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Zhou L, He L, Liu CH, Qiu H, Zheng L, Sample KM, Wu Q, Li J, Xie K, Ampuero J, Li Z, Lv D, Liu M, Romero-Gómez M, Hu Y, Tang H. Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma. J Exp Clin Cancer Res 2023; 42:311. [PMID: 37993901 PMCID: PMC10664624 DOI: 10.1186/s13046-023-02893-w] [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: 08/10/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs. CONCLUSIONS LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.
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Affiliation(s)
- Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
| | - Linye He
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Huandi Qiu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Li Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Klarke Michael Sample
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Qin Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Jiaxin Li
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Kunlin Xie
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Javier Ampuero
- Digestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of Seville, Seville, Spain
| | - Zhihui Li
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Miao Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of Seville, Seville, Spain.
- Digestive Disease Department and CIBERehd, Virgen del Rocío University Hospital, Avenida Manuel Siurot S/N, 41013, Seville, Spain.
| | - Yiguo Hu
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
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Zhao D, Cao J, Zhang L, Zhang S, Wu S. Targeted Molecular Imaging Probes Based on Magnetic Resonance Imaging for Hepatocellular Carcinoma Diagnosis and Treatment. BIOSENSORS 2022; 12:bios12050342. [PMID: 35624643 PMCID: PMC9138815 DOI: 10.3390/bios12050342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is the sixth most commonly malignant tumor and the third leading cause of cancer-related death in the world, and the early diagnosis and treatment of patients with HCC is core in improving its prognosis. The early diagnosis of HCC depends largely on magnetic resonance imaging (MRI). MRI has good soft-tissue resolution, which is the international standard method for the diagnosis of HCC. However, MRI is still insufficient in the diagnosis of some early small HCCs and malignant nodules, resulting in false negative results. With the deepening of research on HCC, researchers have found many specific molecular biomarkers on the surface of HCC cells, which may assist in diagnosis and treatment. On the other hand, molecular imaging has progressed rapidly in recent years, especially in the field of cancer theranostics. Hence, the preparation of molecular imaging probes that can specifically target the biomarkers of HCC, combined with MRI testing in vivo, may achieve the theranostic purpose of HCC in the early stage. Therefore, in this review, taking MR imaging as the basic point, we summarized the recent progress regarding the molecular imaging targeting various types of biomarkers on the surface of HCC cells to improve the theranostic rate of HCC. Lastly, we discussed the existing obstacles and future prospects of developing molecular imaging probes as HCC theranostic nanoplatforms.
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Affiliation(s)
- Dongxu Zhao
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jian Cao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215006, China;
| | - Lei Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Shaohua Zhang
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Song Wu
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Urology, The Affiliated South China Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
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Suda T, Yamashita T, Sunagozaka H, Okada H, Nio K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. Dickkopf-1 Promotes Angiogenesis and is a Biomarker for Hepatic Stem Cell-like Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23052801. [PMID: 35269944 PMCID: PMC8911428 DOI: 10.3390/ijms23052801] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/26/2022] [Accepted: 02/27/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer stemness evinces interest owing to the resulting malignancy and poor prognosis. We previously demonstrated that hepatic stem cell-like hepatocellular carcinoma (HpSC-HCC) is associated with high vascular invasion and poor prognosis. Dickkopf-1 (DKK-1), a Wnt signaling regulator, is highly expressed in HpSC-HCC. Here, we assessed the diagnostic and prognostic potential of serum DKK-1. Its levels were significantly higher in 391 patients with HCC compared with 205 patients with chronic liver disease. Receiver operating characteristic curve analysis revealed the optimal cutoff value of DKK-1 to diagnose HCC and predict the 3-year survival as 262.2 and 365.9 pg/mL, respectively. HCC patients with high-serum DKK-1 levels showed poor prognosis. We evaluated the effects of anti-DKK-1 antibody treatment on tumor growth in vivo and of recombinant DKK-1 on cell proliferation, invasion, and angiogenesis in vitro. DKK-1 knockdown decreased cancer cell proliferation, migration, and invasion. DKK-1 supplementation promoted angiogenesis in vitro; this effect was abolished by an anti-DKK-1 antibody. Co-injection of the anti-DKK-1 antibody with Huh7 cells inhibited their growth in NOD/SCID mice. Thus, DKK-1 promotes proliferation, migration, and invasion of HCC cells and activates angiogenesis in vascular endothelial cells. DKK-1 is a prognostic biomarker for HCC and a functional molecule for targeted therapy.
