine, Organ Transplantation Clinical Medical Center of Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, 361000, China.
- Department of Organ Transplantation, School of Medicine, Organ Transplantation Clinical Medical Center of Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, 361005, Fujian, China.
| | - Qiuping Gu
- Department of Gastroenterology, Ganzhou People's Hospital, No. 16, Meiguan Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, People's Republic of China.
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Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [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: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
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Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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Zhang Z, Qiao Y, Sun Q, Peng L, Sun L. A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability. Cell Death Discov 2023; 9:350. [PMID: 37741815 PMCID: PMC10518014 DOI: 10.1038/s41420-023-01640-6] [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: 12/20/2022] [Revised: 08/26/2023] [Accepted: 09/05/2023] [Indexed: 09/25/2023] Open
Abstract
Liver cancer stem cells (LCSCs) are recognized as key contributors to hepatocarcinogenesis, progression, and recurrence. Consequently, eradicating LCSCs has a great chance of increasing long-term survival in patients with liver cancer. Parthenolide (PTL), a natural sesquiterpene lactone product, possesses robust antitumor activity. However, the effects of PTL on LCSCs and underlying mechanisms remain unknown. Here we show that administration of PTL stimulated cell cycle arrest at the G1 phase, induced apoptosis, and decreased the stemness of LCSCs. Further research indicates that PTL caused the production of ROS and the reduction of oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential (MMP) levels of LCSCs. RNA sequencing (RNA-Seq) further shows that PTL decreased SLC25A1 expression at the mRNA level and that inhibition of SLC25A1 synergistically decreased the expression of IDH2 and several pivotal genes involved in mitochondrial respiratory chain complex, resulting in the production of ROS and mitochondrial dysfunction. In addition, the inhibitory effect of PTL on mitochondrial function and self-renewal capacity of LCSCs was abolished by the knockdown of SLC25A1 or treatment with SLC25A1 inhibitor CTPI-2. Importantly, PTL prevented liver cancer growth in vivo without clearly causing toxicity. Our research shows that PTL inhibits the growth and stemness of LCSCs through SLC25A1-mediated mitochondrial function. PTL may be a potential candidate natural agent for liver cancer treatment.
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Affiliation(s)
- Zhichun Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yuan Qiao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Qiuyue Sun
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Liang Peng
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100029, China.
| | - Lichao Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Sonam Dongsar T, Tsering Dongsar T, Molugulu N, Annadurai S, Wahab S, Gupta N, Kesharwani P. Targeted therapy of breast tumor by PLGA-based nanostructures: The versatile function in doxorubicin delivery. ENVIRONMENTAL RESEARCH 2023; 233:116455. [PMID: 37356522 DOI: 10.1016/j.envres.2023.116455] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/15/2023] [Accepted: 06/17/2023] [Indexed: 06/27/2023]
Abstract
Breast carcinoma is a molecularly diverse illness, and it is among the most prominent and often reported malignancies in female across the globe. Surgical intervention, chemotherapy, immunotherapy, gene therapy, and endocrine treatment are among the currently viable treatment options for the carcinoma of breast. Chemotherapy is among the most prevalent cancer management strategy. Doxorubicin (DOX) widely employed as a cytostatic medication for the treatment of a variety of malignancies. Despite its widespread acceptance and excellent efficacy against an extensive line up of neoplasia, it has a variety of shortcomings that limit its therapeutic potential in the previously mentioned indications. Employment of nanoparticulate systems has come up as a unique chemo medication delivery strategy and are being considerably explored for the amelioration of breast carcinoma. Polylactic-co-glycolic acid (PLGA)-based nano systems are being utilized in a number of areas within the medical research and medication delivery constitutes one of the primary functions for PLGA given their inherent physiochemical attributes, including their aqueous solubility, biocompatibility, biodegradability, versatility in formulation, and limited toxicity. Herein along with the different application of PLGA-based nano formulations in cancer therapy, the present review intends to describe the various research investigations that have been conducted to enumerate the effectiveness of DOX-encapsulated PLGA nanoparticles (DOX-PLGA NPs) as a feasible treatment option for breast cancer.
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Affiliation(s)
- Tenzin Sonam Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Tenzin Tsering Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nagashekhara Molugulu
- School of Pharmacy, Monash University, Bandar Sunway, Jalan Lagoon Selatan, 47500, Malaysia
| | - Sivakumar Annadurai
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Neelima Gupta
- Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, 470003, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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Yu D, Lu Z, Wang R, Xiang Y, Li H, Lu J, Zhang L, Chen H, Li W, Luan X, Chen L. FXR agonists for colorectal and liver cancers, as a stand-alone or in combination therapy. Biochem Pharmacol 2023; 212:115570. [PMID: 37119860 DOI: 10.1016/j.bcp.2023.115570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/01/2023]
Abstract
Farnesoid X receptor (FXR, NR1H4) is generally considered as a tumor suppressor of colorectal and liver cancers. The interaction between FXR, bile acids (BAs) and gut microbiota is closely associated with an increased risk of colorectal and liver cancers. Increasing evidence shows that FXR agonists may be potential therapeutic agents for colorectal and liver cancers. However, FXR agonists alone do not produce the desired results due to the complicated pathogenesis and single therapeutic mechanism, which suggests that effective treatments will require a multimodal approach. Based on the principle of improvingefficacy andreducingside effects, combination therapy is currently receiving considerable attention. In this review, colorectal and liver cancers are grouped together to discuss the effects of FXR agonists alone or in combination for combating the two cancers. We hope that this review will provide a theoretical basis for the clinical application of novel FXR agonists or combination with FXR agonists against colorectal and liver cancers.
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Affiliation(s)
- Danmei Yu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhou Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Ruyu Wang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yusen Xiang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongtao Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lijun Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Weihua Li
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Xin Luan
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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11
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Vita F, Olaizola I, Amato F, Rae C, Marco S, Banales JM, Braconi C. Heterogeneity of Cholangiocarcinoma Immune Biology. Cells 2023; 12:cells12060846. [PMID: 36980187 PMCID: PMC10047186 DOI: 10.3390/cells12060846] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche.
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Affiliation(s)
- Francesca Vita
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Department of Oncology, University of Turin, 10043 Turin, Italy
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
| | - Francesco Amato
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Colin Rae
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Sergi Marco
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), 28029 Madrid, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
- Correspondence:
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12
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Shi J, Guo C, Li Y, Ma J. The long noncoding RNA TINCR promotes self-renewal of human liver cancer stem cells through autophagy activation. Cell Death Dis 2022; 13:961. [PMID: 36385098 PMCID: PMC9668904 DOI: 10.1038/s41419-022-05424-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is an extraordinarily heterogeneous tumor, which holds high recurrence and metastasis rates. Liver cancer stem cells (LCSCs) have been considered to be important influencing factors of these pathological properties, but the underlying mechanisms are poorly understood in HCC. Considerable evidences have shown that autophagy has an important role in cancer stemness. However, it is still unknown whether a long noncoding RNA (lncRNA) TINCR is involved in autophagy and self-renewal maintenance of HCC. In this study, TINCR was found to be highly expressed in HCC tissues and LCSCs. In vitro and in vivo assays for the first time showed that TINCR was required for LCSC self-renewal and tumorigenesis. Moreover, gene ontology analysis revealed the involvement of autophagy in the maintenance of TINCR-regulated stemness. Mechanically, TINCR was associated with polypyrimidine tract binding protein 1 (PTBP1) protein, which further promoted the transcription activity of autophagy related gene ATG5. In conclusion, we demonstrated that TINCR regulated LCSC self-renewal by autophagy activation through PTBP1/ATG5 regulatory pathway, offering a potential new target for HCC therapy.
