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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [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: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [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: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Choi SH, Lee HY, Yun SH, Jang SJ, Kim SU, Park JY, Ahn SH, Kim DY. Identification of new biomarkers of hepatic cancer stem cells through proteomic profiling. JOURNAL OF LIVER CANCER 2025; 25:123-133. [PMID: 40108769 PMCID: PMC12010825 DOI: 10.17998/jlc.2025.03.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUNDS/AIMS In hepatocellular carcinoma (HCC), which exhibits high mortality and recurrence rates globally, the traits of cancer stem cells (CSCs) that significantly influence recurrence and metastasis are not well understood. CSCs are self-renewing cell types identified in most liquid and solid cancers, contributing to tumor initiation, growth, resistance, recurrence, and metastasis following chemo-radiotherapy or trans-arterial chemoembolization therapy. METHODS CSCs are classified based on the expression of cell surface markers such as CD133, which varies depending on the tumor type. Proteomic analysis of liver cancer cell lines with cancer stem cell potential and HCC cancer cell lines lacking stem cell propensity was conducted to compare and analyze specific expression patterns. RESULTS Proteomic profiling and enrichment analysis revealed higher expression of the calcium-binding protein S100 family in CD133+ Huh7 cells than in CD133- or wild-type cells. Furthermore, elevated expression of S100 family members was confirmed in an actual CD133+ liver cancer cell line via protein-protein network analysis and quantitative polymerase chain reaction (qPCR). CONCLUSION The S100 family members are not only new markers of cancer stem cells but will also assist in identifying new treatment strategies for CSC metastasis and tumor advancement.
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Affiliation(s)
- Sung Hoon Choi
- Institute of Health & Environment, Seoul National University, Seoul, Korea
- KoBioLabs Inc., Seoul, Korea
| | - Ha Young Lee
- Digital Omics Research Center, Ochang Institute of Biological and Environmental Science, Korea Basic Science Institute, Cheongju, Korea
| | - Sung Ho Yun
- Digital Omics Research Center, Ochang Institute of Biological and Environmental Science, Korea Basic Science Institute, Cheongju, Korea
| | - Sung Jae Jang
- Institute of Health & Environment, Seoul National University, Seoul, Korea
- Department of Environmental Health Sciences, Seoul National University Graduate School of Public Health, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
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Baghel K, Mehrotra S, Prajapati VK. Revolutionizing pancreatic cancer treatment with CAR-T therapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:331-353. [PMID: 39978971 DOI: 10.1016/bs.apcsb.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.
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Affiliation(s)
- Kirti Baghel
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Kim B. MicroRNA Profiling of PRELI-Modulated Exosomes and Effects on Hepatic Cancer Stem Cells. Int J Mol Sci 2024; 25:13299. [PMID: 39769068 PMCID: PMC11678812 DOI: 10.3390/ijms252413299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
The increasing incidence and mortality rates of liver cancer have heightened the demand for the development of effective anticancer drugs with minimal side effects. In this study, the roles of exosomes derived from liver cancer stem cells (LCSCs) with PRELI (Protein of Relevant Evolutionary and Lymphoid Interest) modulation and their miRNAs were investigated to explore their therapeutic properties for liver cancer. Various techniques, such as miRNA profiling, microRNA transfection, overexpression, flow cytometry, Western blotting, and immunocytochemistry, were used to evaluate the effects of exosomes under PRELI up- and downregulation. Downregulated PRELI cellular exosomes (DPEs) reduced the levels of five markers-CD133, CD90, CD24, CD13, and EpCAM-in LCSCs, with the exception of OV-6. Conversely, upregulated PRELI cellular exosomes (UPEs) significantly increased the expression of CD90, CD24, and CD133 in NHs, with the maximum increase in CD24. PRELI upregulation altered expression levels of miRNAs, including hsa-miR-378a-3p (involved in stem-like properties), hsa-miR-25-3p (contributing to cell proliferation), and hsa-miR-423-3p (driving invasiveness). Exosomes with downregulated PRELI inhibited the AKT/mTORC1 signaling pathway, whereas LCSCs transfected with the candidate miRNAs activated it. Additionally, under PRELI upregulation, exosomes showed increased surface marker expression, promoting cancer progression. The modulation of PRELI in LCSCs affected miRNA expression significantly, revealing candidate miRNA targets for liver cancer treatment. Exosomes with PRELI downregulation show potential as a novel therapeutic strategy. Consequently, this study proposes the potential of PRELI-induced exosomes and the three miRNAs as a liver anticancer therapeutic candidate.
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Affiliation(s)
- Boyong Kim
- EVERBIO, 131, Jukhyeon-gil, Gwanghyewon-myeon, Jincheon-gun 27809, Republic of Korea
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Hernández-Magaña A, Bensussen A, Martínez-García JC, Álvarez-Buylla ER. A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence. NPJ Syst Biol Appl 2024; 10:99. [PMID: 39223160 PMCID: PMC11369243 DOI: 10.1038/s41540-024-00422-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the gene expression profile of hepatocytes and mesenchymal cells in senescent, quiescent, proliferative, and stem-like states. The epigenetic landscape associated with the regulatory network was analyzed. We observed that the loss of p53, p16, RB, or the constitutive activation of β-catenin and YAP1 increases the robustness of the proliferative stem-like phenotypes. Additionally, we found that p53 inactivation facilitates the transition of proliferative hepatocytes into stem-like mesenchymal phenotype. Thus, phenotypic plasticity may be altered, and stem-like phenotypes related to CSCs may be easier to attain following the mutation acquisition.
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Affiliation(s)
- Alexis Hernández-Magaña
- Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Antonio Bensussen
- Departamento de Control Automático, Cinvestav-IPN, Ciudad de México, México
| | | | - Elena R Álvarez-Buylla
- Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México.
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, México.
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Simbulan-Rosenthal CM, Islam N, Haribabu Y, Alobaidi R, Shalamzari A, Graham G, Kuo LW, Sykora P, Rosenthal DS. CD133 Stimulates Cell Proliferation via the Upregulation of Amphiregulin in Melanoma. Cells 2024; 13:777. [PMID: 38727313 PMCID: PMC11083289 DOI: 10.3390/cells13090777] [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: 03/05/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
CD133, a cancer stem cell (CSC) marker in tumors, including melanoma, is associated with tumor recurrence, chemoresistance, and metastasis. Patient-derived melanoma cell lines were transduced with a Tet-on vector expressing CD133, generating doxycycline (Dox)-inducible cell lines. Cells were exposed to Dox for 24 h to induce CD133 expression, followed by RNA-seq and bioinformatic analyses, revealing genes and pathways that are significantly up- or downregulated by CD133. The most significantly upregulated gene after CD133 was amphiregulin (AREG), validated by qRT-PCR and immunoblot analyses. Induced CD133 expression significantly increased cell growth, percentage of cells in S-phase, BrdU incorporation into nascent DNA, and PCNA levels, indicating that CD133 stimulates cell proliferation. CD133 induction also activated EGFR and the MAPK pathway. Potential mechanisms highlighting the role(s) of CD133 and AREG in melanoma CSC were further delineated using AREG/EGFR inhibitors or siRNA knockdown of AREG mRNA. Treatment with the EGFR inhibitor gefitinib blocked CD133-induced cell growth increase and MAPK pathway activation. Importantly, siRNA knockdown of AREG reversed the stimulatory effects of CD133 on cell growth, indicating that AREG mediates the effects of CD133 on cell proliferation, thus serving as an attractive target for novel combinatorial therapeutics in melanoma and cancers with overexpression of both CD133 and AREG.
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Affiliation(s)
- Cynthia M Simbulan-Rosenthal
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Nusrat Islam
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Yogameenakshi Haribabu
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Ryyan Alobaidi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Azadeh Shalamzari
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Garrett Graham
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Li-Wei Kuo
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
| | - Peter Sykora
- Amelia Technologies, LLC., Washington, DC 20001, USA;
| | - Dean S Rosenthal
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA; (C.M.S.-R.); (N.I.); (Y.H.); (R.A.); (A.S.); (G.G.); (L.-W.K.)
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Pospieszna J, Dams-Kozlowska H, Udomsak W, Murias M, Kucinska M. Unmasking the Deceptive Nature of Cancer Stem Cells: The Role of CD133 in Revealing Their Secrets. Int J Mol Sci 2023; 24:10910. [PMID: 37446085 DOI: 10.3390/ijms241310910] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer remains a leading cause of death globally, and its complexity poses a significant challenge to effective treatment. Cancer stem cells and their markers have become key players in tumor growth and progression. CD133, a marker in various cancer types, is an active research area as a potential therapeutic target. This article explores the role of CD133 in cancer treatment, beginning with an overview of cancer statistics and an explanation of cancer stem cells and their markers. The rise of CD133 is discussed, including its structure, functions, and occurrence in different cancer types. Furthermore, the article covers CD133 as a therapeutic target, focusing on gene therapy, immunotherapy, and approaches to affect CD133 expression. Nanoparticles such as gold nanoparticles and nanoliposomes are also discussed in the context of CD133-targeted therapy. In conclusion, CD133 is a promising therapeutic target for cancer treatment. As research in this area progresses, it is hoped that CD133-targeted therapies will offer new and effective treatment options for cancer patients in the future.
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Affiliation(s)
- Julia Pospieszna
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
| | - Wachirawit Udomsak
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Marek Murias
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Uniwersytetu Poznanskiego 10 Street, 61-614 Poznan, Poland
| | - Malgorzata Kucinska
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
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Sun L, Yao HJ, Li JC, Zhao BQ, Wang YA, Zhang YG. Activated Carbon nanoparticles Loaded with Metformin for Effective Against Hepatocellular Cancer Stem Cells. Int J Nanomedicine 2023; 18:2891-2910. [PMID: 37283712 PMCID: PMC10239765 DOI: 10.2147/ijn.s382519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/16/2023] [Indexed: 06/08/2023] Open
Abstract
Introduction Hepatocellular cancer stem cells (CSCs) play crucial roles in hepatocellular cancer initiation, development, relapse, and metastasis. Therefore, eradication of this cell population is a primary objective in hepatocellular cancer therapy. We prepared a nanodrug delivery system with activated carbon nanoparticles (ACNP) as carriers and metformin (MET) as drug (ACNP-MET), which was able to selectively eliminate hepatocellular CSCs and thereby increase the effects of MET on hepatocellular cancers. Methods ACNP were prepared by ball milling and deposition in distilled water. Suspension of ACNP and MET was mixed and the best ratio of ACNP and MET was determined based on the isothermal adsorption formula. Hepatocellular CSCs were identified as CD133+ cells and cultured in serum-free medium. We investigated the effects of ACNP-MET on hepatocellular CSCs, including the inhibitory effects, the targeting efficiency, self-renewal capacity, and the sphere-forming capacity of hepatocellular CSCs. Next, we evaluated the therapeutic efficacy of ACNP-MET by using in vivo relapsed tumor models of hepatocellular CSCs. Results The ACNP have a similar size, a regular spherical shape and a smooth surface. The optimal ratio for adsorption was MET: ACNP=1:4. ACNP-MET could target and inhibit the proliferation of CD133+ population and decrease mammosphere formation and renewal of CD133+ population in vitro and in vivo. Conclusion These results not only suggest that nanodrug delivery system increased the effects of MET, but also shed light on the mechanisms of the therapeutic effects of MET and ACNP-MET on hepatocellular cancers. ACNP, as a good nano-carrier, could strengthen the effect of MET by carrying drugs to the micro-environment of hepatocellular CSCs.