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Ayob AZ, Ramasamy TS. Prolonged hypoxia switched on cancer stem cell-like plasticity in HepG2 tumourspheres cultured in serum-free media. In Vitro Cell Dev Biol Anim 2021; 57:896-911. [PMID: 34750738 DOI: 10.1007/s11626-021-00625-y] [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: 08/05/2021] [Accepted: 09/29/2021] [Indexed: 10/19/2022]
Abstract
Tumour hypoxia drives resistance and aggressiveness, and in large part, contributes to treatment failure thereby causing cancer-related deaths. The rapid and uncontrolled tumour growth develops not only a hypoxic niche but also a nutrient-deprived condition due to insufficient blood supply; together, these create a stressful tumour niche, further promoting higher aggressiveness and resistance features of cancer. However, how cellular responses in the prolonged stress is associated with cancer stem cells (CSCs), which is linked to these features, remains unclear. Here, we established HepG2 tumoursphere culture in a hypoxic and serum-free condition that recapitulated differential responses to prolonged tumour growth pressures, evident by their progressive changes in the morphology of tumoursphere formation over a course of 15-day culture. HepG2 tumourspheres formed larger sphere sizes of > 200 μm in hypoxic conditions, concomitant with higher cell yield and upregulation of PCNA marker at day 7, corresponding with higher self-renewal capacity when cultured in SFM compared to SM. Notably, prolonged growth of HepG2 tumourspheres for 15 days under hypoxic and SFM condition increased their sphere counts, yet significantly reduced their cell yield along with downregulation of PCNA expression. Gene expression analysis showed that HepG2 tumourspheres on day 15 exhibited enhanced expression of markers of quiescence, stemness, EMT, and chemoresistance. Interestingly, analysis of HIF1α and HIF2α and their target gene expression indicated complementary HIF expression with preferential upregulation of HIF2α was observed in HepG2 tumourspheres in prolonged hypoxic and serum-free conditions, suggesting HIF2α-dependency and plausibility of the HIF1α-HIF2α switch that govern their survival by promoting CSC-like programmes. Altogether, these findings suggest the implication of prolonged hypoxia and nutrient deprivation stress in promoting CSC-like programmes in cancer cells recapitulating their plasticity, hence having opened many research directions that enable development of effective targeting of CSCs and precision medicine for treating cancer.
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Affiliation(s)
- Ain Zubaidah Ayob
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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SOX2 and Bcl-2 as a Novel Prognostic Value in Hepatocellular Carcinoma Progression. ACTA ACUST UNITED AC 2021; 28:3015-3029. [PMID: 34436030 PMCID: PMC8395510 DOI: 10.3390/curroncol28040264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/21/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022]
Abstract
Sex-determining region Y-box 2 (SOX2) is a stem cell transcription factor and a major regulator of self-renewal and pluripotency of cancer stem cells (CSCs). In many types of cancer, SOX2 is dysregulated due to overexpression associated with tumor progression and low survival rate. Many HCC cases encounter recurrence and metastasis which might be due to CSCs and also apoptosis. Since little is known about the expression pattern of SOX2 and apoptotic genes in HCC, we aimed to determine the prognostic significance of SOX2, Bax, and Bcl-2 in clinicopathological features, tumor progression, and survival rate of the HCC patients. The expression of SOX2, Bax, and Bcl-2 were evaluated using qRT-PCR in 53 formalin-fixed, paraffin-embedded tissues (FFPE) of patients and 44 controls. Correlation of these genes was analyzed with clinicopathological features and tumor progression. The correlationship between SOX2 expression and ALBI grade as prognostic indicators were calculated. Survival rates were determined by Kaplan–Meier survival curves. SOX2 and Bcl-2 were remarkably overexpressed in HCC patients compared to controls (p = 0.04 and p = 0.003, respectively). A significant association was found for both SOX2 and Bcl-2 overexpression with TNM staging (p = 0.02, p = 0.04) and tumor grading (p = 0.01, p = 0.003), respectively. A significant correlation was observed: patients with SOX2 overexpression had a lower 5-year overall survival rate (p = 0.04); however, there was no significant association between Bcl-2 and survival (p = 0.5). Collectively, overexpression of SOX2 and Bcl-2, alone or combined, may be a potential marker to evaluate prognosis and response to HCC treatment.
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Yamashita T, Koshikawa N, Shimakami T, Terashima T, Nakagawa M, Nio K, Horii R, Iida N, Kawaguchi K, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kitao A, Kobayashi S, Takahara S, Imai Y, Yoshimura K, Murayama T, Nakamoto Y, Yoshida E, Yoshimura T, Seiki M, Kaneko S. Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma. Hepatology 2021; 74:760-775. [PMID: 33609304 DOI: 10.1002/hep.31758] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 01/03/2021] [Accepted: 01/11/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUNDS AND AIMS Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). APPROACH AND RESULTS In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001). CONCLUSIONS LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.