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Affiliation(s)
- Jing Shi
- grid.459333.bAffiliated Hospital of Qinghai University, Xining, 810001 Qinghai Province China ,grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
| | - Cao Guo
- grid.216417.70000 0001 0379 7164Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Yang Li
- grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
| | - Junli Ma
- grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
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13
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Belanova A, Chmykhalo V, Shkurat T, Trotsenko A, Zolotukhin P. Trimethylglycine betaine effects on NFκB, HIF1A and NFE2L2/AP-1 pathways, mitochondrial activity, glucose import, and levels of ROS, thiols and lipids in HeLa cells. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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14
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He J, Zhou C, Xu X, Zhou Z, Danoy M, Shinohara M, Xiao W, Zhu D, Zhao X, Feng X, Mao Y, Sun W, Sakai Y, Yang H, Pang Y. Scalable Formation of Highly Viable and Functional Hepatocellular Carcinoma Spheroids in an Oxygen-Permeable Microwell Device for Anti-Tumor Drug Evaluation. Adv Healthc Mater 2022; 11:e2200863. [PMID: 35841538 DOI: 10.1002/adhm.202200863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/30/2022] [Indexed: 01/27/2023]
Abstract
For high-throughput anti-cancer drug screening, microwell arrays may serve as an effective tool to generate uniform and scalable tumor spheroids. However, microwell arrays are commonly anchored in non-oxygen-permeable culture plates, leading to limited oxygen supply for avascular spheroids. Herein, a polydimethylsiloxane (PDMS)-based oxygen-permeable microwell device is introduced for generating highly viable and functional hepatocellular carcinoma (HCC) spheroids. The PDMS sheets at the bottom of the microwell device provide a high flux of oxygen like in vivo neighboring hepatic sinusoids. Owing to the better oxygen supply, the generated HepG2 spheroids are larger in size and exhibit higher viability and proliferation with less cell apoptosis and necrosis. These spheroids also exhibit lower levels of anaerobic cellular respiration and express higher levels of liver-related functions. In anti-cancer drug testing, spheroids cultured in PDMS plates show a significantly stronger resistance against doxorubicin because of the stronger stem-cell and multidrug resistance phenotype. Moreover, higher expression of vascular endothelial growth factor-A produces a stronger angiogenesis capability of the spheroids. Overall, compared to the spheroids cultured in conventional non-oxygen-permeable plates, these spheroids can be used as a more favorable model for early-stage HCCs and be applied in high-throughput anti-cancer drug screening.
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Affiliation(s)
- Jianyu He
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China
| | - Chang Zhou
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China
| | - Xiaolei Xu
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China.,Department of Hepatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Changping District, Beijing, 102218, P. R. China
| | - Zhenzhen Zhou
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China
| | - Mathieu Danoy
- Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, Tokyo, 113-033, Japan
| | - Marie Shinohara
- Institute of Industrial Science, University of Tokyo, Tokyo, 153-8505, Japan
| | - Wenjin Xiao
- Centre de Recherche des Cordeliers, INSERM UMR-S1138, CNRS SNC5014, University of Paris, Paris, 75006, France
| | - Dong Zhu
- Clinical Laboratory, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Changping District, Beijing, 102218, P. R. China
| | - Xiuying Zhao
- Clinical Laboratory, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Changping District, Beijing, 102218, P. R. China
| | - Xiaobin Feng
- Department of Hepatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Changping District, Beijing, 102218, P. R. China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences (CAMS), Dongcheng District, Beijing, 100005, P. R. China
| | - Wei Sun
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China.,Department of Mechanical Engineering and Mechanics, College of Engineering, Drexel University, Philadelphia, PA, 19104, USA
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, Tokyo, 113-033, Japan
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences (CAMS), Dongcheng District, Beijing, 100005, P. R. China
| | - Yuan Pang
- Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Haidian District, Beijing, 100084, P. R. China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, P. R. China
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15
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Hasannia M, Abnous K, Taghdisi SM, Nekooei S, Ramezani M, Alibolandi M. Synthesis of doxorubicin-loaded peptosomes hybridized with gold nanorod for targeted drug delivery and CT imaging of metastatic breast cancer. J Nanobiotechnology 2022; 20:391. [PMID: 36045404 PMCID: PMC9429417 DOI: 10.1186/s12951-022-01607-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 08/19/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cancer nanomedicines based on synthetic polypeptides have attracted much attention due to their superior biocompatibility and biodegradability, stimuli responsive capability through secondary conformation change, adjustable functionalities for various cargos such as peptides, proteins, nucleic acids and small therapeutic molecules. Recently, a few nanoformulations based on polypeptides comprising NK105, NC6004, NK911, CT2103, have entered phase I-III clinical trials for advanced solid tumors therapy. In the current study, we prepared polypeptide-based vesicles called peptosome via self-assembly of amphiphilic polypeptide-based PEG-PBLG diblock copolymer. RESULTS In this regard, poly(γ-benzyl L-glutamate (PBLG) was synthesized via ring opening polymerization (ROP) of γ-benzyl L-glutamate-N-carboxyanhydride (BLG-NCA) using N-hexylamine as initiator. Then amine-terminated PBLG was covalently conjugated to heterofuctional maleimide PEG-carboxylic acid or methyl-PEG-carboxylic acid. The PEG-PBLG peptosomes were prepared through double emulsion method for the co-delivery of doxorubicin.HCl and gold nanorods as hydrophilic and hydrophobic agents in interior compartment and membrane of peptosomes, respectively (Pep@MUA.GNR-DOX) that DOX encapsulation efficiency and loading capacity were determined 42 ± 3.6 and 1.68 ± 3.6. Then, theranostic peptosomes were decorated with thiol-functionalized EpCAM aptamer throught thiol-maleimide reaction producing Apt-Pep@MUA.GNR-DOX for targeted delivery. The non-targeted and targeted peptosomes showed 165.5 ± 1.1 and 185 ± 4.7 nm diameters, respectively while providing sustained, controlled release of DOX. Furthermore, non-targeted and targeted peptosomes showed considerable serum stability. In vitro study on MCF-7 and 4T1 cells showed significantly higher cytotoxicity for Apt-Pep@MUA.GNR-DOX in comparison with Pep@MUA.GNR-DOX while both system did not show any difference in cytotoxicity against CHO cell line. Furthermore, Apt-Pep@MUA.GNR-DOX illustrated higher cellular uptake toward EpCAM-overexpressing 4T1 cells compared to Pep@MUA.GNR-DOX. In preclinical stage, therapeutic and diagnostic capability of the prepared Pep@MUA.GNR-DOX and Apt-Pep@MUA.GNR-DOX were investigated implementing subcutaneous 4T1 tumor model in BALB/c mice. The obtained data indicated highest therapeutic index for Apt-Pep@MUA.GNR-DOX compared to Pep@MUA.GNR-DOX and free DOX. Moreover, the prepared system showed capability of CT imaging of tumor tissue in 4T1 tumorized mice through tumor accumulation even 24 h post-administration. CONCLUSION In this regard, the synthesized theranostic peptosomes offer innovative hybrid multipurpose platform for fighting against breast cancer.
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Affiliation(s)
- Maliheh Hasannia
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mohammad Taghdisi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sirous Nekooei
- Department of Radiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. .,Pharmaceutical Technology Institute, Nanotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Vasefifar P, Motafakkerazad R, Maleki LA, Najafi S, Ghrobaninezhad F, Najafzadeh B, Alemohammad H, Amini M, Baghbanzadeh A, Baradaran B. Nanog, as a key cancer stem cell marker in tumor progression. Gene X 2022; 827:146448. [PMID: 35337852 DOI: 10.1016/j.gene.2022.146448] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/16/2022] [Accepted: 03/18/2022] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are a small population of malignant cells that induce tumor onset and development. CSCs share similar features with normal stem cells in the case of self-renewal and differentiation. They also contribute to chemoresistance and metastasis of cancer cells, leading to therapeutic failure. To identify CSCs, multiple cell surface markers have been characterized, including Nanog, which is found at high levels in different cancers. Recent studies have revealed that Nanog upregulation has a substantial association with the advanced stages and poor prognosis of malignancies, playing a pivotal role through tumorigenesis of multiple human cancers, including leukemia, liver, colorectal, prostate, ovarian, lung, head and neck, brain, pancreatic, gastric and breast cancers. Nanog through different signaling pathways, like JAK/STAT and Wnt/β-catenin pathways, induces stemness, self-renewal, metastasis, invasiveness, and chemoresistance of cancer cells. Some of these signaling pathways are common in various types of cancers, but some have been found in one or two cancers. Therefore, this review aimed to focus on the function of Nanog in multiple cancers based on recent studies surveying the suitable approaches to target Nanog and inhibit CSCs residing in tumors to gain favorable results from cancer treatments.