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Affiliation(s)
- Lan Sun
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Hong-Juan Yao
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People’s Republic of China
| | - Jing-Cao Li
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Bao-Quan Zhao
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Yong-An Wang
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Ying-Ge Zhang
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
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Hong S, Song JM. High-Resolution In Situ High-Content Imaging of 3D-Bioprinted Single Breast Cancer Spheroids for Advanced Quantification of Benzo( a)pyrene Carcinogen-Induced Breast Cancer Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2023; 15:11416-11430. [PMID: 36812369 DOI: 10.1021/acsami.2c17877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells, are critically correlated with carcinogenesis and are strongly affected by the environmental factors. Environmental carcinogens, such as benzo(a)pyrene (BaP), are associated with the overproduction of CSCs in various types of cancers, including breast cancer. In this report, we present a sophisticated 3D breast cancer spheroid model for the direct identification and quantitative determination of CSCs induced by carcinogens within intact 3D spheroids. To this end, hydrogel microconstructs containing MCF-7 breast cancer cells were bioprinted within direct-made diminutive multi-well chambers, which were utilized for the mass cultivation of spheroids and in situ detection of CSCs. We found that the breast CSCs caused by BaP-induced mutations were higher in the biomimetic MCF-7 breast cancer spheroids than that in standard 2D monolayer cultures. Precisely controlled MCF-7 cancer spheroids could be generated by serially cultivating MCF-7 cells within the printed hydrogel microconstructs, which could be further utilized for high-resolution in situ high-content 3D imaging analysis to spatially identify the emergence of CSCs at the single spheroid level. Additionally, potential therapeutic agents specific to breast CSCs were successfully evaluated to verify the effectiveness of this model. This bioengineered 3D cancer spheroid system provides a novel approach to investigating the emergence of CSC induced by a carcinogen for environmental hazard assessment in a reproducible and scalable format.
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Affiliation(s)
- Sera Hong
- College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Joon Myong Song
- College of Pharmacy, Seoul National University, Seoul 08826, South Korea
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11
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Jeng KS, Chang CF, Sheen IS, Jeng CJ, Wang CH. Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:1417. [PMID: 36674932 PMCID: PMC9861908 DOI: 10.3390/ijms24021417] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - I-Shyang Sheen
- Department of Hepato Gastroenterology, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan
| | - Chi-Juei Jeng
- Postgraduate of Institute of Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hsuan Wang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
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Matsukuma H, Kobayashi Y, Oka S, Higashijima F, Kimura K, Yoshihara E, Sasai N, Shiraishi K. Prominin-1 deletion results in spermatogenic impairment, sperm morphological defects, and infertility in mice. Reprod Med Biol 2023; 22:e12514. [PMID: 37292088 PMCID: PMC10244806 DOI: 10.1002/rmb2.12514] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/30/2023] [Accepted: 04/09/2023] [Indexed: 06/10/2023] Open
Abstract
Purpose Spermatogenesis is a complex process orchestrated by several essential genes. Prominin-1 (Prom1/PROM1) is a gene that is expressed in the testis but with a poorly understood role in spermatogenesis. Methods We used Prom1 knockout (Prom1 KO) mice to assess the role of Prom1 in spermatogenesis. To this end, we performed immunohistochemistry, immunofluorescence, western blotting, β-galactosidase staining, and apoptosis assay. Additionally, we analyzed the morphology of sperm and assessed litter sizes. Results We observed that PROM1 is localized to the dividing spermatocytes in seminiferous epithelial cells, sperm, and columnar epithelium in the epididymis. In the Prom1 KO testis, an aberrant increase in apoptotic cells and a decrease in proliferating seminiferous epithelial cells were observed. Cellular FLICE-like inhibitory protein (c-FLIP) and extracellular signal-regulated kinase 1/2 (ERK1/2) expression were also significantly decreased in Prom1 KO testis. In addition, a significantly increased number of epididymal spermatozoa with abnormal morphology and less motility was found in Prom1 KO mice. Conclusions PROM1 maintains spermatogenic cell proliferation and survival via c-FLIP expression in the testis. It is also involved in sperm motility and fertilization potential. The mechanism underlying the effect of Prom1 on sperm morphology and motility remains to be identified.
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Affiliation(s)
- Haruka Matsukuma
- Department of Urology, School of MedicineYamaguchi UniversityUbeJapan
| | - Yuka Kobayashi
- Department of Ophthalmology, School of MedicineYamaguchi UniversityUbeJapan
| | - Shintaro Oka
- Department of Urology, School of MedicineYamaguchi UniversityUbeJapan
| | | | - Kazuhiro Kimura
- Department of Ophthalmology, School of MedicineYamaguchi UniversityUbeJapan
| | - Erika Yoshihara
- Developmental Biomedical Science, Division of Biological SciencesNara Institute of Science and Technology IkomaNaraJapan
| | - Noriaki Sasai
- Developmental Biomedical Science, Division of Biological SciencesNara Institute of Science and Technology IkomaNaraJapan
| | - Koji Shiraishi
- Department of Urology, School of MedicineYamaguchi UniversityUbeJapan
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Systemic TM4SF5 overexpression in Apc Min/+ mice promotes hepatic portal hypertension associated with fibrosis. BMB Rep 2022; 55:609-614. [PMID: 36104259 PMCID: PMC9813423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Indexed: 12/29/2022] Open
Abstract
Mutation of the gene for adenomatous polyposis coli (APC), as seen in ApcMin/+ mice, leads to intestinal adenomas and carcinomas via stabilization of β-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or β-catenin has not been investigated for pathological outcomes. After interbreeding ApcMin/+ with TM4SF5-overexpressing transgenic (TgTM4SF5) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomas beyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilization of β-catenin via reduced glycogen synthase kinase 3β (GSK3β) phosphorylation on Ser9. Additionally, the livers of the dualtransgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3β phosphorylation (opposite to that seen in the colon), β-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old TgTM4SF5 mice similarly had sinusoidal dilatation, immune cell infiltration, and fibrosis. Altogether, systemic overexpression of TM4SF5 aggravates pathological abnormalities in both the colon and the liver. [BMB Reports 2022; 55(12): 609-614].
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Lee J, Kim E, Kang MK, Ryu J, Kim JE, Shin EA, Pinanga Y, Pyo KH, Lee H, Lee EH, Cho H, Cheon J, Kim W, Jho EH, Kim S, Lee JW. Systemic TM4SF5 overexpression in Apc Min/+ mice promotes hepatic portal hypertension associated with fibrosis. BMB Rep 2022; 55:609-614. [PMID: 36104259 PMCID: PMC9813423 DOI: 10.5483/bmbrep.2022.55.12.104] [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: 06/27/2022] [Revised: 07/18/2022] [Accepted: 08/30/2022] [Indexed: 08/30/2023] Open
Abstract
Mutation of the gene for adenomatous polyposis coli (APC), as seen in ApcMin/+ mice, leads to intestinal adenomas and carcinomas via stabilization of β-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or β-catenin has not been investigated for pathological outcomes. After interbreeding ApcMin/+ with TM4SF5-overexpressing transgenic (TgTM4SF5) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomas beyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilization of β-catenin via reduced glycogen synthase kinase 3β (GSK3β) phosphorylation on Ser9. Additionally, the livers of the dualtransgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3β phosphorylation (opposite to that seen in the colon), β-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old TgTM4SF5 mice similarly had sinusoidal dilatation, immune cell infiltration, and fibrosis. Altogether, systemic overexpression of TM4SF5 aggravates pathological abnormalities in both the colon and the liver. [BMB Reports 2022; 55(12): 609-614].
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Affiliation(s)
- Joohyeong Lee
- Department of Pharmacy, Daejeon 34141, Korea
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea
| | - Eunmi Kim
- Department of Pharmacy, Daejeon 34141, Korea
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea
| | | | - Jihye Ryu
- Department of Pharmacy, Daejeon 34141, Korea
| | - Ji Eon Kim
- Department of Pharmacy, Daejeon 34141, Korea
| | - Eun-Ae Shin
- Department of Pharmacy, Daejeon 34141, Korea
| | | | | | - Haesong Lee
- Department of Pharmacy, Daejeon 34141, Korea
| | - Eun Hae Lee
- Department of Pharmacy, Daejeon 34141, Korea
| | - Heejin Cho
- Department of Pharmacy, Daejeon 34141, Korea
| | | | - Wonsik Kim
- Department of Pharmacy, Daejeon 34141, Korea
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, Seoul 02504, Korea
| | - Semi Kim
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Jung Weon Lee
- Department of Pharmacy, Daejeon 34141, Korea
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea
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Characterization of chikusetsusaponin IV and V induced apoptosis in HepG2 cancer cells. Mol Biol Rep 2022; 49:4247-4255. [PMID: 35212926 DOI: 10.1007/s11033-022-07259-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 02/10/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Chikusetsusaponin IV and V (CsIV and CsV), two typical oleanolic acid saponins, are mainly derived from the rhizome of Panax japonicus C.A. Mey. To reveal the anti-cancer effect of CsIV and CsV on liver cancer cells, human hepatic cancer cell lines (HepG2) were exposed to these saponins, and various physiological responses of HepG2 were investigated. METHODS AND RESULTS HepG2 cells were treated with CsIV, CsV and 5-fluorouracil (5-FU). Cell proliferation was measured by CCK-8 assay. The cell cycle arrest, cell apoptosis and intracellular Ca2+ levels were respectively identified by flow cytometry. The mitochondrial membrane potential was detected by fluorescence microscopy. And, the levels of apoptosis-related proteins were analyzed by western blotting. Both CsIV and CsV were demonstrated to inhibit cell viability, and induce cell cycle arrest and apoptosis of HepG2 in a dose-dependent manner. They also enhanced the intracellular Ca2+ level and decreased the mitochondrial membrane potential in HepG2 cells. Furthermore, p53 and p21 were found up-regulated in HepG2 cells treated by CsIV and CsV. The apoptotic proteins, bax, cytochrome c, cleaved caspase-3/-9, were all found activated in HepG2 cells after CsIV and CsV treatment. The anti-apoptotic protein, bcl-2, was significantly down-regulated in all treated HepG2 cells. CONCLUSION Our data demonstrated that CsIV and CsV exerted significant cytotoxic effects on HepG2 cells without affecting normal liver cells. And, these chikusetsusaponins, especially for CsIV, showed a potent effect on promoting cell apoptosis in HepG2 cells, which was associated with the activation of p53-mediated apoptosis pathway.
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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17
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Jangjou A, Meisami AH, Jamali K, Niakan MH, Abbasi M, Shafiee M, Salehi M, Hosseinzadeh A, Amani AM, Vaez A. The promising shadow of microbubble over medical sciences: from fighting wide scope of prevalence disease to cancer eradication. J Biomed Sci 2021; 28:49. [PMID: 34154581 PMCID: PMC8215828 DOI: 10.1186/s12929-021-00744-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/10/2021] [Indexed: 12/29/2022] Open
Abstract
Microbubbles are typically 0.5-10 μm in size. Their size tends to make it easier for medication delivery mechanisms to navigate the body by allowing them to be swallowed more easily. The gas included in the microbubble is surrounded by a membrane that may consist of biocompatible biopolymers, polymers, surfactants, proteins, lipids, or a combination thereof. One of the most effective implementation techniques for tiny bubbles is to apply them as a drug carrier that has the potential to activate ultrasound (US); this allows the drug to be released by US. Microbubbles are often designed to preserve and secure medicines or substances before they have reached a certain area of concern and, finally, US is used to disintegrate microbubbles, triggering site-specific leakage/release of biologically active drugs. They have excellent therapeutic potential in a wide range of common diseases. In this article, we discussed microbubbles and their advantageous medicinal uses in the treatment of certain prevalent disorders, including Parkinson's disease, Alzheimer's disease, cardiovascular disease, diabetic condition, renal defects, and finally, their use in the treatment of various forms of cancer as well as their incorporation with nanoparticles. Using microbubble technology as a novel carrier, the ability to prevent and eradicate prevalent diseases has strengthened the promise of effective care to improve patient well-being and life expectancy.