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Affiliation(s)
- Taro Yamashita
- Department of General MedicineKanazawa University HospitalKanazawaJapan.,Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Naohiko Koshikawa
- Division of Cancer Cell ResearchKanagawa Cancer Center Research InstituteYokohamaJapan.,Institute of Medical ScienceThe University of TokyoTokyoJapan.,Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan
| | - Tetsuro Shimakami
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Takeshi Terashima
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | | | - Kouki Nio
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Rika Horii
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Noriho Iida
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | | | - Kuniaki Arai
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Yoshio Sakai
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Tatsuya Yamashita
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Eishiro Mizukoshi
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Masao Honda
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Azusa Kitao
- Department of RadiologyKanazawa University HospitalKanazawaJapan
| | | | - Shizuko Takahara
- Innovative Clinical Research CenterKanazawa UniversityKanazawa, Kanazawa University HospitalKanazawaJapan
| | - Yasuhito Imai
- Innovative Clinical Research CenterKanazawa UniversityKanazawa, Kanazawa University HospitalKanazawaJapan
| | - Kenichi Yoshimura
- Innovative Clinical Research CenterKanazawa UniversityKanazawa, Kanazawa University HospitalKanazawaJapan.,Center for Integrated Medical ResearchHiroshima University HospitalHiroshimaJapan
| | - Toshinori Murayama
- Innovative Clinical Research CenterKanazawa UniversityKanazawa, Kanazawa University HospitalKanazawaJapan
| | - Yasunari Nakamoto
- Second Department of Internal MedicineUniversity of Fukui School of Medical SciencesYoshida-gunJapan
| | | | | | - Motoharu Seiki
- Faculty of MedicineInstitute of MedicalPharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
| | - Shuichi Kaneko
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
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Yamashita T, Kaneko S. Liver cancer stem cells: Recent progress in basic and clinical research. Regen Ther 2021; 17:34-37. [PMID: 33816720 PMCID: PMC7988346 DOI: 10.1016/j.reth.2021.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis was proposed over 4 decades ago and states that tumor growth is maintained by a small subset of cancer cells analogous to normal tissue stem cells in terms of self-renewal and differentiation capacity. Advances in CSC isolation were initially achieved in hematological malignancies and later in solid tumors, including hepatocellular carcinoma (HCC), the major histological type of liver cancer. Increasing evidence suggests the importance of liver CSCs for tumor growth, metastasis, and chemo/radiation resistance in HCC, but the application of the liver CSC concept for the clinical diagnosis and treatment of HCC has not yet been achieved to the extent initially expected. Furthermore, the heterogeneity and plasticity of liver CSCs has recently been noted and might be related to drug resistance and the rapid growth and/or metastasis of the tumor after treatment. Here, we introduce our recent advancement in liver CSC research and discuss the clinical implications, which may lead to the development of improved diagnostics and treatment in HCC.
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Affiliation(s)
- Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
- Corresponding author. Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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Wang J, Zhuo J, Tao Y, Xu S, Chen Z, Yang F, Ke Q, Xie H, Zheng S, Wang H, Xu X. Salinomycin-Loaded Small-Molecule Nanoprodrugs Enhance Anticancer Activity in Hepatocellular Carcinoma. Int J Nanomedicine 2020; 15:6839-6854. [PMID: 32982236 PMCID: PMC7501963 DOI: 10.2147/ijn.s236928] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Background There is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC. Methods We constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG2000. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice. Results Delivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient. Conclusion Our results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.
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Affiliation(s)
- Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, People's Republic of China
| | - Jianyong Zhuo
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China
| | - Yaoye Tao
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China
| | - Shengjun Xu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China
| | - Zun Chen
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China
| | - Fan Yang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China
| | - Qinghong Ke
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, People's Republic of China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, People's Republic of China
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310003, People's Republic of China
| | - Hangxiang Wang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, People's Republic of China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, People's Republic of China
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Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells. Molecules 2020; 25:molecules25122883. [PMID: 32585841 PMCID: PMC7356887 DOI: 10.3390/molecules25122883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/12/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.
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Kahraman DC, Kahraman T, Cetin-Atalay R. Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment. Mol Cancer Ther 2019; 18:2146-2157. [PMID: 31439713 DOI: 10.1158/1535-7163.mct-19-0004] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/01/2019] [Accepted: 08/15/2019] [Indexed: 11/16/2022]
Abstract
Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.
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Affiliation(s)
- Deniz Cansen Kahraman
- Cancer Systems Biology Laboratory, Graduate School of Informatics, ODTU, Ankara, Turkey.