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Affiliation(s)
- Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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17
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Yu W, Ma Y, Shrivastava SK, Srivastava RK, Shankar S. Chronic alcohol exposure induces hepatocyte damage by inducing oxidative stress, SATB2 and stem cell‐like characteristics, and activating lipogenesis. J Cell Mol Med 2022; 26:2119-2131. [PMID: 35152538 PMCID: PMC8980954 DOI: 10.1111/jcmm.17235] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is a risk factor for hepatocellular carcinoma (HCC). However, the molecular mechanism by which chronic alcohol consumption contributes to HCC is not well understood. The purpose of the study was to demonstrate the effects of chronic ethanol exposure on the damage of human normal hepatocytes. Our data showed that chronic exposure of hepatocytes with ethanol induced changes similar to transformed hepatocytes that is, exhibited colonies and anchorage‐independent growth. These damaged hepatocytes contained high levels of reactive oxygen species (ROS) and showed induction of the SATB2 gene. Furthermore, damaged hepatocytes gained the phenotypes of CSCs which expressed stem cell markers (CD133, CD44, CD90, EpCAM, AFP and LGR5), and pluripotency maintaining factors (Sox‐2, POU5F1/Oct4 and KLF‐4). Ethanol exposure also induced Nanog, a pluripotency maintaining transcription factor that functions in concert with Oct4 and SOX‐2. Furthermore, ethanol induced expression of EMT‐related transcription factors (Snail, Slug and Zeb1), N‐Cadherin, and inhibited E‐cadherin expression in damaged hepatocytes. Ethanol enhanced recruitment of SATB2 to promoters of Bcl‐2, Nanog, c‐Myc, Klf4 and Oct4. Ethanol also induced activation of the Wnt/TCF‐LEF1 pathway and its targets (Bcl‐2, Cyclin D1, AXIN2 and Myc). Finally, ethanol induced hepatocellular steatosis, SREBP1 transcription, and modulated the expression of SREBP1c, ACAC, ACLY, FASN, IL‐1β, IL‐6, TNF‐α, GPC3, FLNB and p53. These data suggest that chronic alcohol consumption may contribute towards the development of HCC by damaging normal hepatocytes with the generation of inflammatory environment, induction of SATB2, stem cell‐like characteristics, and cellular steatosis.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center Kansas City Missouri USA
| | - Yiming Ma
- Kansas City VA Medical Center Kansas City Missouri USA
| | - Sushant K. Shrivastava
- Department of Pharmaceutics Indian Institute of Technology Banaras Hindu University Varanasi U.P. India
| | - Rakesh K. Srivastava
- Kansas City VA Medical Center Kansas City Missouri USA
- Department of Genetics Louisiana State University Health Sciences Center New Orleans Louisina USA
- Stanley S. Scott Cancer Center Department of Genetics Louisiana State University Health Sciences Center New Orleans Louisina USA
- A.B. Freeman School of Business Tulane University New Orleans Louisina USA
| | - Sharmila Shankar
- Kansas City VA Medical Center Kansas City Missouri USA
- John W. Deming Department of Medicine Tulane University School of Medicine New Orleans Louisina USA
- Southeast Louisiana Veterans Health Care System New Orleans Louisina USA
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18
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Sun B, Xu L, Bi W, Ou WB. SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance. Int J Mol Sci 2022; 23:ijms23042053. [PMID: 35216168 PMCID: PMC8876671 DOI: 10.3390/ijms23042053] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
SALL4, a member of the SALL family, is an embryonic stem cell regulator involved in self-renewal and pluripotency. Recently, SALL4 overexpression was found in malignant cancers, including lung cancer, hepatocellular carcinoma, breast cancer, gastric cancer, colorectal cancer, osteosarcoma, acute myeloid leukemia, ovarian cancer, and glioma. This review updates recent advances of our knowledge of the biology of SALL4 with a focus on its mechanisms and regulatory functions in tumors and human hematopoiesis. SALL4 overexpression promotes proliferation, development, invasion, and migration in cancers through activation of the Wnt/β-catenin, PI3K/AKT, and Notch signaling pathways; expression of mitochondrial oxidative phosphorylation genes; and inhibition of the expression of the Bcl-2 family, caspase-related proteins, and death receptors. Additionally, SALL4 regulates tumor progression correlated with the immune microenvironment involved in the TNF family and gene expression through epigenetic mechanisms, consequently affecting hematopoiesis. Therefore, SALL4 plays a critical oncogenic role in gene transcription and tumor growth. However, there are still some scientific hypotheses to be tested regarding whether SALL4 is a therapeutic target, such as different tumor microenvironments and drug resistance. Thus, an in-depth understanding and study of the functions and mechanisms of SALL4 in cancer may help develop novel strategies for cancer therapy.
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Affiliation(s)
| | | | | | - Wen-Bin Ou
- Correspondence: ; Tel./Fax: +86-571-8684-3303
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19
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In Hepatocellular Carcinoma, miRNA-296-3p Targets MSL2 and Suppresses Cell Proliferation and Invasion. JOURNAL OF ONCOLOGY 2021; 2021:7430468. [PMID: 34899909 PMCID: PMC8660223 DOI: 10.1155/2021/7430468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 11/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third-highest cause of cancer-related death in the world. miRNAs have a role in cell division, differentiation, and death biological processes. They are typically dysregulated in cancers, affecting tumor progression. miRNA-296-3p appears to play a crucial role in cancer control, according to new research. However, its expression and roles in HCC are unknown. This study used qRT-PCR and western blotting to detect the miRNA-296-3p and male-specific lethal 2 (MSL2) expression. In addition, cell proliferation, migration, invasion, and apoptosis were studied using CCK-8, flow cytometric analysis, colony formation assay, wound healing test, and transwell assays. The results show that miRNA-296-3p is underexpressed in HCC cell lines, particularly in Huh-7 and HepG2 cells. miRNA-296-3p overexpression lowers the ability of HCC cells to proliferate, migrate, and invade while increasing cell death. Luciferase reporter experiments revealed that the MSL2 is a direct target of miRNA-296-3p. Furthermore, overexpression of miRNA-296-3p reduced MSL2 mRNA and protein levels considerably, according to our findings. Furthermore, the rescue experiments showed that the MSL2 overexpression partially blocked the inhibition effects of miRNA-296-3p mimic on the proliferation and migration of HCC cells. The above results show that miRNA-296-3p may have a repressive effect in HCC by targeting MSL2 and could be used as a therapeutic target for HCC treatment.
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Nahm JH, Park YN. [Up-to-date Knowledge on the Pathological Diagnosis of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 78:268-283. [PMID: 34824185 DOI: 10.4166/kjg.2021.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 11/09/2022]
Abstract
Hepatocellular carcinoma (HCC) has heterogeneous molecular and pathological features and biological behavior. Large-scale genetic studies of HCC were accumulated, and a pathological-molecular classification of HCC was proposed. Approximately 35% of HCCs can be classified into distinct histopathological subtypes according to their molecular characteristics. Among recently identified subtypes, macrotrabecular massive HCC, neutrophil-rich HCC, vessels encapsulating tumor clusters HCC, and progenitor phenotype HCC (HCC with CK19 expression) are associated with a poor prognosis, whereas the lymphocyte-rich HCC subtype is related to a better prognosis. This review provides up-to-date knowledge on the pathological diagnosis of HCC according to the updated World Health Organization Classification of Digestive System Tumors 5th ed.
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Affiliation(s)
- Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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21
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Xu F, Jiang H, Jin M, Peng Q. Application of propofol combined with sevoflurane anesthesia in staged hepatectomy liver detachment and portal vein ligation. Exp Ther Med 2021; 22:921. [PMID: 34335882 PMCID: PMC8290462 DOI: 10.3892/etm.2021.10353] [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: 12/13/2018] [Accepted: 07/07/2019] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the application of propofol combined with sevoflurane anesthesia in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). A retrospective analysis of 40 patients with liver cancer who underwent ALPPS was performed. The study included 21 (control group) and 19 (observation group) patients who were administered propofol anesthesia and propofol in combination with sevoflurane anesthesia, respectively. Changes in liver function indicators, routine blood parameters and blood coagulation function, as well as cognitive function (mini-mental state examination) were recorded. The total bilirubin and direct bilirubin levels and the alanine aminotransferase (ALT) level after the first- and second-stage operation in the two groups was also higher than that prior to the first-stage operation (P<0.05), and the ALT level was significantly lower in the two groups after the second-stage operation compared with that prior to the second-stage operation (P<0.05). The AST level after the first- and second-stage operation was lower than that prior to the first- and second-stage operation, respectively (P<0.05). The white blood cell count after the second-stage operation was significantly lower compared with that prior to the second-stage operation (P<0.05). The plasma fibrinogen (FIB) level was higher after the first-stage operation compared with that prior to the first-stage operation (P<0.05). The prothrombin time in the two groups of patients was higher after the second-stage operation compared with that prior to the second-stage operation (P<0.05), whereas the FIB level was lower (P<0.05) and the international normalized ratio was not significantly different (P>0.05). The degree of cognitive decline prior to the first/second-stage operation, according to mini-mental state examination scores, was different from that after the first/second-stage operation (P<0.05). In conclusion, propofol combined with sevoflurane has a good application value in ALPPS.