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Affiliation(s)
- Ali Jangjou
- Department of Emergency Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Hossein Meisami
- Department of Emergency Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kazem Jamali
- Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hadi Niakan
- Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Milad Abbasi
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mostafa Shafiee
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ahmad Hosseinzadeh
- Thoracic and Vascular Surgery Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Amani
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Vaez
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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Liu J, Lu J, Li W. A Comprehensive Prognostic and Immunological Analysis of a New Three-Gene Signature in Hepatocellular Carcinoma. Stem Cells Int 2021; 2021:5546032. [PMID: 34188686 PMCID: PMC8192212 DOI: 10.1155/2021/5546032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/07/2021] [Accepted: 05/20/2021] [Indexed: 02/05/2023] Open
Abstract
There are few reports on the role of genes associated with the mRNA expression-based stemness index (mRNAsi) in the prognosis and immune regulation of hepatocellular carcinoma (HCC). This study is aimed at analyzing the expression profile and prognostic significance of a new mRNAsi-based three-gene signature in HCC. This three-gene signature was identified by analyzing mRNAsi data from the Cancer Genome Atlas (TCGA) HCC dataset. The prognostic value of the risk score based on the three-gene signature was evaluated by Cox regression and Kaplan-Meier analysis and then verified in the International Cancer Genome Consortium (ICGC) database. Meanwhile, the correlations between the risk score and immune cell infiltration patterns, microsatellite instability (MSI), tumor mutation burden (TMB), immune checkpoint molecules, hypoxia-related genes, immunotherapy response, and compounds targeting the gene signature were explored, respectively. The results showed that compared with normal liver tissues, the mRNAsi score of HCC tissues was significantly increased. PTDSS2, MRPL9, and SOCS were the genes most related to mRNAsi in HCC tissues. Survival analysis results suggested the risk score based on the three-gene signature was an independent predictor of the prognosis for patients with HCC. The nomogram combining the risk score and pathological stage showed a good predictive ability for the overall survival of patients with HCC patients. Meanwhile, the risk score was significantly related to immune cell infiltration patterns, MSI, TMB, several immune checkpoint molecules, and hypoxia-related genes. In addition, the risk score was associated with the immunotherapy response, and fifteen potential therapeutic drugs targeting the three-gene signature were identified. Therefore, we propose to use this three-gene signature including PTDSS2, MRPL9, and SOCS as a potential prognostic biomarker for HCC.
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Affiliation(s)
- Jun Liu
- Reproductive Medicine Center, Yue Bei People's Hospital, Shantou University Medical College, Shaoguan 512025, China
- Medical Research Center, Yue Bei People's Hospital, Shantou University Medical College, Shaoguan 512025, China
| | - Jianjun Lu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510080, China
- Department of Medical Affairs, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Wenli Li
- Reproductive Medicine Center, Yue Bei People's Hospital, Shantou University Medical College, Shaoguan 512025, China
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Zarębska I, Gzil A, Durślewicz J, Jaworski D, Antosik P, Ahmadi N, Smolińska-Świtała M, Grzanka D, Szylberg Ł. The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers. Clin Res Hepatol Gastroenterol 2021; 45:101664. [PMID: 33667731 DOI: 10.1016/j.clinre.2021.101664] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/24/2020] [Accepted: 02/17/2021] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of death among cancers. The poor prognosis of HCC might be caused by a population of cancer stem cells (CSC). CSC have similar characteristics to normal stem cells and are responsible for cancer recurrence, chemoresistance, radioresistance and metastasis. Liver cancer stem cells (LCSC) are identified via specific surface markers, such as CD44, CD90, CD133, and EpCAM (CD326). Recent studies suggested a complex interaction between mentioned LCSC markers and clinical features of HCC. A high expression of CSC is correlated with a negative prognostic factor after surgical resection of HCC and is connected with more aggressive tumor behavior. Moreover, LCSC might be responsible for increasing resistance to sorafenib, a kinase inhibitor drug. A reduction in the LCSC population may be crucial to successful advanced HCC therapy.
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Affiliation(s)
- Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland.
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Damian Jaworski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Navid Ahmadi
- Chair and Department of Oncologic Pathology and Prophylactics, Greater Poland Cancer Center, Poznan University of Medical Sciences, Poland
| | - Marta Smolińska-Świtała
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland; Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Oncology Center, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
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Jeon T, Ko MJ, Seo YR, Jung SJ, Seo D, Park SY, Park KU, Kim KS, Kim M, Seo JH, Park IC, Kim MJ, Bae JH, Song DK, Cho CH, Lee JH, Lee YH. Silencing CDCA8 Suppresses Hepatocellular Carcinoma Growth and Stemness via Restoration of ATF3 Tumor Suppressor and Inactivation of AKT/β-Catenin Signaling. Cancers (Basel) 2021; 13:cancers13051055. [PMID: 33801424 PMCID: PMC7958635 DOI: 10.3390/cancers13051055] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary Although the overexpression of CDCA8 is frequently observed in hepatocellular carcinoma (HCC) tissues, the functions of CDCA8 during HCC development remain to be clarified. The aim of our study was to investigate if targeting CDCA8 could affect liver tumor phenotypes in vitro and in vivo and to identify underlying molecular mechanisms to exert its therapeutic effect. We found that silencing of CDCA8 by siRNA inhibits the growth of parental cancer cell culture and mice tumors and suppresses stemness of CD133+ cancer stem cell population through the common responses of the upregulation of the tumor suppressive ATF3/GADD34 functional pathway and inactivation of the Akt/β–catenin signaling axis. These findings suggest CDCA8 as a novel therapeutic target for both primary HCC treatment and the prevention of metastasis or recurrence providing mode of action performed by a CDCA8 inhibitor. Abstract Big data analysis has revealed the upregulation of cell division cycle associated 8 (CDCA8) in human hepatocellular carcinoma (HCC) and its poorer survival outcome. However, the functions of CDCA8 during HCC development remain unknown. Here, we demonstrate in vitro that CDCA8 silencing inhibits HCC cell growth and long-term colony formation and migration through the accumulation of the G2/M phase cell population. Conversely, CDCA8 overexpression increases the ability to undergo long-term colony formation and migration. RNA sequencing and bioinformatic analysis revealed that CDCA8 knockdown led to the same directional regulation in 50 genes (25 down- and 25 upregulated). It was affirmed based on protein levels that CDCA8 silencing downregulates the levels of cyclin B1 and p-cdc2 and explains how it could induce G2/M arrest. The same condition increased the protein levels of tumor-suppressive ATF3 and GADD34 and inactivated AKT/β–catenin signaling, which plays an important role in cell growth and stemness, reflecting a reduction in sphere-forming capacity. Importantly, it was demonstrated that the extent of CDCA8 expression is much greater in CD133+ cancer stem cells than in CD133− cancer cells, and that CDCA8 knockdown decreases levels of CD133, p-Akt and β-catenin and increases levels of ATF3 and GADD34 in the CD133+ cancer stem cell (CSC) population. These molecular changes led to the inhibition of cell growth and sphere formation in the CD133+ cell population. Targeting CDCA8 also effectively suppressed tumor growth in a murine xenograft model, showing consistent molecular alterations in tumors injected with CDCA8siRNA. Taken together, these findings indicate that silencing CDCA8 suppresses HCC growth and stemness via restoring the ATF3 tumor suppressor and inactivating oncogenic AKT/β–catenin signaling, and that targeting CDCA8 may be the next molecular strategy for both primary HCC treatment and the prevention of metastasis or recurrence.
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Affiliation(s)
- Taewon Jeon
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA 01003, USA
| | - Min Ji Ko
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
| | - Yu-Ri Seo
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
| | - Soo-Jung Jung
- Department of Anatomy, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Daekwan Seo
- Department of Bioinformatics, Psomagen Inc., Rockville, MD 20850, USA;
| | - So-Young Park
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
| | - Keon Uk Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Kwang Seok Kim
- Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (K.S.K.); (I.-C.P.)
| | - Mikyung Kim
- Department of Biochemistry, Keimyung University School of Medicine, Daegu 42601, Korea; (M.K.); (J.H.S.)
| | - Ji Hae Seo
- Department of Biochemistry, Keimyung University School of Medicine, Daegu 42601, Korea; (M.K.); (J.H.S.)
| | - In-Chul Park
- Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (K.S.K.); (I.-C.P.)
| | - Min-Ji Kim
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
| | - Jae-Hoon Bae
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.B.); (D.-K.S.)
| | - Dae-Kyu Song
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.B.); (D.-K.S.)
| | - Chi Heum Cho
- Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Jae-Ho Lee
- Department of Anatomy, Keimyung University School of Medicine, Daegu 42601, Korea;
- Correspondence: (J.-H.L.); (Y.-H.L.)
| | - Yun-Han Lee
- Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Korea; (T.J.); (M.J.K.); (Y.-R.S.); (S.-Y.P.); (M.-J.K.)
- Correspondence: (J.-H.L.); (Y.-H.L.)
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21
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Wu J, Sun L, Liu T, Dong G. Ultrasound-Targeted Microbubble Destruction-Mediated Downregulation of EZH2 Inhibits Stemness and Epithelial-Mesenchymal Transition of Liver Cancer Stem Cells. Onco Targets Ther 2021; 14:221-237. [PMID: 33469303 PMCID: PMC7810681 DOI: 10.2147/ott.s269589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022] Open
Abstract
Background Cancer cells could show the characteristics of cancer stem cells (CSCs) through epithelial-mesenchymal transition (EMT). EZH2 was associated with EMT. Ultrasound-targeted microbubble destruction (UTMD) could enhance gene transfection efficiency. Here, we explored the effect of UTMD-mediated shEZH2 on liver CSCs. Methods EZH2 expression in liver cancer and the overall survival of liver cancer patients were analyzed by bioinformatics. Liver CSCs (CD133+HuH7) were sorted by flow cytometry. After transfection of shEZH2 through UTMD (UTMD-shEZH2) or liposome (LIP-shEZH2), the viability, proliferation, sphere formation, migration, and invasion of CD133+HuH7 cells were detected by MTT, colony formation, tumor-sphere formation, wound healing, and transwell assays, respectively. A mice subcutaneous-xenotransplant tumor model was established by injecting CD133+HuH7 or CD133−HuH7 cells into the limbs of mice. Tumor weight and volume were documented. The expressions of EZH2, EMT-related factors, and STAT3/PI3K/AKT pathway-related factors in CD133+HuH7 cells or tumor tissues were detected by RT-qPCR, Western blot, or immunohistochemical. Results EZH2 was high-expressed in liver cancer, and the patients with high expression of EZH2 had a poor survival. CD133+ HuH7 cells had higher EZH2 expression, higher viability, and stronger sphere-forming and tumor-forming abilities than CD133− HuH7 cells. ShEZH2 inhibited the viability, proliferation, sphere formation, migration, and invasion of CD133+ HuH7 cells, decreased the weight and volume of the xenotransplant tumor, inhibited the expressions of EZH2, Vimentin, N-Cadherin, Twist-1, p-STAT3, p-PI3K, and p-AKT, and increased E-Cadherin expression. UTMD-shEZH2 caused a stronger effect on CD133+ HuH7 cells than LIP-shEZH2. Conclusion UTMD-mediated shEZH2 inhibited the stemness and EMT of liver CSCs in vitro and in vivo through regulating the STAT3/PI3K/AKT pathway.