| | - Tamer Kahraman
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Rengul Cetin-Atalay
- Cancer Systems Biology Laboratory, Graduate School of Informatics, ODTU, Ankara, Turkey
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11
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Rhee H, An C, Kim HY, Yoo JE, Park YN, Kim MJ. Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features. Liver Cancer 2019; 8:24-40. [PMID: 30815393 PMCID: PMC6388566 DOI: 10.1159/000488540] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 03/18/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS The purpose of our study was to examine the histopathologic characteristics of hepatocellular carcinoma (HCC) with irregular rim-like arterial phase enhancement (IRE), which has been reported to be associated with more aggressive tumor behavior. METHODS We investigated 84 pathologically confirmed HCCs in 84 patients who underwent curative hepatic resection after gadoxetate-enhanced magnetic resonance imaging between January 2008 and February 2013. Two abdominal radiologists independently reviewed these images and classified HCCs into two categories: HCC showing IRE (IRE-HCC) and HCC showing hypoenhancement or diffuse arterial enhancement (non-IRE-HCC). Twenty-two HCCs were classified as IRE-HCCs, and 51 were classified as non-IRE-HCCs concordantly by both reviewers. The remaining 11 HCCs, on whose radiologic classifications the reviewers disagreed, were classified as HCCs with intermediate enhancement patterns. The HCC clinicopathologic characteristics and patient outcomes were then compared. RESULTS IRE-HCCs showed more frequent microvascular invasion (91 vs. 35%), lower microvascular density (246.5 vs. 426.5/mm2), higher proportions of sinusoid-like microvascular pattern (55 vs. 0%) and macrotrabecular pattern (45 vs. 0%), and larger areas of tumor necrosis (15 vs. 0%) and fibrous stroma (8.3 vs. 2.1%) than non-IRE-HCCs. IRE-HCCs also expressed higher levels of immunomarkers of hypoxia (carbonic anhydrase IX, 64 vs. 8%) and stemness (EpCAM, 50 vs. 20%). p values were < 0.001 for all comparisons except for EpCAM (p = 0.026). HCCs with intermediate enhancement patterns showed mixed/intermediate pathologic features from both IRE- and non-IRE-HCCs. IRE-HCC patients showed poorer 5-year disease-free survival after curative resection than non-IRE-HCC patients (p = 0.005). CONCLUSIONS IRE-HCCs demonstrate aggressive histopathologic features, including more hypoxic and fibrotic tumor microenvironments and increased stemness, compared to non-IRE-HCCs. IRE might therefore serve as a noninvasive imaging biomarker for aggressive HCC.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chansik An
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye-Young Kim
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myeong-Jin Kim
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea,*Myeong-Jin Kim, MD, PhD, Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul 03722 (South Korea), E-Mail , Young Nyun Park, MD, PhD, Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul 03722 (South Korea), E-Mail
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12
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Inhibitory effect of hybrid liposomes on the growth of liver cancer stem cells. Biochem Biophys Res Commun 2018; 509:268-274. [PMID: 30583860 DOI: 10.1016/j.bbrc.2018.12.118] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/15/2018] [Indexed: 01/27/2023]
Abstract
PURPOSE Cancer stem cells (CSCs), also known as tumor-initiating cells, are involved in tumor progression, metastasis, and drug resistance. Hybrid liposomes (HLs) are nano-sized liposomal particles that can be easily prepared by ultrasonicating a mixture of vesicular and micellar molecules in buffer solutions. In this study, we investigated the inhibitory effects of HL on the growth of CSC subpopulations in liver cancer cells (HepG2) in vitro. METHODS HLs composed of 90 mol% L-α-dimyristoylphosphatidylcholine and 10 mol% polyoxyethylene(23) dodecyl ether were prepared by sonication. Cell viability was determined by the trypan blue exclusion assay. In liver cancer cells, CSCs were identified by the presence of the cell surface marker proteins CD133 and EpCAM by flow cytometry. A soft agar colony formation assay was performed using HepG2 cells pretreated with HLs. RESULTS HLs selectively inhibited liver cancer cell growth without affecting normal hepatocytes. Additionally, HLs induced apoptosis of HepG2 cells by a"ctivating caspase-3. Notably, the CD133(+)/EpCAM(+) CSC sub-population of liver cancer cells treated with HLs was reduced. Furthermore, HLs markedly decreased the number of colony-forming cells. Finally, we confirmed the fusion and accumulation of HLs into the cell membranes of CSCs using a fluorescently labeled lipid (NBDPC). Significant accumulation of HL/NBDPC into the CSCs (particularly EpCAM(+) cells) occurred in a dose-dependent manner. CONCLUSION These results suggest that HLs are a novel nanomedical therapeutic agent for targeting CSCs in liver cancer therapy.
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13
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Ma DQ, Zhang YH, Ding DP, Li J, Chen LL, Tian YY, Ao KJ. Effect of Bmi-1-mediated NF-κB signaling pathway on the stem-like properties of CD133+ human liver cancer cells. Cancer Biomark 2018; 22:575-585. [PMID: 29843222 DOI: 10.3233/cbm-181329] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate the impact of Bmi-1-mediated NF-κB pathway on the biological characteristics of CD133+ liver cancer stem cells (LCSCs). METHODS Flow cytometry was used to isolate CD133+ LCSC cells from Huh7, Hep3B, SK-hep1, and PLC/PRF-5 cells. CD133+ Huh7 cells were divided into Control, Blank, Bmi-1 siRNA, JSH-23 (NF-κB pathway inhibitor), and Bmi-1 + JSH-23 groups. The properties of CD133+ Huh7 cells were detected by the colony-formation and sphere-forming assays. Besides, Transwell assay was applied for the measurement of cell invasion and migration, immunofluorescence staining for the detection of NF-κB p65 nuclear translocation, and qRT-PCR and Western blotting for the determination of SOX2, NANOG, OCT4, Bmi-1, and NF-κB p65 expression. RESULTS CD133+ Huh-7 cells were chosen as the experiment subjects after flow cytometry. Compared with CD133- Huh-7 cells, the expression of CD133, OCT4, SOX2, NANOG, Bmi-1, and NF-κB p65, the nuclear translocation of NF-κB p65, the number of cell colonies and Sphere formation, as well as the abilities of invasion and migration were observed to be increased in CD133+ Huh-7 cells, which was inhibited after treated with Bmi-1 siRNA or JSH-23, meanwhile, the cell cycle was arrested at the G0/G1 and S phases with apparently enhanced cell apoptosis. Importantly, no significant differences in the biological characteristics of CD133 + Huh-7 cells were found between the Blank group and Bmi-1 + JSH-23 group. CONCLUSION Down-regulating Bmi-1 may inhibit the biological properties of CD133+ LCSC by blocking NF-κB signaling pathway, which lays a scientific foundation for the clinical treatment of liver cancer.