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Affiliation(s)
- Fei Xu
- Department of Anesthesiology, Jilin Hepatobiliary Hospital, Changchun, Jilin 130062, P.R. China
| | - Hongbo Jiang
- Changchun Children's Hospital, Changchun, Jilin 132001, P.R. China
| | - Meishan Jin
- Department of BMS, Aviation University of Air Force, Changchun, Jilin 130022, P.R. China
| | - Qihua Peng
- Department of Ultrasonography, Changchun Obstetrics and Gynecology Hospital, Changchun, Jilin 130011, P.R. China
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22
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Mohan CD, Rangappa S, Nayak SC, Sethi G, Rangappa KS. Paradoxical functions of long noncoding RNAs in modulating STAT3 signaling pathway in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2021; 1876:188574. [PMID: 34062154 DOI: 10.1016/j.bbcan.2021.188574] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/03/2021] [Accepted: 05/27/2021] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the lethal and leading types of cancer threatening the globe with a high mortality rate. STAT3 is an oncogenic transcription factor that is aberrantly activated in several human malignancies including HCC. Many STAT3-driven genes control cell proliferation and survival, apoptotic resistance, cell cycle progression, metastasis, and chemotherapeutic resistance. STAT3 signaling is regulated by endogenous modulators such as protein tyrosine phosphatase (PTP), suppressor of cytokine signaling (SOCS), protein inhibitor of activated STAT (PIAS), and various long noncoding RNAs (lncRNAs). Interestingly, lncRNAs have been reported to exhibit oncogenic and tumor suppressor functions, and these effects are mediated through diverse molecular mechanisms including sponging of microRNAs (miRs), transcription activation/inhibition, and epigenetic modifications. In this article, we have discussed the possible role of STAT3 signaling in hepatocarcinogenesis and various mechanisms by which lncRNAs impart their oncogenic or tumor suppressive action by modulating the STAT3 pathway in HCC.
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Affiliation(s)
| | - Shobith Rangappa
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri University, BG Nagara 571448, Nagamangala Taluk, India
| | - S Chandra Nayak
- Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore 570006, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
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Cao QG, Guo Q, Bai J, Dong Y, Zhang XH, Hong WL. The apoptosis mechanisms of HepG2 cells induced by bitter melon seed. J Food Biochem 2021; 45:e13683. [PMID: 33844303 DOI: 10.1111/jfbc.13683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 11/30/2022]
Abstract
Liver cancer is one of the leading causes of cancer-related deaths in the world. Bitter melon seed (BMS) is well known for anti-inflammatory and anticancer properties. MicroRNA-421 (miR-421) is considered as a regulator of cancer initiation, tumor metastasis, and progression, interfering with transcription of the mRNAs responsible for the cancer pathogenesis. HepG2 cells were treated with BMS water extract (BMSW) for 24 hr, and the IC50 was 586.27 ± 0.07 µg/ml. The ROS, mitochondrial membrane potential, the protein expression, and the nuclear fragmentation after the treatment of BMSW were respectively detected. The increase of ROS resulted in the decrease of mitochondrial membrane potential, which induced the apoptosis of cells subsequently. BMSW inhibited the proliferation of HepG2 cells by blocking cell cycle in the S phase and influenced the nuclei and the expression of protein, leading to cellular laxity and apoptosis. The expression level of miR-421 in HepG2 was distinctly down-regulated by 13.74 fold with 600 µg/ml of BMSW. Comprehensive microarray and RT-PCR analysis identified six putative target genes of miR-421 (GADD45B, DUSP6, DUSP3, DUSP10, CASP3, and CAPN2). The relationships of DUSP6, CASP3, and miR-421 were further confirmed by miR-421 mimics/inhibitor transfection by RT-PCR and western blot. The CASP3 was identified as target gene of miR-421. BMSW induced the apoptosis of HepG2 cell by regulating miR-421 and CASP3. PRACTICAL APPLICATIONS: Hepatocellular carcinoma (HCC) is a malignant tumour with the fourth highest mortality rate in the world. Bitter melon seed (BMS) as edible and medical food has significant anticancer activity. Our study indicated the anticancer mechanisms of BMS and provided the scientific basis for the application of BMS in healthy or novel functional foods. BMS can be used as dietary supplements or nutritional fortifiers to improve the survival status of patients with liver cancer due to safety and effectiveness.
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Affiliation(s)
- Qing-Guo Cao
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
| | - Qin Guo
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Jie Bai
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Ying Dong
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Xiao-Hua Zhang
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
| | - Wen-Long Hong
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
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24
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Yoshida GJ, Saya H. Molecular pathology underlying the robustness of cancer stem cells. Regen Ther 2021; 17:38-50. [PMID: 33869685 PMCID: PMC8024885 DOI: 10.1016/j.reth.2021.02.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
Intratumoral heterogeneity is tightly associated with the failure of anticancer treatment modalities including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Such heterogeneity is generated in an evolutionary manner not only as a result of genetic alterations but also by the presence of cancer stem cells (CSCs). CSCs are proposed to exist at the top of a tumor cell hierarchy and are undifferentiated tumor cells that manifest enhanced tumorigenic and metastatic potential, self-renewal capacity, and therapeutic resistance. Properties that contribute to the robustness of CSCs include the abilities to withstand redox stress, to rapidly repair damaged DNA, to adapt to a hyperinflammatory or hyponutritious tumor microenvironment, and to expel anticancer drugs by the action of ATP-binding cassette transporters as well as plasticity with regard to the transition between dormant CSC and transit-amplifying progenitor cell phenotypes. In addition, CSCs manifest the phenomenon of metabolic reprogramming, which is essential for maintenance of their self-renewal potential and their ability to adapt to changes in the tumor microenvironment. Elucidation of the molecular underpinnings of these biological features of CSCs is key to the development of novel anticancer therapies. In this review, we highlight the pathological relevance of CSCs in terms of their hallmarks and identification, the properties of their niche—both in primary tumors and at potential sites of metastasis—and their resistance to oxidative stress dependent on system xc (−).
Intratumoral heterogeneity driven by CSCs is responsible for therapeutic resistance. CTCs survive in the distant organs and achieve colonization, causing metastasis. E/M hybrid cancer cells due to partial EMT exhibit the highest metastatic potential. The CSC niche regulates stemness in metastatic disease as well as in primary tumor. Activation of system xc(-) by CD44 variant in CSCs is a promising therapeutic target.
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Key Words
- ABC, ATP-binding cassette
- ALDH, Aldehyde dehydrogenase
- BMP, Bone morphogenetic protein
- CAF, Cancer-associated fibroblast
- CD44 variant
- CD44v, CD44 variant
- CSC, Cancer stem cell
- CTC, Circulating tumor cell
- CagA, Cytotoxin-associated gene A
- Cancer stem cell
- DTC, Disseminated tumor cell
- E/M, Epithelial/mesenchymal
- ECM, Extracellular matrix
- EGF, Epidermal growth factor
- EMT, Epithelial-to-mesenchymal transition
- EpCAM, Epithelial cell adhesion moleculeE
- Epithelial-to-mesenchymal transition (EMT)
- GSC, Glioma stem cell
- GSH, reduced glutathione
- HGF, Hepatocyte growth factor
- HNSCC, Head and neck squamous cell cancer
- IL, Interleukin
- Intratumoral heterogeneity
- MAPK, mitogen-activated protein kinase
- MET, mesenchymal-to-epithelial transition
- NSCLC, non–small cell lung cancer
- Niche
- Nrf2, nuclear factor erythroid 2–related factor 2
- OXPHOS, Oxidative phosphorylation
- Plasticity
- Prrx1, Paired-related homeodomain transcription factor 1
- ROS, Reactive oxygen species
- SRP1, Epithelial splicing regulatory protein 1
- TGF-β, Transforming growth factor–β
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Affiliation(s)
- Go J Yoshida
- Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan
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Yamashita T, Kaneko S. Liver cancer stem cells: Recent progress in basic and clinical research. Regen Ther 2021; 17:34-37. [PMID: 33816720 PMCID: PMC7988346 DOI: 10.1016/j.reth.2021.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis was proposed over 4 decades ago and states that tumor growth is maintained by a small subset of cancer cells analogous to normal tissue stem cells in terms of self-renewal and differentiation capacity. Advances in CSC isolation were initially achieved in hematological malignancies and later in solid tumors, including hepatocellular carcinoma (HCC), the major histological type of liver cancer. Increasing evidence suggests the importance of liver CSCs for tumor growth, metastasis, and chemo/radiation resistance in HCC, but the application of the liver CSC concept for the clinical diagnosis and treatment of HCC has not yet been achieved to the extent initially expected. Furthermore, the heterogeneity and plasticity of liver CSCs has recently been noted and might be related to drug resistance and the rapid growth and/or metastasis of the tumor after treatment. Here, we introduce our recent advancement in liver CSC research and discuss the clinical implications, which may lead to the development of improved diagnostics and treatment in HCC.