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Affiliation(s)
- Jie Wu
- Department of Ultrasound Intervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China
| | - Lulu Sun
- Department of Ultrasound Intervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China
| | - Tingting Liu
- Department of Ultrasound Intervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China
| | - Gang Dong
- Department of Ultrasound Intervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China
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22
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Luong AB, Do HQ, Tarchi P, Bonazza D, Bottin C, Cabral LKD, Tran LDC, Doan TPT, Crocè LS, Pham HLT, Tiribelli C, Sukowati CHC. The mRNA Distribution of Cancer Stem Cell Marker CD90/Thy-1 Is Comparable in Hepatocellular Carcinoma of Eastern and Western Populations. Cells 2020; 9:2672. [PMID: 33322687 PMCID: PMC7764111 DOI: 10.3390/cells9122672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
Epidemiology of hepatocellular carcinoma (HCC) showed a correlation between incidence and geographical-relevant risk factors. This study aims to compare the distributions of cancer stem cells (CSC) in two distant populations in Asia and Europe. We analyzed 52 and 43 selected HCC patients undergoing hepatectomy in Ho Chi Minh City (Vietnam) and Trieste (Italy). Each patient sample consisted of HCC, peri-HCC, and non-tumoral (distal) tissue. Demographic data were recorded together with clinical findings. The protocol for the collection of tissue samples and RNA was standardized in both laboratories and gene expression analysis was performed in a single laboratory with identical PCR conditions. Baseline data showed comparable laboratory findings between the two cohorts. mRNA distribution showed a comparable pattern of all CSC markers analyzed with the expression of CD90 progressively increasing from distal and peri-HCC to be highest in HCC (p < 0.001), confirmed by immunofluorescence data. CD90 mRNA distribution was related to HBV-related HCC and a tumor diameter less than 5 cm. Patients with high tumoral CD90 mRNA had a shorter time (p < 0.05) to tumor recurrence compared to patients with lower CD90. This comparative study showed that CD90 mRNA expressions are comparable between Eastern and Western HCC cases.
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Affiliation(s)
- An B. Luong
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam
| | - Huy Q. Do
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Laboratory of Stem Cell Research and Application, VNUHCM-University of Science, Ho Chi Minh City 700000, Vietnam
| | - Paola Tarchi
- Clinical Surgery Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Deborah Bonazza
- Surgical Pathology Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Cristina Bottin
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | - Long D. C. Tran
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Thao P. T. Doan
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam;
| | - Lory S. Crocè
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Hoa L. T. Pham
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
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23
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Wu S, Tseng IC, Huang WC, Su CW, Lai YH, Lin C, Lee AYL, Kuo CY, Su LY, Lee MC, Hsu TC, Yu CH. Establishment of an Immunocompetent Metastasis Rat Model with Hepatocyte Cancer Stem Cells. Cancers (Basel) 2020; 12:cancers12123721. [PMID: 33322441 PMCID: PMC7764036 DOI: 10.3390/cancers12123721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/30/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future.
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Affiliation(s)
- Semon Wu
- Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan;
- Correspondence: (S.W.); (C.-H.Y.); Tel.: +886-2-2861-0511(ext. 26234) (S.W.); +886-2-66289779 (C.-H.Y.); Fax: +886-2-2862-3724 (S.W.); +886-2-66289009 (C.-H.Y.)
| | - I-Chieh Tseng
- Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan;
| | - Wen-Cheng Huang
- License Biotech, Co., Ltd., Taipei 10690, Taiwan; (W.-C.H.); (C.-W.S.)
| | - Cheng-Wen Su
- License Biotech, Co., Ltd., Taipei 10690, Taiwan; (W.-C.H.); (C.-W.S.)
| | - Yu-Heng Lai
- Department of Chemistry, Chinese Culture University, Taipei 11114, Taiwan;
| | - Che Lin
- Department of Electrical Engineering and Graduate Institute of Communication Engineering, National Taiwan University, Taipei 10617, Taiwan;
| | - Alan Yueh-Luen Lee
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan;
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Li-Yu Su
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Ming-Cheng Lee
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Te-Cheng Hsu
- Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taipei 30013, Taiwan;
| | - Chun-Hsien Yu
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan
- Department of Pediatrics, School of Medicine, Tzu Chi University, Hualien 97071, Taiwan
- Correspondence: (S.W.); (C.-H.Y.); Tel.: +886-2-2861-0511(ext. 26234) (S.W.); +886-2-66289779 (C.-H.Y.); Fax: +886-2-2862-3724 (S.W.); +886-2-66289009 (C.-H.Y.)
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24
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Essawy F, Sadek H, Abdelaty S, Zahran M, Madkour B, Mashhour K, Ismail A, Amin D. ABO blood group genotypes and risk of hepatocellular carcinoma in a cohort of Egyptian patients. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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25
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Chenaghlou S, Khataee A, Jalili R, Rashidi MR, Khalilzadeh B, Woo Joo S. Gold nanostar-enhanced electrochemiluminescence immunosensor for highly sensitive detection of cancer stem cells using CD133 membrane biomarker. Bioelectrochemistry 2020; 137:107633. [PMID: 32891010 DOI: 10.1016/j.bioelechem.2020.107633] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
Gold nanostars (AuNSs) demonstrate an intense electromagnetic field around tip of branches. In this research, we employed AuNSs-enhanced electrochemiluminescence (ECL) emission from graphitic carbon nitride nanosheets (g-CN nanosheets) to detect CD133 peptide as a cancer stem cell membrane biomarker. In this biosensor, the g-CN nanosheets were decorated with AuNSs (AuNSs@g-CN nanosheets). AuNSs@g-CN nanosheets exhibited strong and stable cathodic ECL emission compared to that of pure g-CN nanosheets. The ECL intensity from the AuNSs@g-CN nanosheets was over 30% higher than that of spherical gold nanoparticles (spherical AuNPs) decorated g-CN nanosheets. The additional ECL enhancement of AuNSs was due to the localized surface plasmon resonance (LSPR) effect located around multiple branch tips of AuNSs. The RSD of ECL curves intensities, obtained from successive potential scans for 10 cycles, were less than 4%, indicating the superior stability of the AuNSs@g-CN nanosheets. Under optimum conditions, the ECL intensity of GCE/AuNSs@g-CN nanosheets/anti-CD133 decreased linearly with CD133 peptide concentration in the range of 0.05-100 ng mL-1. The LOD achieved was 0.257 ng mL-1 (S/N = 3). The applicability of the designed biosensor in real samples was examined through the determination of CD133 peptide in spiked serum samples, from which satisfactory results were obtained.
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Affiliation(s)
- Salimeh Chenaghlou
- Research Laboratory of Advanced Water and Wastewater Treatment Processes, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, 51666-16471 Tabriz, Iran
| | - Alireza Khataee
- Research Laboratory of Advanced Water and Wastewater Treatment Processes, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, 51666-16471 Tabriz, Iran; Institute of Research and Development, Duy Tan University, Da Nang 550000, Viet Nam.
| | - Roghayeh Jalili
- Research Laboratory of Advanced Water and Wastewater Treatment Processes, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, 51666-16471 Tabriz, Iran
| | - Mohammad-Reza Rashidi
- Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, 51666-14711 Tabriz, Iran
| | - Balal Khalilzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, 51666-14711 Tabriz, Iran; Biosensors and Bioelectronics Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Sang Woo Joo
- School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, South Korea.
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26
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Pandit H, Li Y, Zheng Q, Guo W, Yu Y, Li S, Martin RCG. Carcinogenetic initiation contributed by EpCAM+ cancer cells in orthotopic HCC models of immunocompetent and athymic mice. Oncotarget 2020; 11:2047-2060. [PMID: 32547703 PMCID: PMC7275786 DOI: 10.18632/oncotarget.27454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/26/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Overexpression of epithelial cell adhesion molecule (EpCAM) correlates with poor prognosis, therapeutic failure and early tumor recurrence in hepatocellular carcinoma (HCC) patients. The tumor microenvironment dictates the fate of tumor-initiating cancer stem cells (CSCs); however, very limited studies were attempted to evaluate CSC tumorigenesis in the liver microenvironment. Here, we have systemically investigated the role of EpCAM+ cancer cells in tumor initiation in orthotopic HCC models. RESULTS Control mice and the mice with bland steatosis failed to develop tumors. In the mice with steatohepatitis, EpCAM+ CSCs have shown significantly increased ability in terms of tumor initiation and growth, compared to that with EpCAM- non-CSCs inoculation (p < 0.005). For Hep3B inoculation, EpCAM-High group has shown significantly higher tumor growth compared with EpCAM-Low (p < 0.005). For HepG2 inoculation, both EpCAM-High and EpCAM-Low groups confirmed similar tumor incidence and growth. METHODS Diet-induced compromised microenvironments were established to mimic clinical fatty liver and non-alcoholic steatohepatitis (NASH) patients and the tumorigenic capabilities of Hepa1-6 cells were evaluated. CSCs were enriched by spheroid culture and labeled with copGFP for EpCAM+ CSCs and with mCherry for non-CSCs. FACS-sorted cells were inoculated into left liver lobes, and tumor growth was monitored by high-frequency ultrasound. The subpopulations of Hep3B and HepG2 cells in terms of EpCAM-Low and EpCAM-High were evaluated in the orthotopic model of athymic mice. CONCLUSIONS NASH microenvironment promotes the EpCAM+ CSCs initiated tumorigenesis in immunocompetent mouse model. Differential EpCAM expression demonstrates distinct tumor biology in athymic mouse models.
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Affiliation(s)
- Harshul Pandit
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Yan Li
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Qianqian Zheng
- Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China
| | - Wei Guo
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China
| | - Youxi Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Suping Li
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Robert C G Martin
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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27
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Kim BH, Park JW, Kim JS, Lee SK, Hong EK. Stem Cell Markers Predict the Response to Sorafenib in Patients with Hepatocellular Carcinoma. Gut Liver 2020; 13:342-348. [PMID: 30600675 PMCID: PMC6529171 DOI: 10.5009/gnl18345] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/18/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Sorafenib remains the only approved molecular targeted agent for hepatocellular carcinoma (HCC); however, reliable biomarkers that predict its efficacy are still lacking. The aim of this study was to explore whether cancer stem cell (CSC) markers have a predictive role with regard to the sorafenib response in HCC patients. Methods We enrolled 47 patients with HCC for whom tumor samples obtained before starting sorafenib treatment were available. RNA was extracted from formalin-fixed, paraffin-embedded samples, and real-time polymerase chain reaction was used to quantify mRNA expression of the CSC genes EpCAM, CD13, CK8, CD24, CD44, CD90, CD133, SALL4, ALDH1A1, ALB, and AFP. Results Of 47 patients, 14.9% and 74.5% had vascular invasion and extrahepatic spread, respectively. Patients with low CD133 expression tended to have longer progression-free survival (PFS) than those with high CD133 expression (5.5 months vs 4.0 months), although without statistical significance. The expression levels of other markers were not associated with PFS. When examining markers in combination, patients with high CD133 and CD90 expression had shorter PFS rates than those with low expression (2.7 months vs 5.5 months; p=0.04). Patients with low CD133 and EpCAM expression demonstrated better PFS than those with high expression (7.0 months vs 4.2 months; p=0.04). Multivariable analysis indicated that an Eastern Cooperative Oncology Group performance status score of 1 and high CD133/CD90 expression were significantly associated with shorter PFS. Conclusions Overexpression of the CSC markers CD133 and CD90 in HCC was associated with poorer response to sorafenib. These two genes may serve as predictive biomarkers for sorafenib therapy.