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Affiliation(s)
- De-Qiang Ma
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Yin-Hua Zhang
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - De-Ping Ding
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Juan Li
- Maternal and Child Health-Care Hospital, Shiyan, Hubei 442000, China
| | - Lin-Li Chen
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - You-You Tian
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Kang-Jian Ao
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
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14
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Shirasaki T, Honda M, Yamashita T, Nio K, Shimakami T, Shimizu R, Nakasyo S, Murai K, Shirasaki N, Okada H, Sakai Y, Sato T, Suzuki T, Yoshioka K, Kaneko S. The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication. Sci Rep 2018; 8:13143. [PMID: 30177680 PMCID: PMC6120883 DOI: 10.1038/s41598-018-31421-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 08/15/2018] [Indexed: 12/17/2022] Open
Abstract
Osteopontin (OPN) is involved in cell proliferation, migration, inflammation, and tumor progression in various tissues. OPN induces stemness by interacting with CD44, but the functional relevance of OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear. In this study, we investigated the effect of OPN on HCV replication and IFN signaling in cancer stem cells (CSCs) positive for epithelial cell adhesion molecule (EpCAM) and CD44. We show that the EpCAM+/CD44+ CSCs show marked HCV replication when compared to EpCAM−/CD44− cells. In addition, OPN significantly enhances this HCV replication in EpCAM+/CD44+ CSCs and markedly suppresses IFN-stimulated gene expression. The GSK-3β inhibitor BIO increases the EpCAM+/CD44+ CSC population and OPN expression and impairs IFN signaling via STAT1 degradation. Taken together, our data suggest that OPN enhances HCV replication in the EpCAM+/CD44+ CSCs, while it also negatively regulates the IFN signaling pathway via inhibition of STAT1 phosphorylation and degradation. Therefore, OPN may represent a novel therapeutic target for treating HCV-related hepatocellular carcinoma.
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Affiliation(s)
- Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. .,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of General Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Ryougo Shimizu
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Saki Nakasyo
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Kazuhisa Murai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Natsumi Shirasaki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hikari Okada
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tokiharu Sato
- Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Katsuji Yoshioka
- Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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15
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Yang T, Chen Y, Zhao P, Xue H, You J, Li B, Liu Y, He C, Zhang X, Fan L, Lee RJ, Li L, Ma X, Xu C, Xiang G. Enhancing the therapeutic effect via elimination of hepatocellular carcinoma stem cells using Bmi1 siRNA delivered by cationic cisplatin nanocapsules. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:2009-2021. [PMID: 29842934 DOI: 10.1016/j.nano.2018.05.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 04/26/2018] [Accepted: 05/20/2018] [Indexed: 12/24/2022]
Abstract
Resistance of hepatocellular carcinoma (HCC) to systemic chemotherapy is partially due to presence of drug-resistant cancer stem cells. Bmi1 protein is essential for survival and proliferation of HCC cancer stem cells (CSCs). Here, we report that Bmi1 siRNA (Bmi1siR) loaded in cationic nanocapsules of cisplatin (NPC) eliminated stem cells in situ HCC in mice. NPC/Bmi1siR was fabricated via electrostatic complexation of Bmi1 siRNA to NPCs, which had cores composed of cisplatin and were coated with cationic lipids. In vivo, NPC/Bmi1siR showed higher anti-tumor activity in HCC bearing mice compared with cisplatin or NPC. Critically, both flow cytometry (FACS) analysis in vitro and histological examination in vivo revealed that side population or CD133+ HCC cells were dramatically decreased by NPC/Bmi1siR treatment, suggesting that HCC CSCs were eliminated. Altogether, our results suggest that drug resistance of HCC can be overcome by co-delivering Bmi1 siRNA with cisplatin in cationic nanocapsules.
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Affiliation(s)
- Tan Yang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yuyuan Chen
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Pengxuan Zhao
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Huiying Xue
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jia You
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Bin Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yong Liu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Chuanchuan He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Xiaojuan Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Lingling Fan
- Stem Cell Center, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Robert J Lee
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Lei Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Xiang Ma
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
| | - Guangya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
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16
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Wang K, Sun D. Cancer stem cells of hepatocellular carcinoma. Oncotarget 2018; 9:23306-23314. [PMID: 29796190 PMCID: PMC5955417 DOI: 10.18632/oncotarget.24623] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 02/12/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma is a malignant tumor arising from hepatocytes. The hepatocellular carcinoma is dictated by a subset of cells with stem cell-like features. These cells are apoptosis-resistant and have particular biomarkers, which serve as seeds in different stages of tumorigenesis including initiation, progression, metastasis, and relapse of hepatocellular carcinoma. Signaling pathways of cancer stem cells are novel targets for the radical intervention of hepatocellular carcinoma.