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Affiliation(s)
- Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
- Corresponding author. Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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Zhu K, Li Y, Xu Y. The FTO m 6A demethylase inhibits the invasion and migration of prostate cancer cells by regulating total m 6A levels. Life Sci 2021; 271:119180. [PMID: 33571513 DOI: 10.1016/j.lfs.2021.119180] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/27/2021] [Accepted: 02/05/2021] [Indexed: 12/27/2022]
Abstract
AIMS N6-Methyladenosine (m6A) is the most frequent posttranscriptional modification and plays important roles in tumorigenesis and metastasis. The roles of fat mass and obesity-associated (FTO) in metabolic diseases have been widely explored. However, the molecular mechanisms and physiological functions of FTO in prostate cancer remain largely unknown. This study aimed to explore the exact functions of FTO in the progression of prostate cancer metastasis. MAIN METHODS Dot blot and m6A RNA methylation quantification assays were performed to determine m6A levels. The protein and mRNA expression levels were detected using immunoblot (IB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Cell invasion and migration abilities were measured using transwell and wound healing assays. Bioinformatics was used to measure the expression level of FTO and possible correlation between FTO levels and advanced tumor stage. Immunofluorescence (IF) was performed to measure the cellular localization of FTO. KEY FINDINGS FTO was downregulated in prostate cancer tissues and cell lines, and the m6A content was increased. Importantly, patients with lower FTO expression had advanced tumor stage and higher Gleason scores. Gain- and loss-of-function assays revealed that FTO inhibits prostate cancer cell invasion and migration in vitro. Moreover, we confirmed that FTO can decrease the total m6A level. SIGNIFICANCE The present study revealed that the FTO m6A demethylase inhibits prostate cancer cell invasion and migration by regulating total m6A levels.
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Affiliation(s)
- Kai Zhu
- Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Ying Li
- Department of Paediatrics, Heping Hospital affiliated to Changzhi Medical College, Changzhi 046000, China.
| | - Yikai Xu
- Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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27
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Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11:3489-3501. [PMID: 33537099 PMCID: PMC7847682 DOI: 10.7150/thno.54648] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.
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MESH Headings
- Antigen Presentation/drug effects
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Fatty Liver/genetics
- Fatty Liver/immunology
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation, Neoplastic
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B/pathology
- Hepatitis B/therapy
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/pathology
- Hepatitis C/therapy
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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28
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Liu L, Borlak J. Advances in Liver Cancer Stem Cell Isolation and their Characterization. Stem Cell Rev Rep 2021; 17:1215-1238. [PMID: 33432485 DOI: 10.1007/s12015-020-10114-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2020] [Indexed: 12/24/2022]
Abstract
Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e. self-renewal and pluripotency the need arises to develop robust protocols for the isolation and characterization of CSCs. As with other malignancies, hepatic tumors are composed of a heterogeneous population of cells including liver cancer stem cells (LCSC). Yet, a precise understanding of why stem cells become cancerous is still lacking. There is unmet need to develop robust protocols for the successful isolation of LCSCs from human tissue resection material as to assist in the development of molecular targeted therapies. Here we review the research progress made in the isolation and characterization of LCSCs by considering a wide range of cell surface markers and sorting methods, as applied to side populations, microsphere cultures and the gradient centrifugation method. We emphasize the different fluorescence activated cell sorting methods and the possibility to enrich LCSCs by immunomagnetic beads. We review the specificity of functional assays by considering ABCG transporter and ALDH1 enzyme activities and evaluate the in vivo tumorigenicity of LCSCs in highly sensitive bioassays. Finally, we evaluate different LCSC markers in association with viral and non-viral liver disease and explore the potential of novel drug delivery systems targeting CD133, EpCAM, CD13 and CD90 for the development of molecular targeted therapies. Graphical Abstract.
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Affiliation(s)
- Lu Liu
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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29
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Forouzanfar F, Guest PC, Jamialahmadi T, Sahebkar A. Hepatoprotective Effect of Trehalose: Insight into Its Mechanisms of Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1328:489-500. [PMID: 34981500 DOI: 10.1007/978-3-030-73234-9_34] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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30
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He D, Zhang X, Tu J. Diagnostic significance and carcinogenic mechanism of pan-cancer gene POU5F1 in liver hepatocellular carcinoma. Cancer Med 2020; 9:8782-8800. [PMID: 32978904 PMCID: PMC7724499 DOI: 10.1002/cam4.3486] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/30/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The prognostic and clinicopathological significance of POU Class 5 Homeobox 1 (POU5F1) among various cancers are disputable heretofore. The diagnostic value and functional mechanism of POU5F1 in liver hepatocellular carcinoma (LIHC) have not been studied thoroughly. METHODS An integrative strategy of meta-analysis, bioinformatics, and wet-lab approach was used to explore the diagnostic and prognostic significance of POU5F1 in various types of tumors, especially in LIHC. Meta-analysis was utilized to investigate the impact of POU5F1 on prognosis and clinicopathological parameters in various cancers. The expression level and diagnostic value of POU5F1 were assessed by qPCR in plasma collected from LIHC patients and controls. The correlation between POU5F1 and tumor infiltrating immune cells (TIICs) in LIHC was evaluated by CIBERSORT. Gene set enrichment analysis (GSEA) was performed based on TCGA. Hub genes and related pathways were identified on the basis of co-expression genes of POU5F1. RESULTS Elevated POU5F1 was associated with poor OS, DFS, RFS, and DSS in various cancers. POU5F1 was confirmed as an independent risk factor for LIHC and correlated with tumor occurrence, stage, and invasion depth. The combination of POU5F1 and AFP in plasma was with high diagnostic validity (AUC = 0.902, p < .001). Specifically, the level of POU5F1 was correlated with infiltrating levels of B cells, T cells, dendritic cells, and monocytes in LIHC. GSEA indicated that POU5F1 participated in multiple cancer-related pathways and cell proliferation pathways. Moreover, CBX3, CCHCR1, and NFYC were filtered as the central hub genes of POU5F1. CONCLUSION Our study identified POU5F1 as a pan-cancer gene that could not only be a prognostic and diagnostic biomarker in various cancers, especially in LIHC, but functionally carcinogenic in LIHC.
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Affiliation(s)
- Dingdong He
- Center for Gene Diagnosis, and Clinical LabZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Xiaokang Zhang
- Center for Gene Diagnosis, and Clinical LabZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jiancheng Tu
- Center for Gene Diagnosis, and Clinical LabZhongnan Hospital of Wuhan UniversityWuhanChina
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31
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Jun JH, Jung J, Kim JY, Hwang SG, Bae SH, Kim GJ. Upregulation of C-Reactive Protein by Placenta-Derived Mesenchymal Stem Cells Promotes Angiogenesis in A Rat Model with Cirrhotic Liver. Int J Stem Cells 2020; 13:404-413. [PMID: 33122469 PMCID: PMC7691864 DOI: 10.15283/ijsc20052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/11/2020] [Accepted: 09/21/2020] [Indexed: 12/15/2022] Open
Abstract
Background and Objectives Liver cirrhosis is accompanied by abnormal vascular shunts. The Wnt pathway is essential for endothelial cell survival and proliferation. C-reactive protein (CRP), which is produced by hepatocyte, activates angiogenesis in cardiovascular diseases. Methods and Results The expression of CRP in CCl4-injured rat livers was detected using qRT-PCR and Western blotting after transplantation of placenta-derived mesenchymal stem cells (PD-MSCs) into rats. To determine whether CRP functions in hepatic regeneration by promoting angiogenesis through the Wnt pathway, we detected VEGF and β-catenin in liver tissues and BrdU and β-catenin in hepatocytes by immunofluorescence. The expression levels of CRP, Wnt pathway-related and angiogenic factors were increased in CCl4-injured and PD-MSCs transplanted rat livers. In vitro, the expression levels of Wnt signaling and angiogenic factors were decreased in siRNA-CRP-transfected rat hepatocytes. Conclusions CRP upregulation by PD-MSCs participates in vascular remodeling to promote liver regeneration via the Wnt signaling pathway during hepatic failure.
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Affiliation(s)
- Ji Hye Jun
- Department of Biomedical Science, CHA University, Seongnam, Korea
| | - Jieun Jung
- Non-Clinical Evaluation Center, CHA Advanced Research Institute, Seongnam, Korea
| | - Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam, Korea
| | - Seong-Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Catholic University Medical College, Seoul, Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Korea
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32
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Ghandadi M, Valadan R, Mohammadi H, Akhtari J, Khodashenas S, Ashari S. Wnt-β-catenin Signaling Pathway, the Achilles' Heels of Cancer Multidrug Resistance. Curr Pharm Des 2020; 25:4192-4207. [PMID: 31721699 DOI: 10.2174/1381612825666191112142943] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. METHODS In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. RESULT AND CONCLUSION Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/β- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/β-catenin signaling can be a potential target for modulating cancer MDR.