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Affiliation(s)
- Bo Hyun Kim
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Joong-Won Park
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Jin Sook Kim
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Sook-Kyung Lee
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Eun Kyung Hong
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
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28
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Yu W, Roy SK, Ma Y, LaVeist TA, Shankar S, Srivastava RK. Higher expression of SATB2 in hepatocellular carcinoma of African Americans determines more aggressive phenotypes than those of Caucasian Americans. J Cell Mol Med 2019; 23:7999-8009. [PMID: 31602781 PMCID: PMC6850930 DOI: 10.1111/jcmm.14652] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/16/2019] [Indexed: 12/20/2022] Open
Abstract
In the United States, Hepatocellular Carcinoma (HCC) incidence has tripled over the past two decades. The disease has disproportionately affected minority and disadvantaged populations. The purpose of this study was to examine the expression of SATB2 gene in HCC cells derived from African Americans (AA) and Caucasian Americans (CA) and assess its oncogenic potential by measuring cell viability, spheroid formation, epithelial‐mesenchymal transition (EMT), stem cell markers and pluripotency maintaining factors in cancer stem cells (CSCs). We compared the expression of SATB2 in human primary hepatocytes, HCC cells derived from AA and CA, and HCC CSCs. Hepatocellular carcinoma cells derived from AA expressed the higher level of SATB2 than those from CA. By comparison, normal human hepatocytes did not express SATB2. Higher expression of SATB2 in HCC cells from AA was associated with greater growth rate, cell viability, colony formation and EMT characteristics than those from CA. Knockout of SATB2 in CSCs by Crispr/Cas9 technique significantly inhibited the expression of SATB2 gene, stem cell markers (CD24, CD44 and CD133), pluripotency maintaining factors (c‐Myc, KLF4, SOX2 and OCT4), and EMT compared with non‐targeting control group. The expression of SATB2 was negatively correlated with miR34a. SATB2 rescued the miR‐34a‐mediated inhibition of CSC's viability. These data suggest that SATB2 is an oncogenic factor, and its higher expression may explain the disparity in HCC outcomes among AA.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Sanjit K Roy
- Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, USA
| | - Yiming Ma
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Thomas A LaVeist
- Department of Health Policy and Management, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, MO, USA.,Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, USA.,Department of Genetics, Louisiana State University Health Sciences Center-New Orleans, New Orleans, LA, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, MO, USA.,Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, USA.,Department of Genetics, Louisiana State University Health Sciences Center-New Orleans, New Orleans, LA, USA
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29
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The Emerging Roles of Cancer Stem Cells and Wnt/Beta-Catenin Signaling in Hepatoblastoma. Cancers (Basel) 2019; 11:cancers11101406. [PMID: 31547062 PMCID: PMC6826653 DOI: 10.3390/cancers11101406] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/11/2019] [Accepted: 09/11/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatoblastoma (HB) is the most common form of primary liver malignancy found in pediatric populations. HB is considered to be clonal and arises from hepatoblasts, or embryonic liver progenitor cells. These less differentiated tumor-initiating progenitor cells, or cancer stem cells (CSCs), may contribute to tumor recurrence and resistance to therapies, and have high metastatic abilities. Phenotypic heterogeneity, undesired genetic and epigenetic alterations, and dysregulated signaling pathways provide CSCs with a survival advantage over current therapies. The molecular and cellular basis of HB and the mechanism of CSC induction are not fully understood. The Wnt/beta-catenin pathway is one of the major developmental pathways and is believed to play an important role in the pathogenesis of HB and CSC formation. This review summarizes the cellular and molecular characteristics of HB with a specific emphasis on CSCs and Wnt/beta-catenin signaling.
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Park YY, An CH, Oh ST, Chang ED, Lee J. Expression of CD133 is associated with poor prognosis in stage II colorectal carcinoma. Medicine (Baltimore) 2019; 98:e16709. [PMID: 31393377 PMCID: PMC6708874 DOI: 10.1097/md.0000000000016709] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
CD133 is currently believed to be one of the best colorectal cancer stem cell markers. This study aimed to evaluate prognostic significance of CD133 expression in colorectal cancer patients.A total of 303 patients with stage I to III colorectal cancer who underwent curative surgical resection from 2003 to 2008 at a single institution were included. CD133 expression was evaluated using immunohistochemical staining, and clinicopathological data were retrospectively reviewed. The patients were dichotomized after scoring CD133 expression (0 to 2+: low CD133 expression vs 3+ to 4+: high CD133 expression) according to the extent of area of CD133 positive tumor cells (<50% vs ≥50%) and pattern of staining (membranous staining of the luminal surface and/or staining of cellular debris in the tumor glands and cytoplasm).The 5-year overall survival (OS) (61.9% vs 80.2%, P = .001) and disease-free survival (64.8% vs 75.8%, P = .026) were poorer in the high CD133 expression group than the low CD133 expression group. In the multivariate analysis for risk factors of OS in the whole population, higher nodal stage (N2 compared to N0: hazard ratio [HR] 3.141; 95% confidence interval [CI] 1.718-5.744, P < .001), perineural invasion (HR 2.262; 95% CI 1.347-3.798, P = .002) and high CD133 expression (HR 1.929; 95% CI 1.221-3.048, P = .005) were independent poor prognostic factors of OS. Subgroup analyses according to each TNM stage revealed that CD133 expression was associated with OS only within the stage II patients (HR 3.167 95% CI 1.221-8.216, P = .018). Furthermore, the stage II patients demonstrating the high CD133 expression showed survival benefit of adjuvant chemotherapy, regardless of high-risk feature positivity (HR 0.201 95% CI 0.054-0.750, P = .017).High CD133 expression is correlated with poor prognosis in colorectal cancer patients after radical resection. The CD133 expression may serve as a more potent and informative biomarker for prognosis than conventional high-risk features in the stage II colorectal cancer patients.
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Affiliation(s)
| | | | | | - Eun Deock Chang
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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31
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Li N, Jiang Y, Plantefève R, Michaud F, Nosrati Z, Tremblay C, Saatchi K, Häfeli UO, Kadoury S, Moran G, Joly F, Martel S, Soulez G. Magnetic Resonance Navigation for Targeted Embolization in a Two-Level Bifurcation Phantom. Ann Biomed Eng 2019; 47:2402-2415. [PMID: 31290038 DOI: 10.1007/s10439-019-02317-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/28/2019] [Indexed: 12/22/2022]
Abstract
This work combines a particle injection system with our proposed magnetic resonance navigation (MRN) sequence with the intention of validating MRN in a two-bifurcation phantom for endovascular treatment of hepatocellular carcinoma (HCC). A theoretical physical model used to calculate the most appropriate size of the magnetic drug-eluting bead (MDEB, 200 μm) aggregates was proposed. The aggregates were injected into the phantom by a dedicated particle injector while a trigger signal was automatically sent to the MRI to start MRN which consists of interleaved tracking and steering sequences. When the main branch of the phantom was parallel to B0, the aggregate distribution ratio in the (left-left, left-right, right-left and right-right divisions was obtained with results of 8, 68, 24 and 0% respectively at baseline (no MRN) and increased to 84%, 100, 84 and 92% (p < 0.001, p = 0.004, p < 0.001, p < 0.001) after implementing our MRN protocol. When the main branch was perpendicular to B0, the right-left branch, having the smallest baseline distribution rate of 0%, reached 80% (p < 0.001) after applying MRN. Moreover, the success rate of MRN was always more than 92% at the 1st bifurcation in the experiments above.
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Affiliation(s)
- Ning Li
- Polytechnique Montréal, Chemin de Polytechnique, 2500 Chemin de Polytechnique, Montréal, QC, 28 H3T 1J4, Canada.,Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada
| | - Yuting Jiang
- Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada.,Department of Radiology, Radiation-Oncology and Nuclear Medicine and Institute of Biomedical Engineering, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC, H3T 1J4, Canada
| | - Rosalie Plantefève
- Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada
| | - Francois Michaud
- Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada.,Department of Radiology, Radiation-Oncology and Nuclear Medicine and Institute of Biomedical Engineering, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC, H3T 1J4, Canada
| | - Zeynab Nosrati
- University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Charles Tremblay
- Polytechnique Montréal, Chemin de Polytechnique, 2500 Chemin de Polytechnique, Montréal, QC, 28 H3T 1J4, Canada
| | - Katayoun Saatchi
- University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Urs O Häfeli
- University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Samuel Kadoury
- Polytechnique Montréal, Chemin de Polytechnique, 2500 Chemin de Polytechnique, Montréal, QC, 28 H3T 1J4, Canada.,Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada
| | | | - Florian Joly
- INRIA Paris, 2 rue Simone Iff, 75012, Paris, France
| | - Sylvain Martel
- Polytechnique Montréal, Chemin de Polytechnique, 2500 Chemin de Polytechnique, Montréal, QC, 28 H3T 1J4, Canada
| | - Gilles Soulez
- Laboratory of Clinical Image Processing, Le Centre de recherche du CHUM (CRCHUM), 900 Rue Saint-Denis, Montréal, QC, H2X 0A9, Canada. .,Department of Radiology, Radiation-Oncology and Nuclear Medicine and Institute of Biomedical Engineering, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC, H3T 1J4, Canada.
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32
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Zhang H, Hao C, Wang H, Shang H, Li Z. Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma. Int J Exp Pathol 2019; 100:133-138. [PMID: 31058377 PMCID: PMC6540673 DOI: 10.1111/iep.12315] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/10/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022] Open
Abstract
Carboxypeptidase A4 (CPA4), a member of the metallo-carboxypeptidase family, is overexpressed in liver cancer and is associated with cancer progression. The role of CPA4 in hepatocellular carcinoma (HCC) remains unclear. In this study, we aimed to evaluate the relevance of CPA4 to the proliferation and expression of stem cell characteristics of hepatocellular carcinoma cells. Western blot analysis showed high CPA4 expression in the liver cancer cell line Bel7402 and low expression in HepG2 cells. Knock-down of CPA4 decreased cancer cell proliferation as detected by MTT and clone formation assays. The serum-free culture system revealed that downregulated CPA4 suppressed the sphere formation capacities of tumour cells. However, upregulated CPA4 increased the proliferation and sphere formation capacity. In addition, the protein expression of CD133, ALDH1 and CD44 also increased in cells with upregulated CPA4. In vivo, the overexpression of CPA4 in tumour cells that were subcutaneously injected into nude mice markedly increased the growth of the tumours. These data suggest that CPA4 expression leads to poor prognoses by regulating tumour proliferation and the expression of stem cell characteristics and may therefore serve as a potential therapeutic target of HCC.
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Affiliation(s)
- Hongtao Zhang
- Department of Hepatopancreatobiliary SurgeryTianjin Nan‐Kai HospitalTianjinChina
| | - Chengfei Hao
- Department of Hepatopancreatobiliary SurgeryTianjin Nan‐Kai HospitalTianjinChina
- Tianjin Medical UniversityTianjinChina
| | - Haibo Wang
- Department of Hepatopancreatobiliary SurgeryTianjin Nan‐Kai HospitalTianjinChina
| | - Haitao Shang
- Department of Hepatopancreatobiliary SurgeryTianjin Nan‐Kai HospitalTianjinChina
| | - Zhonglian Li
- Department of Hepatopancreatobiliary SurgeryTianjin Nan‐Kai HospitalTianjinChina
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Dreval K, Tryndyak V, Kindrat I, Twaddle NC, Orisakwe OE, Mudalige TK, Beland FA, Doerge DR, Pogribny IP. Cellular and Molecular Effects of Prolonged Low-Level Sodium Arsenite Exposure on Human Hepatic HepaRG Cells. Toxicol Sci 2019; 162:676-687. [PMID: 29301061 DOI: 10.1093/toxsci/kfx290] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Inorganic arsenic is a human carcinogen associated with several types of cancers, including liver cancer. Inorganic arsenic has been postulated to target stem cells, causing their oncogenic transformation. This is proposed to be one of the key events in arsenic-associated carcinogenesis; however, the underlying mechanisms for this process remain largely unknown. To address this question, human hepatic HepaRG cells, at progenitor and differentiated states, were continuously treated with a noncytotoxic concentration of 1 μM sodium arsenite (NaAsO2). The HepaRG cells demonstrated active intracellular arsenite metabolism that shared important characteristic with primary human hepatocytes. Treatment of proliferating progenitor-like HepaRG cells with NaAsO2 inhibited their differentiation into mature hepatocyte-like cells, up-regulated genes involved in cell growth, proliferation, and survival, and down-regulated genes involved in cell death. In contrast, treatment of differentiated hepatocyte-like HepaRG cells with NaAsO2 resulted in enhanced cell death of mature hepatocyte-like cells, overexpression of cell death-related genes, and down-regulation of genes in the cell proliferation pathway, while biliary-like cells remained largely unaffected. Mechanistically, the cytotoxic effect of arsenic on mature hepatocyte-like HepaRG cells may be attributed to arsenic-induced dysregulation of cellular iron metabolism. The inhibitory effect of NaAsO2 on the differentiation of progenitor cells, the resistance of biliary-like cells to cell death, and the enhanced cell death of functional hepatocyte-like cells resulted in stem-cell activation. These effects favored the proliferation of liver progenitor cells that can serve as a source of initiation and driving force of arsenic-mediated liver carcinogenesis.