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Affiliation(s)
- Kewei Wang
- Institute of Cell Biotechnology, China and Russia Medical Research Center, Harbin Medical University, Harbin, China.,Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin, China.,Key Laboratory of Etiology and Epidemiology (23618504), National Health and Family Planning Commission of the People's Republic of China, Harbin, China.,Harbin Medical University, Harbin, China
| | - Dianjun Sun
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin, China.,Key Laboratory of Etiology and Epidemiology (23618504), National Health and Family Planning Commission of the People's Republic of China, Harbin, China.,Harbin Medical University, Harbin, China
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17
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Seino S, Tsuchiya A, Watanabe Y, Kawata Y, Kojima Y, Ikarashi S, Yanai H, Nakamura K, Kumaki D, Hirano M, Funakoshi K, Aono T, Sakai T, Sakata J, Takamura M, Kawai H, Yamagiwa S, Wakai T, Terai S. Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers. Oncotarget 2018; 9:21844-21860. [PMID: 29774107 PMCID: PMC5955154 DOI: 10.18632/oncotarget.25074] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 03/22/2018] [Indexed: 12/24/2022] Open
Abstract
The high heterogeneity of hepatocellular carcinomas (HCCs) complicates stratification of HCC patients for treatment. Therefore, it is necessary to establish a comprehensive panel of HCC biomarkers related to tumour behaviour and cancer prognosis. Resected HCCs from 251 patients were stained for hepatic progenitor cell (HPC) markers epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), delta-like 1 homolog (DLK1), and cytokeratin 19 (CK19). Staining patterns were analysed for their prognostic association with relapse-free survival and overall survival. α-Fetoprotein (AFP), lectin-reactive α-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin (DCP) were assessed as indicators of HPC protein expression. Expression pattern of HPC markers correlated with tumour malignancy indicated by high AFP/AFP-L3 serum levels, more frequent vascular invasion, and poorer tumour differentiation. EpCAM expression, DCP ≥300 mAU/ml, age ≥60, and Child-Pugh score grade B or C were independent prognostic factors of poor outcome and were used in a new scoring system for HCC prognosis after operation. Expression of two or more HPC markers was a significant predictor of poor HCC outcome and serum levels of AFP/AFP-L3 correlated with the expression of HPC proteins. Our study paved the way for further elucidation of the association among HPC markers, serum tumour markers, and HCC clinical outcome for precision medicine.
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Affiliation(s)
- Satoshi Seino
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Yuzo Kawata
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Yuichi Kojima
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Shunzo Ikarashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Hiroyuki Yanai
- Drug Discovery Laboratories, Chiome Bioscience Inc., 907 Nogawa, Miyamae-Ku, Kawasaki-Shi, Kanagawa 216-0001, Japan
| | - Koji Nakamura
- Drug Discovery Laboratories, Chiome Bioscience Inc., 907 Nogawa, Miyamae-Ku, Kawasaki-Shi, Kanagawa 216-0001, Japan
| | - Daisuke Kumaki
- Division of Gastroenterology and Hepatology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan
| | - Masaaki Hirano
- Division of Gastroenterology and Hepatology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan
| | - Kazuhiro Funakoshi
- Division of Gastroenterology and Hepatology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan
| | - Takashi Aono
- Division of Surgery, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan
| | - Takeshi Sakai
- Division of Diagnostic Pathology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Hirokazu Kawai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Satoshi Yamagiwa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan
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18
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Zhong L, Kong JN, Dinkins MB, Leanhart S, Zhu Z, Spassieva SD, Qin H, Lin HP, Elsherbini A, Wang R, Jiang X, Nikolova-Karakashian M, Wang G, Bieberich E. Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice. J Lipid Res 2018; 59:795-804. [PMID: 29567647 DOI: 10.1194/jlr.m080879] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 02/26/2018] [Indexed: 02/06/2023] Open
Abstract
Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver tumor, but not adjacent tissue, exhibited substantial accumulation of lipid droplets, suggesting that nSMase2 deficiency is associated with tumor growth and increased neutral lipid generation in the tumor. Tumor tissue expressed significantly increased levels of CD133 and EpCAM mRNA, two markers of liver cancer stem-like cells (CSCs) and higher levels of phosphorylated signal transducer and activator of transcription 3, an essential regulator of stemness. CD133(+) cells showed strong labeling for SM and ceramide. In conclusion, these results suggest that SMase-2 deficiency plays a role in the survival or proliferation of CSCs, leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis.