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Affiliation(s)
- Morteza Ghandadi
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Pharmacognosy and Pharmaceutical Biotechnology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Valadan
- Molecular and Cell Biology Research Center (MCBRC), Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran.,Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of toxicology and pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Javad Akhtari
- Molecular and Cell Biology Research Center (MCBRC), Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran.,Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shabanali Khodashenas
- Department of Medical Biotechnology, Faculty of Medical Sciences, Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sorour Ashari
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of toxicology and pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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Ni JS, Zheng H, Ou YL, Tao YP, Wang ZG, Song LH, Yan HL, Zhou WP. miR-515-5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway. Surg Oncol 2020; 34:113-120. [PMID: 32891315 DOI: 10.1016/j.suronc.2020.03.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 01/27/2020] [Accepted: 03/28/2020] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) have been identified as critical modulators of cell migration and invasion, which are the major causes of cancer progression including hepatocellular carcinoma (HCC). However, the accurate role of miR-515-5p in HCC is still uncertain. Here, we report that miR-515-5p expression is down-regulated in HCC tissues and cell lines, and associated with absence of capsule formation (p = 0.015)﹑microvascular invasion(p = 0.003)﹑and advantange TNM stage (II-III) (p = 0.014) in HCC patients. Overexpression of miR-515-5p inhibited migration and invasion of HCC cells in vitro and in vivo, while miR-515-5p knockdown has the inverse effect. Moreover, using miRNA databases and dual-luciferase report assay, we find miR-515-5p directly binds to the 3'-untranslated region (3'-UTR) of interleukin 6 (IL6). In addition, the regulatory association between miR-515-5p and the IL-6/Janus kinase (JNK)/signal transducer and activator of transcription-3 (STAT3) signaling pathway was explored. Furthermore, overexpression of miR-515-5p inhibited the activation of the JAK/STAT3 signaling pathway, which was rescued by overexpression of IL-6. The results of the current study indicate that miR-515-5p overexpression may serve an important role in inhibiting migration and invasion of HCC cells via suppression of IL-6/JAK/STAT3 signaling pathway activation. MiR-515-5p may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Jun-Sheng Ni
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Hepatocellular Carcinoma (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China
| | - Hao Zheng
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Hepatocellular Carcinoma (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China; Department of Reproductive Heredity Center, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Yang-Liu Ou
- Department of Hepatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Yuan-Ping Tao
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Hepatocellular Carcinoma (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China
| | - Zhen-Guang Wang
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Hepatocellular Carcinoma (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China
| | - Li-Hua Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Hong-Li Yan
- Department of Reproductive Heredity Center, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China.
| | - Wei-Ping Zhou
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Hepatocellular Carcinoma (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China.
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Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki KI, Calderwood SK, Takigawa M, Okamoto K. Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor ( CCN2/CTGF): CRISPR against Cancer. Cancers (Basel) 2020; 12:cancers12040881. [PMID: 32260433 PMCID: PMC7226423 DOI: 10.3390/cancers12040881] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/24/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022] Open
Abstract
Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.
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Affiliation(s)
- Yuka Okusha
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
- Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Takanori Eguchi
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (E.A.); (M.T.)
- Correspondence: or
| | - Manh T. Tran
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
| | - Chiharu Sogawa
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
| | - Kaya Yoshida
- Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8504, Japan;
| | - Mami Itagaki
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
- Research program for undergraduate students, Okayama University Dental School, Okayama 700-8525, Japan
| | - Eman A. Taha
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
- Department of Biochemistry, Ain Shams University Faculty of Science, Cairo 11566, Egypt
| | - Kisho Ono
- Department of Oral and Maxillofacial Surgery, Okayama University Hospital, Okayama 700-0914, Japan;
| | - Eriko Aoyama
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (E.A.); (M.T.)
| | - Hirohiko Okamura
- Department of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8525, Japan;
| | - Ken-ichi Kozaki
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
| | - Stuart K. Calderwood
- Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (E.A.); (M.T.)
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.O.); (M.T.T.); (C.S.); (M.I.); (E.A.T.); (K.-i.K.); (K.O.)
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Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. Cancers (Basel) 2020; 12:cancers12020523. [PMID: 32102440 PMCID: PMC7072357 DOI: 10.3390/cancers12020523] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.
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Li Y, Wang J, Song K, Liu S, Zhang H, Wang F, Ni C, Zhai W, Liang J, Qin Z, Zhang J. S100A4 promotes hepatocellular carcinogenesis by intensifying fibrosis-associated cancer cell stemness. Oncoimmunology 2020; 9:1725355. [PMID: 32117590 PMCID: PMC7028350 DOI: 10.1080/2162402x.2020.1725355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/03/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
A cancer-promoting role of fibrogenesis in the liver has long been speculated; however, the molecular mechanisms regarding this phenomenon are largely unknown. We demonstrated in our previous study that macrophage-derived S100A4 promotes liver fibrosis via activation of hepatic stellate cells; however, whether and how S100A4 directly contributes to the development of fibrosis-associated liver cancer remains elusive. High expression of S100A4 in the fibrotic region was observed in human liver tumor tissues which associated with advanced disease severity. Through an established hepatocarcinogenesis model involving apparent liver fibrogenesis, we found that S100A4-deficient mice developed significantly less and smaller liver tumor nodules, with no change in the liver inflammation but decreased liver fibrosis and expression of stem cell markers in hepatocellular carcinoma (HCC) tissues. Mechanistically, S100A4 directly promoted stem cell-associated genes signatures in a way synergistic with its interacting protein, extracellular matrix component collagen I. This process is dependent on the receptor of advanced glycation end products (RAGE) and β-catenin signaling. Furthermore, the liver tumor sphere formation in vitro and tumor growth in vivo were greatly enhanced only when the cancer cells were pretreated with both S100A4 and collagen I. Our work firstly demonstrated a key role of S100A4 in synergy with extracellular matrix in the promotion of hepatocellular carcinoma by affecting the stemness of cancer cells.
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Affiliation(s)
- Yanan Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jun Wang
- Department of Immunobiology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - Kun Song
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Shuangqing Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Huilei Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fei Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Ni
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wenlong Zhai
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jialu Liang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jinhua Zhang
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China
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Rhee H, Chung T, Yoo JE, Nahm JH, Woo HY, Choi GH, Han DH, Park YN. Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression. Hepatol Int 2020; 14:239-248. [PMID: 31993941 DOI: 10.1007/s12072-020-10012-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/07/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear. METHODS The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry. RESULTS Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis ≥ 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type. CONCLUSION The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Taek Chung
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Department of Biomedical Systems Informatics, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Ha Young Woo
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Qin JM. Postoperative recurrent factors and therapeutic and preventive strategies for hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2019; 27:1407-1418. [DOI: 10.11569/wcjd.v27.i23.1407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. The recurrence rate is about 50% at 3 years and over 70% at 5 years after hepatectomy for HCC. The high recurrence rate seriously affects the curative effect and long-term survival of patients with HCC, and is the primary cause of death after operation. Postoperative recurrence of HCC is a complex multi-step, multi-factorial process involving three factors: the body, microenvironment, and tumor tissue, which include body immunity, local pH value, interstitial pressure, vascular osmotic pressure, inflammatory reaction, tumor cell adhesion, extracellular matrix degradation, cell migration, cell proliferation, and tumor angiogenesis. HCC recurrence is closely related to abnormal gene expression and related molecular function changes, but the molecular mechanism has not been fully elucidated. How to treat the recurrence of HCC after operation directly affects the prognosis of patients with HCC, and treatments include reoperation, liver transplantation, local minimally invasive treatment, radiotherapy, molecular targeted drugs, immunotherapy, and traditional Chinese medicine treatment. It is difficult to cure or control tumor progression by a single therapy. Two or more therapeutic methods need to be combined organically to achieve a synergistic therapeutic effect. According to the specific situation of patients with HCC, it is key to analyze the individual characteristics of patients, to combine the clinical experience of clinicians and the best evidence, to adopt the individualized treatment plan, and to choose the appropriate treatment methods. For HCC patients with high-risk factors for recurrence, selecting the appropriate treatment is important to reduce the recurrence of HCC after operation and prolong the survival of patients.