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Affiliation(s)
- Kostiantyn Dreval
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Volodymyr Tryndyak
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Iryna Kindrat
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.,Department of Biological and Medical Chemistry, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine
| | - Nathan C Twaddle
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Orish Ebere Orisakwe
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.,Department of Experimental Pharmacology and Toxicology, University of Port-Harcourt, Rivers State, Nigeria
| | - Thilak K Mudalige
- Office of Regulatory Affairs, Arkansas Regional Laboratory, U.S. Food and Drug Administration, Jefferson, Arkansas 72079
| | - Frederick A Beland
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Daniel R Doerge
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Igor P Pogribny
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
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34
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Hany H, Shalaby A, Al Kashef W, Kandil W, Shahin RA, El-Alfy H, Besheer T, Farag R, Mohamed M. Evaluation of the role of Notch1 expression in hepatic carcinogenesis with clinico-pathological correlation. Pathology 2018; 50:730-736. [PMID: 30389219 DOI: 10.1016/j.pathol.2018.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/14/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023]
Abstract
The role of Notch pathway in hepatocarcinogenesis is unclear with conflicting results reported from different researchers. This study aimed to investigate the exact role of Notch1 in hepatocarcinogenesis and its influence on survival and to determine the possibility of it being a target therapy. Differential immunohistochemical expression of Notch1 in 100 cases of hepatocellular carcinoma (HCC) and adjacent non-neoplastic liver tissue was performed. The results showed that expression of Notch1 was significantly higher in the non-neoplastic hepatic tissues than in HCC tissues (p < 0.001), but there was no significant difference in Notch1 expression between cirrhotic and non-cirrhotic liver tissue (p = 0.197). Notch1 expression was higher in low grade than in high grade HCC (p = 0.036). Notch1 expression showed reverse correlation with mitotic count (p = 0.008), and necrosis (p = 0.005). The disease free survival was shorter in patients displaying low levels of Notch1 expression (p = 0.045). The overall survival showed no significant difference between high and low levels of Notch1 expression; however, it was somewhat longer in patients with high Notch1 expression (p = 0.220). In conclusion, the tumour suppressor role of Notch1 was supported and the use of Notch1 agonists may have a role in improving the prognosis of HCC.
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Affiliation(s)
- Heba Hany
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Asem Shalaby
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt; Pathology Department, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
| | - Wagdi Al Kashef
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Wageha Kandil
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Rehab-Allah Shahin
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem El-Alfy
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Tarek Besheer
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Raghda Farag
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Mie Mohamed
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
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35
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Kim S, Cho CY, Lee D, Song DG, Kim HJ, Jung JW, Kim JE, Park D, Lee H, Um H, Park J, Choi Y, Kim Y, Nam SH, Lee JW. CD133-induced TM4SF5 expression promotes sphere growth via recruitment and blocking of protein tyrosine phosphatase receptor type F (PTPRF). Cancer Lett 2018; 438:219-231. [PMID: 30217560 DOI: 10.1016/j.canlet.2018.09.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/04/2018] [Accepted: 09/07/2018] [Indexed: 01/23/2023]
Abstract
CD133 is a surface marker of liver cancer stem cells. Transmembrane 4 L six family member 5 (TM4SF5) promotes sphere growth and circulation. However, it is unknown how CD133 and TM4SF5 cross-talk with each other for cancer stem cell properties. Here, we investigated the significance of inter-relationships between CD133, TM4SF5, CD44, and protein tyrosine phosphatase receptor type F (PTPRF) in a three-dimensional (3D) sphere growth system. We found that CD133 upregulated TM4SF5 and CD44, whereas TM4SF5 and CD44 did not affect CD133 expression. Signaling activity following CD133 phosphorylation caused TM4SF5 expression and sphere growth. TM4SF5 bound to CD133 and promoted c-Src activity for CD133 phosphorylation as a positive feedback loop, leading to CD133-mediated sphere growth that was inhibited by TM4SF5 inhibition or suppression. TM4SF5 also bound PTPRF and promoted paxillin phosphorylation. Decreased sphere growth upon CD133 suppression was recovered by TM4SF5 expression and partially by PTPRF suppression. TM4SF5 inhibition enhanced PTPRF levels and abolished PTPRF suppression-mediated sphere growth. Altogether, CD133-induced TM4SF5 expression and function were important for liver cancer sphere growth and may be a promising target to block metastasis.
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Affiliation(s)
- Somi Kim
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Chang Yun Cho
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Doohyung Lee
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Dae-Geun Song
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, 25451, Republic of Korea
| | - Hye-Jin Kim
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jae Woo Jung
- Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Ji Eon Kim
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Dasomi Park
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Haesong Lee
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyejin Um
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jinsoo Park
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yoonjeong Choi
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yoomin Kim
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seo Hee Nam
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jung Weon Lee
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
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36
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Palomeras S, Ruiz-Martínez S, Puig T. Targeting Breast Cancer Stem Cells to Overcome Treatment Resistance. Molecules 2018; 23:E2193. [PMID: 30200262 PMCID: PMC6225226 DOI: 10.3390/molecules23092193] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/22/2018] [Accepted: 08/24/2018] [Indexed: 12/15/2022] Open
Abstract
Despite advances in breast cancer diagnosis and treatment, many patients still fail therapy, resulting in disease progression, recurrence, and reduced overall survival. Historically, much focus has been put on the intrinsic subtyping based in the presence (or absence) of classical immunohistochemistry (IHC) markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-related protein (HER2). However, it is widely understood that tumors are composed of heterogeneous populations of cells with a hierarchical organization driven by cancer stem cells (CSCs). In breast tumors, this small population of cells displaying stem cell properties is known as breast CSCs (BCSCs). This rare population exhibit a CD44⁺/CD24-/low phenotype with high ALDH activity (ALDH⁺), and possesses higher tolerability to chemotherapy, hormone therapy, and radiotherapy and is able to reproduce the bulk of the tumor after reduction of cell populations sensitive to first-line therapy leading to disease relapse. In this review, we present special attention to BCSCs with future directions in the establishment of a therapy targeting this population. Drugs targeting the main BCSCs signaling pathways undergoing clinical trials are also summarized.
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Affiliation(s)
- Sònia Palomeras
- New Therapeutic Targets Laboratory (TargetsLab) Oncology Unit, Department of Medical Sciences, University of Girona, Girona Institute for Biomedical Research, Emili Grahit 77, Girona 17003, Spain.
| | - Santiago Ruiz-Martínez
- New Therapeutic Targets Laboratory (TargetsLab) Oncology Unit, Department of Medical Sciences, University of Girona, Girona Institute for Biomedical Research, Emili Grahit 77, Girona 17003, Spain.
| | - Teresa Puig
- New Therapeutic Targets Laboratory (TargetsLab) Oncology Unit, Department of Medical Sciences, University of Girona, Girona Institute for Biomedical Research, Emili Grahit 77, Girona 17003, Spain.
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Pandit H, Li Y, Li X, Zhang W, Li S, Martin RCG. Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma. BMC Cancer 2018; 18:783. [PMID: 30075764 PMCID: PMC6091111 DOI: 10.1186/s12885-018-4683-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 07/19/2018] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is among the deadliest cancers due to its heterogeneity, contributing to chemoresistance and recurrence. Cancer stem-like cells (CSCs) are suggested to play an important role in HCC tumorigenesis. This study investigates the role of Wnt/β-catenin pathway in CSC enrichment and the capabilities of these CSCs in tumor initiation in orthotopic immunocompetent mouse model. Methods HCC-CSCs were enriched using established serum-free culture method. Wnt/β-catenin pathway activation and its components were analyzed by western blot and qRT-PCR. The role of β-catenin in enrichment of CSC spheroids was confirmed using siRNA interference. Tumorigenic capabilities were confirmed using orthotopic immunocompetent mouse model by injecting 2 × 106 Hepa1–6 CSC spheroids or control cells in upper left liver lobe. Results The serum-free cultured Hepa1–6 cells demonstrated self-renewal, spheroid formation, higher EpCAM expression, increased Hoechst-33342 efflux, and upregulated Wnt/β-catenin signaling. Wnt/β-catenin pathway upregulation was implicated with the downstream targets, i.e., c-MYC, Cyclin-D1, and LEF1. Also, we found that GSK-3β serine-9 phosphorylation increased in Hepa1–6 spheroids. Silencing β-catenin by siRNA reversed spheroid formation phenotype. Mice injected with Hepa1–6 CSC spheroids showed aggressive tumor initiation and growth compared with mice injected with control cells. Conclusions Successfully induced Hepa1–6 spheroids were identified with CSC-like properties. Aberrant β-catenin upregulation mediated by GSK-3β was observed in the Hepa1–6 spheroids. The β-catenin mediated CSC enrichment in the induced spheroids possesses the capability of tumor initiation in immunocompetent mice. Our study suggests plausible cell dedifferentiation mediated by β-catenin contributes to CSC-initiated HCC tumor growth in vivo. Electronic supplementary material The online version of this article (10.1186/s12885-018-4683-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Harshul Pandit
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Yan Li
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA.
| | - Xuanyi Li
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA
| | - Weizhong Zhang
- Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, 130022, China
| | - Suping Li
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA
| | - Robert C G Martin
- Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA. .,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA. .,Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, 315 E. Broadway - #312, Louisville, KY, 40202, USA.
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Liu H, Wang Y, Xing X, Sun Y, Wei D, Chen G, Liu Q, Chen S, Liu X, Liu J. Comparative proteomics of side population cells derived from human hepatocellular carcinoma cell lines with varying metastatic potentials. Oncol Lett 2018; 16:335-345. [PMID: 29928419 PMCID: PMC6006459 DOI: 10.3892/ol.2018.8666] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 03/16/2018] [Indexed: 02/07/2023] Open
Abstract
Metastasis and recurrence following surgery are major reasons for the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) are thought to be able to cause cancer, and to be the primary cause of tumor recurrence and metastasis. The underlying mechanisms of the metastatic potential of CSCs is poorly understood. In the present study, side population (SP) cells were isolated from 4 HCC cell lines, and their self-renewal and migratory abilities were compared. The results demonstrate that SP cells from different cell lines exhibited similar self-renewal abilities but different metastatic potentials. Furthermore, the overall proteomes of the SP cells were systematically quantified. This revealed 11 and 19 differentially expressed proteins (DEPs), upregulated and downregulated, respectively, associated with increased metastatic potential. These proteins were involved in the 'regulation of mRNA processing' and 'cytoskeleton organization' biological processes. The majority of the proteins were involved in 'cell proliferation', 'migration' and 'invasion of cancer', and may promote HCC metastasis in a synergistic manner. The AKT and nuclear factor-κB signaling pathways may contribute to the regulation of HCC metastasis through regulating the DEPs in SP cells. To the best of our knowledge, the present study is the first to demonstrate the overall proteome difference among SP cells from the different HCC cell lines with different metastatic potentials. The present study provides novel information regarding the metastatic potential of CSCs, which will facilitate further investigation of the topic.