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Affiliation(s)
- Liansheng Zhong
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY.,Department of Bioinformatics, Key Laboratory of Cell Biology of Ministry of Public Health, College of Basic Medical Sciences, China Medical University, Shenyang, People's Republic of China
| | - Ji Na Kong
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
| | - Michael B Dinkins
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
| | - Silvia Leanhart
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
| | - Zhihui Zhu
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | - Stefka D Spassieva
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | - Haiyan Qin
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | - Hsuan-Pei Lin
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | - Ahmed Elsherbini
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | | | - Xue Jiang
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY.,Rehabilitation Center, ShengJing Hospital of China Medical University, Shenyang, People's Republic of China
| | | | - Guanghu Wang
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY
| | - Erhard Bieberich
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY .,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA
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19
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Yang R, An LY, Miao QF, Li FM, Han Y, Wang HX, Liu DP, Chen R, Tang SQ. Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes. Oncotarget 2017; 7:35894-35916. [PMID: 27145285 PMCID: PMC5094971 DOI: 10.18632/oncotarget.9116] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 04/16/2016] [Indexed: 12/18/2022] Open
Abstract
AIM To investigate the use of thermosensitive magnetoliposomes (TMs) loaded with magnetic iron oxide (Fe3O4) and the anti-cancer stem cell marker CD90 (CD90@TMs) to target and kill CD90+ liver cancer stem cells (LCSCs). METHODS The hepatocellular carcinoma cell line Huh7 was used to separate CD90+ LCSCs by magnetic-activated cell sorting. CD90@TMs was characterized and their ability to target CD90+ LCSCs was determined. Experiments were used to investigate whether CD90@TMs combined with magnetic hyperthermia could effectively eliminate CD90+ LCSCs. RESULTS The present study demonstrated that CD90+ LCSCs with stem cells properties were successfully isolated. We also successfully prepared CD90@TMs that was almost spherical and uniform with an average diameter of 130±4.6 nm and determined that magnetic iron oxide could be incorporated and retained a superparamagnetic response. CD90@TMs showed good targeting and increased inhibition of CD90+ LCSCs in vitro and in vivo compared to TMs. CONCLUSIONS CD90@TMs can be used for controlled and targeted delivery of anticancer drugs, which may offer a promising alternative for HCC therapy.
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Affiliation(s)
- Rui Yang
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Li Y An
- Jiangsu Key Laboratory of Molecular and Fuctional Imaging, Department of Radiology, Zhongda Hospital, Nanjing, People's Republic of China
| | - Qin F Miao
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Feng M Li
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Yong Han
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Hui X Wang
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Dang P Liu
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Rong Chen
- Department of Oncology, Zhongda Hospital, Nanjing, People's Republic of China
| | - Sha Q Tang
- School of Medicine, Southeast University, Nanjing, People's Republic of China
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20
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Nahm JH, Rhee H, Kim H, Yoo JE, San Lee J, Jeon Y, Choi GH, Park YN. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. Oncotarget 2017; 8:99359-99371. [PMID: 29245907 PMCID: PMC5725098 DOI: 10.18632/oncotarget.22078] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 10/11/2017] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinomas (HCCs) expressing stemness markers are characterized by an aggressive behavior, which might be promoted by an altered tumor stroma. Transarterial chemoembolization (TACE) induces severe hypoxia, and its effect on stemness and tumor stroma of HCCs remains unclear. The purpose of this study was to evaluate the sequential changes of stemness and tumor stroma under TACE-induced hypoxia using biopsy and resection-matched HCCs. Methods Forty-six biopsy and resection matched HCCs including 10 cases with and 36 cases without preoperative TACE were selected. Immunohistochemistry for stemness (keratin 19 [K19], epithelial cell adhesion molecule [EpCAM], and CD133), hypoxia (carbonic anhydrase IX [CAIX] and vascular endothelial growth factor [VEGF]), and tumor stromal (α-smooth muscle actin [α-SMA] and fibroblast activation protein [FAP]) markers were performed and compared in matched biopsied and resected HCCs with and without TACE. Results The accuracy of K19, EpCAM, CD133, CAIX, VEGF, α-SMA and FAP detected on biopsied HCCs was 64% ∼ 86%, using the expression status in resected HCCs as a reference standard in non-TACE group. The sequential change of hypoxia, stemness and stromal marker expression in matched biopsied and resected HCC was greater in TACE group than in non-TACE group (P < 0.05 for all). The degree of stemness marker expression was well correlated with those of tumor stromal markers, and the degree of CAIX expression was well correlated with that of K19 (P < 0.05). Conclusions Stemness marker expression is considered to be increased along with tumor stromal alteration under TACE-induced hypoxia, which might promote the aggressive biology of HCC.