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Affiliation(s)
- Jian-Min Qin
- Department of General Surgery, the Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
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39
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Clerici E, Comito T, Franzese C, Di Brina L, Tozzi A, Iftode C, Navarria P, Mancosu P, Reggiori G, Tomatis S, Scorsetti M. Role of stereotactic body radiation therapy in the treatment of liver metastases: clinical results and prognostic factors. Strahlenther Onkol 2019; 196:325-333. [DOI: 10.1007/s00066-019-01524-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 09/12/2019] [Indexed: 12/14/2022]
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Boscolo Sesillo F, Sacco A. Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas. J Vis Exp 2019. [PMID: 31566597 DOI: 10.3791/59897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Although significant efforts have enabled the identification of common mutations associated with RMS and allowed discrimination of different RMS subtypes, major challenges still exist for the development of novel treatments to further improve prognosis. Although identified by the expression of myogenic markers, there is still significant controversy over whether RMS has myogenic or non-myogenic origins, as the cell of origin is still poorly understood. In the present study, a reliable method is provided for the tumorsphere assay for mouse RMS. The assay is based on functional properties of tumor cells and allows the identification of rare populations in the tumor with tumorigenic functions. Also described are procedures for testing recombinant proteins, integrating transfection protocols with the tumorsphere assay, and evaluating candidate genes involved in tumor development and growth. Described further is a procedure for allograft transplantation of tumorspheres into recipient mice to validate tumorigenic function in vivo. Overall, the described method allows reliable identification and testing of rare RMS tumorigenic populations that can be applied to RMS arising in different contexts. Finally, the protocol can be utilized as a platform for drug screening and future development of therapeutics.
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Affiliation(s)
- Francesca Boscolo Sesillo
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute; Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Female Pelvic Medicine and Reconstructive Surgery, University California San Diego
| | - Alessandra Sacco
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute;
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Wu HJ, Chu PY. Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications. Int J Mol Sci 2019; 20:ijms20174154. [PMID: 31450710 PMCID: PMC6747544 DOI: 10.3390/ijms20174154] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/12/2019] [Accepted: 08/23/2019] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.
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Affiliation(s)
- Hsing-Ju Wu
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Medical Research, Chang Bing Show Chwan Memorial Hospital, Lukang Town, Changhua County 505, Taiwan
| | - Pei-Yi Chu
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 231, Taiwan.
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan.
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Jiang G, Huang CK, Zhang X, Lv X, Wang Y, Yu T, Cai X. Wnt signaling in liver disease: emerging trends from a bibliometric perspective. PeerJ 2019; 7:e7073. [PMID: 31275745 PMCID: PMC6590390 DOI: 10.7717/peerj.7073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/05/2019] [Indexed: 12/20/2022] Open
Abstract
Background The Wnt signaling pathway, an evolutionarily conserved molecular transduction cascade, has been identified as playing a pivotal role in various physiological and pathological processes of the liver, including homeostasis, regeneration, cirrhosis, and hepatocellular carcinoma (HCC). In this study, we aimed to use a bibliometric method to evaluate the emerging trends on Wnt signaling in liver diseases. Methods Articles were retrieved from the Web of Science Core Collection. We used a bibliometric software, CiteSpace V 5.3.R4, to analyze the active countries or institutions in the research field, the landmark manuscripts, important subtopics, and evolution of scientific ideas. Results In total, 1,768 manuscripts were published, and each was cited 33.12 times on average. The U.S. published most of the articles, and the most active center was the University of Pittsburgh. The top 5 landmark papers were identified by four bibliometric indexes including citation, burstness, centrality, and usage 2013. The clustering process divided the whole area into nine research subtopics, and the two major important subtopics were "liver zonation" and "HCC." Using the "Part-of-Speech" technique, 1,743 terms representing scientific ideas were identified. After 2008, the bursting phrases were "liver development," "progenitor cells," "hepatic stellate cells," "liver regeneration," "liver fibrosis," "epithelial-mesenchymal transition," and etc. Conclusion Using bibliometric methods, we quantitatively summarized the advancements and emerging trends in Wnt signaling in liver diseases. These bibliometric findings may pioneer the future direction of this field in the next few years, and further studies are needed.
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Affiliation(s)
- Guangyi Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chiung-Kuei Huang
- Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Xinjie Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xingyu Lv
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tunan Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Elufioye TO, Habtemariam S. Hepatoprotective effects of rosmarinic acid: Insight into its mechanisms of action. Biomed Pharmacother 2019; 112:108600. [PMID: 30780110 DOI: 10.1016/j.biopha.2019.108600] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/11/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Liver diseases such as hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are one of the major health challenges in the world and many conditions such as inadequate nutrition, viral infection, ethanol and drug abuse, xenobiotic exposure, and metabolic diseases have been implicated in the development and progression of liver diseases. Several factors including lipid peroxidation, production of reactive oxygen species (ROS), peroxynitrite formation, complement factors and proinflammatory mediators, such as cytokines and chemokines, are involved in hepatic diseases. Rosmarinic acid (RA) is a natural phenolic compound found mainly in the family Lamiaceae consisting of several medicinal plants, herbs and spices. Several biological activities have been reported for RA and these include antioxidant properties as a ROS scavenger and lipid peroxidation inhibitor, anti-inflammatory, neuroprotective and antiangiogenic among others. This review is aimed at discussing the effects of RA on the liver, highlighting its hepatoprotective potential and the underlying mechanisms.
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Affiliation(s)
- Taiwo O Elufioye
- Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Nigeria.
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Chatham, Maritime Kent, ME4 4TB, UK
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Shen Z, Zhang C, Qu L, Lu C, Xiao M, Ni R, Liu J. MKP-4 suppresses hepatocarcinogenesis by targeting ERK1/2 pathway. Cancer Cell Int 2019; 19:61. [PMID: 30923463 PMCID: PMC6423746 DOI: 10.1186/s12935-019-0776-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/08/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Mitogen-activated protein kinase phosphatases-4 (MKP-4) is reported to exert a prognostic merit in hepatocarcinogenesis. However, the underlying molecular mechanisms have not been clearly defined. METHODS Immunoprecipitation-mass spectrometry (IP-MS) approach was used to identify interactive proteins with MKP-4. Western blot and immunohistochemistry were employed to detect proteins in HCC tissues. Cell counting kit-8, colony formation, Edu incorporation and sphere formation assays were performed to investigate functions of MKP-4/ERK1/2 interaction. Tumor xenografts in nude mice were used to determine effects in vivo. RESULTS Extracellular signal-regulated kinase 1 and 2 (ERK1/2) were identified as binding partners of MKP-4. Knockdown of MKP-4 increased cell proliferation and cancer stem cell (CSC) traits while upregulation of MKP-4 or pre-incubation with ERK1/2 inhibition reversed these effects. Mechanistically MKP-4 negatively regulated phosphorylation of ERK1/2 and reduced expressions of CyclinD1 and c-Myc. Both xenograft tumor models and clinical analysis of HCC patients indicated that lower expression of MKP-4 and higher expressions of ERK1/2 were associated with worse prognosis. CONCLUSIONS MKP-4-mediated dephosphorylation of ERK1/2 might serve as a novel tumor-suppressive mechanism and provide a potential therapy for HCC.
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Affiliation(s)
- Zhongyi Shen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
- Clinical Medicine Medical College, Nantong University, Nantong, Jiangsu People’s Republic of China
| | - Chengliang Zhang
- Clinical Medicine Medical College, Nantong University, Nantong, Jiangsu People’s Republic of China
| | - Lishuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Mingbing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Runzhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
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Fekir K, Dubois-Pot-Schneider H, Désert R, Daniel Y, Glaise D, Rauch C, Morel F, Fromenty B, Musso O, Cabillic F, Corlu A. Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance. Cancer Res 2019; 79:1869-1883. [DOI: 10.1158/0008-5472.can-18-2110] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 01/04/2019] [Accepted: 02/26/2019] [Indexed: 11/16/2022]
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Analysis on Effects of Comprehensive Nursing Care Applied in Interventional Therapy for Patients with Liver Cirrhosis and Liver Cancer. IRANIAN JOURNAL OF PUBLIC HEALTH 2019; 48:494-500. [PMID: 31223577 PMCID: PMC6570817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND This study aimed to investigate the effects of comprehensive nursing intervention in interventional therapy for patients with liver cirrhosis and liver cancer. METHODS Overall, 512 liver cirrhosis patients complicated with liver cancer receiving interventional therapy in the Department of Oncology of the Second Hospital of Dalian Medical University (Dalian, China) from March 2010 to March 2016 were retrospectively analyzed. Patients were divided into observation group (n=310) and control group (n=202). Comprehensive nursing intervention was applied to observation group and conventional nursing care was applied to control group. RESULTS The degrees of satisfaction before and after nursing intervention, quality-of-life scores, incidences of postoperative complications and survival rates at 20 months after operation of the two groups were compared. The degree of great satisfaction in observation group was significantly higher than that in control group (P<0.001). The quality-of-life scores of the patients in observation group were obviously higher than those in control group (P<0.001). The incidence of postoperative complications in observation group was significantly lower than that in control group (P<0.001). The survival rates in observation group was significantly higher than that in control group (P=0.035). CONCLUSION The application of comprehensive nursing intervention in the interventional therapy for liver cirrhosis and liver cancer can notably improve the life quality of the patients, lower the incidence of postoperative complications and increase the survival rate, which is worthy of clinical popularization and application.