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Affiliation(s)
- Hongzhi Liu
- Liver Disease Center, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xiaohua Xing
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Ying Sun
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Dahai Wei
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Geng Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Qinying Liu
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Teaching Hospital of Fujian Medical University, Fujian Provincial Tumor Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Shanshan Chen
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Teaching Hospital of Fujian Medical University, Fujian Provincial Tumor Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Jingfeng Liu
- Liver Disease Center, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350007; P.R. China
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39
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Su P, Yang Y, Wang G, Chen X, Ju Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int J Oncol 2018; 53:1343-1353. [PMID: 29956726 DOI: 10.3892/ijo.2018.4461] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 05/30/2018] [Indexed: 11/06/2022] Open
Abstract
Resistance to conventional chemotherapeutic agents, including irinotecan (CPT‑11), 5-fluorouracil and capecitabine is a major cause for therapeutic failure in patients with colorectal cancer (CRC). Increasing evidence has demonstrated that cancer cells exhibiting stem cell-like characteristics are associated with the development of resistance to chemotherapeutic agents. As a plant polyphenol, curcumin has been demonstrated to have the ability to ameliorate resistance of CRC to chemotherapeutic agents, but the associations among curcumin, cancer stem cells (CSCs) and chemoresistance of CRC remain unclear. The present study established a CPT‑11-resistant colon cancer cell line, LoVo/CPT‑11 cells, and detected the expression levels of CSC identification markers [cluster of differentiation (CD)44, CD133, epithelial cell adhesion molecule (EpCAM) and CD24] in parental cells and CPT‑11-resistant cells. It was revealed that the expression levels of the colon CSC markers in LoVo/CPT‑11 cells were significantly higher compared those in parental cells at the mRNA and protein level. The effect of curcumin on the chemoresistance to CPT‑11 and the expression levels of CSC identification markers in LoVo/CPT‑11 cells separately treated with curcumin and CPT‑11 were further investigated. The results revealed that curcumin significantly attenuated chemoresistance to CPT‑11, and treatment with curcumin resulted in a significant reduction of the expression levels of CSC identification markers. Furthermore, a tumor sphere formation assay was used to enrich colon CSCs from LoVo/CPT‑11 cells, and demonstrated that curcumin efficiently diminished the traits of colon CSCs, as evidenced by the inability to form tumor spheres, the reduction in the expression of CSC identification markers, and apoptosis-induced effects on sphere-forming cells treated with curcumin alone or in combination with CPT‑11. Altogether, the present data demonstrated that curcumin attenuated resistance to chemotherapeutic drugs through induction of apoptosis of CSCs among colon cancer cells. These findings may provide novel evidence for the therapeutic application of curcumin in CRC intervention.
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Affiliation(s)
- Pengfei Su
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China
| | - Yong Yang
- Department of General Surgery, Heping Hospital Affiliated with Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Guoxin Wang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China
| | - Xiaowu Chen
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China
| | - Yongle Ju
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China
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40
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Abu Elella MH, Mohamed RR, Sabaa MW. Synthesis of novel grafted hyaluronic acid with antitumor activity. Carbohydr Polym 2018; 189:107-114. [DOI: 10.1016/j.carbpol.2018.02.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/17/2018] [Accepted: 02/01/2018] [Indexed: 12/27/2022]
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41
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Wang X, Deng Q, Feng K, Chen S, Jiang J, Xia F, Ma K, Bie P. Insufficient radiofrequency ablation promotes hepatocellular carcinoma cell progression via autophagy and the CD133 feedback loop. Oncol Rep 2018; 40:241-251. [PMID: 29749472 PMCID: PMC6059746 DOI: 10.3892/or.2018.6403] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 04/19/2018] [Indexed: 12/22/2022] Open
Abstract
Insufficient radiofrequency ablation (iRFA) often leads to residual hepatocellular carcinoma (HCC) progression. However, the mechanism is still poorly understood. In the present study, we demonstrated that LC3B protein expression levels were significantly increased in the residual hepatocellular carcinoma cells after radiofrequency ablation (RFA) treatment in vivo. Moreover, iRFA promoted autophagy, autophagosome formation and autophagic flux in Huh-7 and SMMC7721 cell lines in vitro. In addition, iRFA induced HCC cell viability and invasion. However, blockade of autophagy by the autophagosome inhibitor 3-methyladenine (3-MA) suppressed iRFA-induced cell viability and invasion. Furthermore, we revealed that the expression of liver cancer stem cell marker CD133 was also significantly increased in the residual hepatocellular carcinoma cells after RFA treatment in vivo, and was positively correlated with LC3B protein expression. iRFA also promoted CD133 protein expression in Huh-7 and SMMC7721 cell lines in vitro. CD133 was localized to autophagosomes, and was suppressed by 3-MA or chloroquine (CQ) after iRFA treatment. CD133 downregulation also suppressed iRFA-induced cell viability, invasion and autophagy. Collectively, our results indicated that RFA may promote residual HCC cell progression by autophagy and CD133 feedback loop.
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Affiliation(s)
- Xiaofei Wang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Qingsong Deng
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Kai Feng
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Shihan Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Jiayun Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Feng Xia
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Kuansheng Ma
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Ping Bie
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
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42
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Zekri ARN, El-Sisi ER, Youssef ASED, Kamel MM, Nassar A, Ahmed OS, El Kassas M, Barakat AB, Abd El-Motaleb AI, Bahnassy AA. MicroRNA Signatures for circulating CD133-positive cells in hepatocellular carcinoma with HCV infection. PLoS One 2018; 13:e0193709. [PMID: 29534065 PMCID: PMC5849309 DOI: 10.1371/journal.pone.0193709] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
AIM Molecular characterization of the CD133+ stem cells associated with hepatocarinogensis through identifying the expression patterns of specific microRNAs (miRNAs). METHODS We investigated the expression pattern of 13 miRNAs in purified CD133+ cells separated from the peripheral blood of healthy volunteers, chronic hepatitis C (CHC), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients a long with bone marrow samples from the healthy volunteers and the LC patients using custom miScript miRNA PCR array. RESULTS The differential expression of the 13 studied miRNAs in CD133+ cells separated from the HCC patients' peripheral blood compared to the controls revealed that miR-602, miR-181b, miR-101, miR-122, miR-192, miR-125a-5p, and miR-221 were significantly up regulated (fold change = 1.8, 1.7, 2, 5.4, 1.6, 2.9 & 1.5 P value = 0.039, 0.0019, 0.0013, 0.0370, 00024, 0.000044 &0.000007 respectively). As for the HCC group compared to the CHC group; miR-602, miR-122, miR-181b, miR-125a-5p, and miR-192 were significantly up regulated (fold change = 13, 3.1, 2.8, 1.6 & 1.56, P value = 0.01, 0.001, 0.000004, 0.002 & 0.007 respectively). Upon comparing the HCC group to the LC group; miR-199a-3p, miR-192, miR-122, miR-181b, miR-224, miR-125a-5p, and miR-885-5p were significantly up regulated (fold change = 5, 6.7, 2.3, 3, 2.5, 4.2 & 39.5 P value = 0.001025, 0.000024, 0.000472, 0.000278, 0.000004, 0.000075 & 0.0000001 respectively) whereas miR-22 was significantly down regulated (fold change = 0.57 P value = 0.00002). Only, miR-192, miR-122, miR-181b and miR-125a-5p were significant common miRNAs in CD133+ cells of the HCC group compared to the other non-malignant groups. CONCLUSION We identified a miRNA panel comprised of four miRNAs (miR-192, miR-122, miR-181b and miR-125a-5p) that may serve as a molecular tool for characterization of the CD133+ cells associated with different stages of hepatocarinogensis. This panel may aid in developing a new target therapy specific for those CD133+ cells.
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Affiliation(s)
- Abdel-Rahman N. Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Enas Reda El-Sisi
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Amira Salah El-Din Youssef
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mahmoud M. Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Auhood Nassar
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ola Sayed Ahmed
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Photobiology and Molecular Biology Department, Laser Institute for Research and Applications (LIRA), Beni-Suef University, Beni Suef, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Helwan, Egypt
| | | | | | - Abeer A. Bahnassy
- Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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Chao HM, Huang HX, Chang PH, Tseng KC, Miyajima A, Chern E. Y-box binding protein-1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/β-catenin pathway. Oncotarget 2018; 8:2604-2616. [PMID: 27911878 PMCID: PMC5356827 DOI: 10.18632/oncotarget.13733] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 11/22/2016] [Indexed: 12/14/2022] Open
Abstract
Y-box binding protein-1 (YB-1) is a pleiotropic molecule that binds DNA to regulate genes on a transcriptional level in the nucleus and binds RNA to modulate gene translation in the cytoplasm. In our previous studies, YB-1 was also characterized as a fetal hepatic protein that regulates the maturation of hepatocytes and is upregulated during liver regeneration. Moreover, YB-1 has been shown to be expressed in human hepatocellular carcinoma (HCC). However, the role of YB-1 in HCC remains unclear. Here, we aimed to characterize the role of YB-1 in HCC. Based on the results of loss-of-function in HCC and gain-of-function in mice liver using hydrodynamic gene delivery, YB-1 promoted hepatic cells proliferation in vitro and in vivo. YB-1 was also involved in HCC cell proliferation, migration, and drug-resistance. The results of extreme limiting dilution sphere forming analysis and cancer initiating cell marker analysis were also shown that YB-1 maintained HCC initiating cells population. YB-1 also induced the epithelial-mesenchymal transition and stemness-related gene expression. Knockdown of YB-1 suppressed the expression of Wnt ligands and β-catenin, impaired Wnt/β-catenin signaling pathway and reduced the numbers of HCC initiating cells. Moreover, YB-1 displayed nuclear localization particularly in the HCC initiating cells, the EpCAM+ cells or sphere cells. Our findings suggested that YB-1 was a key factor in HCC tumorigenesis and maintained the HCC initiating cell population.
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Affiliation(s)
- Hsiao-Mei Chao
- niChe Laboratory for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Hong-Xuan Huang
- niChe Laboratory for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Po-Hsiang Chang
- niChe Laboratory for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Kuo-Chang Tseng
- niChe Laboratory for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Atsushi Miyajima
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
| | - Edward Chern
- niChe Laboratory for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
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44
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Zhao Q, Zhou H, Liu Q, Cao Y, Wang G, Hu A, Ruan L, Wang S, Bo Q, Chen W, Hu C, Xu D, Tao F, Cao J, Ge Y, Yu Z, Li L, Wang H. Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models. Oncotarget 2018; 7:47431-47443. [PMID: 27329727 PMCID: PMC5216952 DOI: 10.18632/oncotarget.10164] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 06/06/2016] [Indexed: 12/31/2022] Open
Abstract
High expression of cancer stem cell (CSC) markers is related to poor prognosis of patients with hepatocellular carcinoma (HCC). However, the expression of these markers in patient-derived xenograft (PDX) models and the relationship of the expression levels of these markers between HCC patients and their PDX models at subsequent low passages are unclear. To investigate the prognostic impact of putative CSC markers in patients with HCC and in related PDX models, the expression of CD133, CD90, CD44, ALDH1, CK7, CK19, OCT4, SOX2, vimentin, nestin, CD13 and EpCam were assessed by quantitative reverse transcription-PCR (qRT-PCR) and then were validated using immunohistochemistry in tumor or peritumoral tissues from patients and tumor tissues from PDX models. Cumulative survival analysis of the patients and animals was conducted using the Kaplan-Meier method and the log-rank test. Only the expression levels of CD133 and CD44 were higher in tumor tissues than in the peritumoral tissues of HCC patients by qRT-PCR. High consistency of the prognostic value of the expression of CD133/CD44 was observed in HCC patients and the PDX models. High expression levels of CD133 and CD44 were positively related to the poor prognosis of HCC patients and to that in the PDX models. PDX HCC models in the present study have been suggested to be predictive of disease outcome, which could shed light on personalized medicine and the mechanisms of CSC marker expression on prognosis.
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Affiliation(s)
- Qihong Zhao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Heng Zhou
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Qifei Liu
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Ye Cao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Gang Wang
- Department of Oncology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Anla Hu
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Liang Ruan
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Sufang Wang
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Qingli Bo
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Wenjun Chen
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Chuanlai Hu
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Dexiang Xu
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Fangbiao Tao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Jiyu Cao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Yongsheng Ge
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Zongfan Yu
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Li
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Hua Wang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Institute for Liver Disease, Anhui Medical University, Hefei, China
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45
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Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice. Oncotarget 2018; 7:28903-13. [PMID: 25826080 PMCID: PMC5045365 DOI: 10.18632/oncotarget.3293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 02/08/2015] [Indexed: 01/02/2023] Open
Abstract
Dkk2 a antagonist of the Wnt/β-catenin-signaling pathway was shown to be silenced in diverse cancers. More recent data indicate that Dkk family members may also possess functions independent of Wnt-signaling during carcinogenesis. The detailed biological function of Dkks and its relevance for liver cancer is unknown. We analyzed the effects of a genetic deletion of Dkk2 (Dkk2−/−) in a hepatocarcinogenesis model using DEN/Phenobarbital. Untreated Dkk2−/− animals, showed considerable atypia with variation of hepatocyte size and chromatin density. In livers of Dkk2−/− mice nodule formation was seen at 9 months of age with focal loss of trabecular architecture and atypical hepatocytes and after DEN induction Dkk2−/− mice developed significantly more liver tumors compared to controls. Whole transcriptome analysis of untreated Dkk2−/− liver tissue revealed a Dkk2-dependent genetic network involving Wnt/β-Catenin but also multiple additional oncogenic factors, such as e.g. Pdgf-b, Gdf-15 and Hnf4a. Dkk2−/− tumor cells showed a significant deregulation of stemness genes associated with enhanced colony forming properties. Integration of the Dkk2−/− signature into human data was strongly associated with patients survival. Dkk2 deletion results in alterations of liver morphology leading to an increased frequency of liver cancer. The associated genetic changes included factors not primarily related to Wnt/β-Catenin-signaling and correlated with the clinical outcome of HCC-patients.
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46
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Ding Q, Xia Y, Ding S, Lu P, Sun L, Liu M. An alternatively spliced variant of CXCR3 mediates the metastasis of CD133+ liver cancer cells induced by CXCL9. Oncotarget 2018; 7:14405-14. [PMID: 26883105 PMCID: PMC4924724 DOI: 10.18632/oncotarget.7360] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/28/2016] [Indexed: 12/21/2022] Open
Abstract
Metastasis of liver cancer is closely linked to tumor microenvironment, in which chemokines and their receptors act in an important role. The CXCR3, the receptor of chemokine CXCL9, belongs to a superfamily of rhodopsin-like seven transmembrane GPCRs and CXCR subfamily. In HCC tissues, CXCR3 was frequently upregulated and correlated with tumor size, tumor differentiation, portal invasion and metastasis. In the study, CXCR3-A isoform that was bound by CXCL9 was found to cause significant change of ERK1/2 phosphorylation level in the MAPK signaling pathway, consequently upregulating the MMP2 and MMP9 expression and promoting invasion and metastasis of CD133+ liver cancer cells. Also, CXCR3-A suppressed the adhesion ability of CD133+ liver cancer cells that stimulated by CXCL9 for 24h. These findings suggest that CXCR3 and its ligand CXCL9 could promote the metastasis of liver cancer cells and might be a potential target for the intervention of liver cancer metastasis.
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Affiliation(s)
- Qiang Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yujia Xia
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuping Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Panpan Lu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Liang Sun
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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47
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Lai YS, Cheng CC, Lee MT, Chao WT, Lai YCC, Hsu YH, Liu YH. The Prognostic Value of Cytokeratin and Sal-Like Protein 4 Expression in Hepatocellular Carcinoma and Intra-Hepatic Cholangiocarcinoma in Taiwan. Int J Med Sci 2018; 15:1746-1756. [PMID: 30588199 PMCID: PMC6299409 DOI: 10.7150/ijms.28440] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 10/31/2018] [Indexed: 02/07/2023] Open
Abstract
Background: We previously reported that modulation of cytokeratin18 induces pleomorphism of liver cells, higher cell motility, and higher drug sensitivity to sorafenib treatment of hepatoma cells. These relationships were established by in vitro experiments. The aim of this study was to determine the in vivo association between cytokeratin expression and tumor behavior, as well as cancer stem cells of hepatocellular carcinoma and intra-hepatic cholangiocarcinoma in Taiwan. Methods: Cytokeratins and sal-like protein 4 expression was determined in 83 hepatocellular carcinoma and 30 intra-hepatic cholangiocarcinoma specimens by immunohistochemistry. The relationship between cytokeratins and sal-like protein 4 expression with hepatitis virus infection, clinicopathologic factors, and survival was analyzed. Further, the correlation among cytokeratins and sal-like protein 4 expression was studied. Results: In addition to cytokeratin8/18, the expression of cytokeratin7/19 and sal-like protein 4 was noted in hepatocellular carcinoma; however, only cytokeratin19 expression had a significant correlation with poor overall survival and poor disease-free survival. The expression of cytokeratins and sal-like protein 4 was not correlated with hepatitis virus infection. The expression of cytokeratin19, but not 7, 8, and 18, was correlated with sal-like protein 4 expression in hepatocellular carcinoma. Cytokeratin7 expression was decreased and the sal-like protein 4 expression was absent in all 30 intra-hepatic cholangiocarcinoma cases. The expression of cytokeratins had not statistically significant correlation with overall and disease-free survival in patients with intra-hepatic cholangiocarcinoma. Conclusions: The expression of cytokeratin19 was associated with sal-like protein 4 expression, as well as poor overall and disease-free survival in hepatocellular carcinoma patients in Taiwan.
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Affiliation(s)
- Yih-Shyong Lai
- Department of Pathology, Chang Bing Show Chwan Memorial Hospital, Changhua County 505, Taiwan
| | - Chiung-Chi Cheng
- Department of Pathology, Chang Bing Show Chwan Memorial Hospital, Changhua County 505, Taiwan.,Center for General Education, Providence University, Taichung City 433, Taiwan
| | - Ming-Tsung Lee
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua City 500, Taiwan
| | - Wei-Ting Chao
- Department of Life Science, Tunghai University, Taichung City 407, Taiwan
| | - Yen-Chang Clark Lai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan
| | - Yung-Hsiang Hsu
- Department of Pathology, Tzu Chi University, Hualien County 970, Taiwan
| | - Yi-Hsiang Liu
- Department of Pathology, Chang Bing Show Chwan Memorial Hospital, Changhua County 505, Taiwan.,Department of Pathology, Tzu Chi University, Hualien County 970, Taiwan
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48
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Harada Y, Kazama S, Morikawa T, Murono K, Yasuda K, Otani K, Nishikawa T, Tanaka T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Yamaguchi H, Ishihara S, Watanabe T. Leucine-rich repeat-containing G protein-coupled receptor 5 and CD133 expression is associated with tumor progression and resistance to preoperative chemoradiotherapy in low rectal cancer. Oncol Lett 2017; 14:7791-7798. [PMID: 29250176 PMCID: PMC5727605 DOI: 10.3892/ol.2017.7207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 10/03/2017] [Indexed: 12/15/2022] Open
Abstract
Preoperative chemoradiotherapy has been performed as a standard therapy for advanced low rectal cancer. Cancer stem cells (CSCs) have been reported to contribute to resistance to treatment and patient prognosis. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and cluster of differentiation (CD133) are putative markers for CSCs. However, their prognostic ability remains unknown, and evaluation of a single marker can be insufficient due to the heterogeneity of cancer. LGR5 and CD133 expression was immunohistochemically evaluated in surgical specimens of 56 patients who received curative resection following chemoradiotherapy for advanced low rectal cancer. In addition, the correlations between their expression levels, and clinicopathological features and patient prognosis were asessed. LGR5 expression was significantly correlated with lymphatic invasion, lymph node metastasis, and tumor node metastasic (TNM) stage. CD133 expression was significantly correlated with vascular invasion and the tumor regression grade. Combined expression was significantly correlated with lymphatic invasion, tumor regression grade and TNM stage, but not with overall, and disease-free survival. LGR5 and CD133 expressions may represent useful markers associated with tumor progression and resistance to chemoradiotherapy in patients with low rectal cancer. Furthermore, combined expression of these markers may be a more useful marker compared with the expression of each single marker.
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Affiliation(s)
- Yuzo Harada
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Shinsuke Kazama
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Teppei Morikawa
- Department of Pathology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Koji Murono
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Koji Yasuda
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Kensuke Otani
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Takeshi Nishikawa
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Toshiaki Tanaka
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Tomomichi Kiyomatsu
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Kazushige Kawai
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Keisuke Hata
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Hiroaki Nozawa
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Hironori Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Soichiro Ishihara
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Toshiaki Watanabe
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
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Al-Ansary GH, Eldehna WM, Ghabbour HA, Al-Rashood STA, Al-Rashood KA, Eladwy RA, Al-Dhfyan A, Kabil MM, Abdel-Aziz HA. Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation. J Enzyme Inhib Med Chem 2017; 32:986-991. [PMID: 28726519 PMCID: PMC6010115 DOI: 10.1080/14756366.2017.1347166] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 06/09/2017] [Accepted: 06/21/2017] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC50 = 21 and 29 μM, respectively) and MDA-MB-468 (IC50 = 23 and 24 μM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d.
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Affiliation(s)
- Ghada H. Al-Ansary
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Wagdy M. Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Hazem A. Ghabbour
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Sara T. A. Al-Rashood
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Khalid A. Al-Rashood
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Radwa A. Eladwy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt
| | - Abdullah Al-Dhfyan
- Stem Cell & Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital & Research Center, MBC-03, Riyadh, Saudi Arabia
| | - Maha M. Kabil
- Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Hatem A. Abdel-Aziz
- Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt
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50
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Moghadam AR, Patrad E, Tafsiri E, Peng W, Fangman B, Pluard TJ, Accurso A, Salacz M, Shah K, Ricke B, Bi D, Kimura K, Graves L, Najad MK, Dolatkhah R, Sanaat Z, Yazdi M, Tavakolinia N, Mazani M, Amani M, Ghavami S, Gartell R, Reilly C, Naima Z, Esfandyari T, Farassati F. Ral signaling pathway in health and cancer. Cancer Med 2017; 6:2998-3013. [PMID: 29047224 PMCID: PMC5727330 DOI: 10.1002/cam4.1105] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/10/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022] Open
Abstract
The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.
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Affiliation(s)
- Adel Rezaei Moghadam
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Elham Patrad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Elham Tafsiri
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Warner Peng
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Benjamin Fangman
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Timothy J Pluard
- Saint Luke's HospitalUniversity of Missouri at Kansas CityKansas CityMissouri
| | - Anthony Accurso
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Michael Salacz
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kushal Shah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Brandon Ricke
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Danse Bi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kyle Kimura
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Leland Graves
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Marzieh Khajoie Najad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Roya Dolatkhah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zohreh Sanaat
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mina Yazdi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Naeimeh Tavakolinia
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mohammad Mazani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Mojtaba Amani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Robyn Gartell
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Colleen Reilly
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zaid Naima
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Tuba Esfandyari
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Faris Farassati
- Research Service (151)Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation4801 E Linwood BlvdKansas CityMissouri64128‐2226
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