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Xie Y, Du J, Liu Z, Zhang D, Yao X, Yang Y. MiR-6875-3p promotes the proliferation, invasion and metastasis of hepatocellular carcinoma via BTG2/FAK/Akt pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:7. [PMID: 30621734 PMCID: PMC6323674 DOI: 10.1186/s13046-018-1020-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/26/2018] [Indexed: 12/30/2022]
Abstract
Background Increasing evidence supports the association of microRNA with tumor occurrence and development. However, the expression of miR-6875-3p and its role in cell proliferation, invasion and metastasis in hepatocellular carcinoma (HCC) remains elusive. Methods The expression of miR-6875-3p and BTG2 in HCC tissues and cell lines was detected by using in situ hybridization, immunohistochemistry and qRT-PCR, respectively. A western blot assay, qRT-PCR and Luciferase reporter assay were employed to study the interaction between miR-6875-3p and BTG2. Cell proliferation invasion and metastasis were measured by MTT, transwell and matrigel analyses in vitro. In vivo, tumorigenicity and metastasis assays were performed in nude mice. Results We found that miR-6875-3p were elevated expressed in HCC tissues and cell lines, and negatively correlated with BTG2 expression, while positively correlated with tumor staging, size, degree of differentiation, and vascular invasion of HCC. Moreover, in vitro and in vivo assays showed that miR-6875-3p regulates EMT and improve the proliferation, metastasis and stem cell-like properties of HCC cells. BTG2 was identified as a direct and functional target of miR-6875-3p via the 3’-UTR of BTG2. We also confirmed that miR-6875-3p plays its biological functions via the BTG2/FAK/Akt pathway. Conclusion Our study provides evidence that high expression of miR-6875-3p can promote tumorigenesis of HCC in vitro and in vivo, so as to function as a novel oncogene in HCC. In mechanism, we found that miR-6875-3p plays its biological functions via the BTG2/FAK/Akt pathway. Electronic supplementary material The online version of this article (10.1186/s13046-018-1020-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yingjun Xie
- Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, People's Republic of China
| | - Jian Du
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, People's Republic of China
| | - Zefeng Liu
- Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, People's Republic of China
| | - Dan Zhang
- Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, People's Republic of China
| | - Xiaoxiao Yao
- Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, People's Republic of China
| | - Yongsheng Yang
- Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, People's Republic of China.
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Li TY, Chiang BH. 4-Acetylantroquinonol B from antrodia cinnamomea enhances immune function of dendritic cells against liver cancer stem cells. Biomed Pharmacother 2018; 109:2262-2269. [PMID: 30551483 DOI: 10.1016/j.biopha.2018.11.101] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/05/2018] [Accepted: 11/25/2018] [Indexed: 12/12/2022] Open
Abstract
The functions of 4-acetylantroquinonol B (4-AAQB), a ubiquinone derivative isolated from the mycelium of Antrodia cinnamomea, in immunotherapy for liver cancer were investigated. We found that 4-AAQB could inhibit liver cancer stem cell related manifestations and activate the antitumor ability of dendritic cells. Specifically, 4-AAQB can inhibit EpCAM, AFP and related pathways of HepG2 cells. It also significantly decreases the expression of β-catenin, inhibits the tumorigenicity and decreases the secretion of immune escape related cytokines. Moreover, 4-AAQB can stimulate the proliferation of immune cells and promote the endocytosis of immature dendritic cells. When co-cultured immature dendritic cells with EpCAM+ HepG2 cells, 4-AAQB enhanced the expression of MHC class I and II on the surface of liver cancer stem cells and dendritic cells, increased the expression of costimulatory molecules CD80 of dendritic cells and cytokines related to immune activation. In conclusion, 4-AAQB from Antrodia cinnamomea can enhance immune function of dendritic cells against liver cancer stem cells, and may have the potential to be used for liver cancer prevention and immunotherapy.
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Affiliation(s)
- Ting-Yi Li
- Institute of Food Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Been-Huang Chiang
- Institute of Food Science and Technology, National Taiwan University, Taipei, 10617, Taiwan.
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Scorsetti M, Comito T, Clerici E, Franzese C, Tozzi A, Iftode C, Di Brina L, Navarria P, Mancosu P, Reggiori G, Fogliata A, Tomatis S, Torzilli G, Cozzi L. Phase II trial on SBRT for unresectable liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up. Radiat Oncol 2018; 13:234. [PMID: 30477560 PMCID: PMC6258482 DOI: 10.1186/s13014-018-1185-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/16/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The aim of this study was to evaluate long-term efficacy and survival prognostic factors of stereotactic body radiation therapy (SBRT) for un-resectable liver metastases in patients enrolled in a prospective phase II trial. METHODS AND MATERIALS 5-year local control (LC), overall survival (OS), progression free survival (PFS) and toxicity rates were analyzed in patients with un-resectable liver metastases enrolled in a Phase II Trial on liver SBRT, with a prescription dose of 75Gy in 3 consecutive fractions. RESULTS A total of 61 patients with 76 lesions were enrolled, with a median follow-up time of 6.1 years. One, three and 5 year LC rates were 94 ± 3.1%, 78.0 ± 5.9% and 78.0 ± 5.9%, without reaching the median LC time. Median OS was 27.6 months and the survival rates were 85.2 ± 4.5%, 31.1 ± 5.9% and 18.0 ± 4.9% at 1, 3 and 5-year after SBRT, respectively. Univariate analysis showed that favorable primary site (colorectal, breast and gynecological) of metastases (p = 0.001) improved survival. Toxicity was moderate. One patient experienced G3 late chest wall pain, which resolved within 1 year from SBRT. No cases of Radiation Induced Liver Disease (RILD) were detected. CONCLUSIONS Long-term results of this Phase II study suggest the efficacy and safety of SBRT for un-resectable liver metastases after 5-year of follow up. Selection of cases with positive prognostic factors may improve long-term survival of these oligo-metastastic patients and may confirm the role of SBRT as an effective alternative local therapy for liver metastases.
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Affiliation(s)
- Marta Scorsetti
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089, Rozzano, Milan, Italy
| | - Tiziana Comito
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Elena Clerici
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Ciro Franzese
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Angelo Tozzi
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Cristina Iftode
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Lucia Di Brina
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Pierina Navarria
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Pietro Mancosu
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Giacomo Reggiori
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Antonella Fogliata
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Stefano Tomatis
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089, Rozzano, Milan, Italy.,Department of Hepato-biliary Surgery, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Luca Cozzi
- Radiotherapy and Radiosurgery Department, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy. .,Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089, Rozzano, Milan, Italy. .,Radiotherapy and Radiosurgery Department, Humanitas Research Hospital and Cancer Center, Via Manzoni 56, 20089, Milan, Rozzano, Italy.
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Huang F, Chen J, Lan R, Wang Z, Chen R, Lin J, Fu L. Hypoxia induced δ-Catenin to enhance mice hepatocellular carcinoma progression via Wnt signaling. Exp Cell Res 2018; 374:94-103. [PMID: 30458179 DOI: 10.1016/j.yexcr.2018.11.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/12/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022]
Abstract
Hypoxia frequently occurs in solid tumors, hepatocellular carcinoma included. Hypoxia-inducible factors (HIFs) upregulated in hypoxia can induce various downstream target genes to resist hypoxia stress, resulting in tumor growth, angiogenesis and metastasis in vivo. Therefore, hypoxia associated genes are usually cancer progression associated genes and can be potential therapy targets for cancer therapy. In our present work, we find that the hypoxia-inducible transcriptional factor, HIF1α, can directly upregulate the expression of the gene Ctnnd2, which codes the protein δ-Catenin. Then, δ-Catenin can stabilize β-Catenin by disrupting the destruction complex, which leads to the activation of Wnt signaling. As a result, δ-Catenin can promote the proliferation and migration of HCC cells in vitro, further enhance mice HCC tumorigenesis in vivo. In summary, our work reveals that δ-Catenin is a direct downstream target gene of HIF1α. It can activate Wnt signaling via β-Catenin stabilization. δ-Catenin can enhance HCC progression.
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Affiliation(s)
- Fei Huang
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China.
| | - Junying Chen
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
| | - Ruilong Lan
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
| | - Zeng Wang
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
| | - Ruiqing Chen
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
| | - Jingan Lin
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
| | - Lengxi Fu
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian key Lab of Individualized Active Immunotherapy, Fuzhou 350005, China; Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou 350005, China
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