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Affiliation(s)
- Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyungjin Rhee
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jee San Lee
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Youngsic Jeon
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Gi Hong Choi
- Departments of General Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
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21
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Zhang Y, Zhao W, Han H, Li S, Chen D, Zhang Z. MicroRNA-31 suppresses the self-renewal capability of α2δ1 + liver tumor-initiating cells by targeting ISL1. Oncotarget 2017; 8:87647-87657. [PMID: 29152108 PMCID: PMC5675660 DOI: 10.18632/oncotarget.21140] [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: 03/06/2017] [Accepted: 08/26/2017] [Indexed: 01/15/2023] Open
Abstract
Accumulating evidence demonstrates that miRNAs, a class of small non-coding RNAs, are involved in the regulation of tumor-initiating cells (TICs) which are considered to be the origin of cancer development according to the cancer stem cell hypothesis. We have previously identified that miR-31 may play suppressive roles in α2δ1+ hepatocellular carcinoma (HCC) TICs. Here, we confirm that the expression of miR-31 is significantly downregulated in α2δ1+ HCC TICs. Overexpression of miR-31 in α2δ1+ HCC TICs results in significant suppression of the self-renewal and tumorigenicity abilities of these cells. Conversely, knockdown the expression of miR-31 in PLC/PRF/5 cells is able to reprogram them into TICs with stem cell-like properties. Furthermore, the expression of ISL LIM Homeobox 1(ISL1), a transcription factor involved in recognition of undifferentiated cardiac progenitors, is negatively regulated by miR-31, and the luciferase reporters’ activities with the 3′-UTRs of ISL1 are inhibited significantly by miR-31. Collectively, our results suggest that miR-31 can negatively regulate the self-renewal ability of α2δ1+ liver TICs via silencing ISL1.
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Affiliation(s)
- Yuan Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Haibo Han
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Sheng Li
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Dongji Chen
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhiqian Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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22
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Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90. Sci Rep 2017; 7:11292. [PMID: 28900199 PMCID: PMC5596021 DOI: 10.1038/s41598-017-11848-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 08/30/2017] [Indexed: 12/19/2022] Open
Abstract
Cancer stem cells (CSCs) are a pivotal target for eradicating hepatocellular carcinoma (HCC). We previously reported that distinctive CSCs regulating tumorigenicity (EpCAM+ CSCs) and metastasis (CD90+ CSCs) have different epithelial/mesenchymal gene expression signatures. Here, we examined the influence of sorafenib, a multiple-receptor tyrosine kinase inhibitor used as a first-line treatment for advanced HCC, on EpCAM+ and CD90+ CSCs. CD90+ cells showed higher c-Kit gene/protein expression than EpCAM+ cells. Sorafenib treatment reduced the number of CD90+ cells with attenuated c-Kit phosphorylation, whereas it enriched the EpCAM+ cell population. We evaluated the role of CD90+ and EpCAM+ CSCs in vivo by subcutaneously injecting these CSCs together in immune-deficient mice. We observed that sorafenib subtly affected the suppression of primary tumor growth maintained by EpCAM+ CSCs, but completely inhibited the lung metastasis mediated by CD90+ CSCs. We further evaluated the effect of sorafenib on extracellular vesicle (EV) production and found that sorafenib suppressed the production of EVs containing TGF-β mRNA in CD90+ cells and inhibited the cell-cell communication and motility of EpCAM+ cells. Our data suggest the following novel effects of sorafenib: suppressing CD90+ CSCs and inhibiting the production of EVs regulating distant metastasis.
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23
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Choi SH, Lee SW, Ok M, Kim KS, Kim S, Ahn SH. Gene Expression Profiling of Hepatocellular Carcinoma Derived Cancer Stem Like Cell under Hypoxia. Yonsei Med J 2017; 58:925-933. [PMID: 28792135 PMCID: PMC5552646 DOI: 10.3349/ymj.2017.58.5.925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/17/2017] [Accepted: 05/22/2017] [Indexed: 01/16/2023] Open
Abstract
PURPOSE Cancer stem like cells (CSCs), with unlimited self-renewal potential and other stem cell characteristics, occur in several cancers including hepatocellular carcinoma (HCC). Although CSCs can initiate tumors, malignant proliferation, relapse and multi-drug resistance, the ways how to activate them still remain unknown. This study aims to evaluate whether CSC acquire tumorigenic characters under tumor hypoxia, analyzed by microarray analysis. MATERIALS AND METHODS CSCs were purified from HCC patients and Affymetrix microarray was used to investigate their gene expression profiles. The results were validated by real-time polymerase chain reaction (PCR). RESULTS The results of the microarray indicated that 18 genes were up-regulated and 10 genes were down-regulated in CSCs. Several genes were identified to be significantly involved in the regulation of CSCs such as HCC. Furthermore, the up-regulated genes were related with metabolism, angiogenesis and hypoxia, whereas the down-regulated genes were related with apoptosis and inflammation. CONCLUSION The results may help to understand the mechanisms of tumor development through CSCs which acquired their distinctive tumorogenic properties by hypoxic stimulation.
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Affiliation(s)
- Sung Hoon Choi
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Division of Bioconvergence, Drug and Disease Target Group, Korea Basic Science Institute, Ochang, Korea
| | - Sang Woo Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Minseon Ok
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Sik Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| | | | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
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24
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Tamaki N, Kuno A, Matsuda A, Tsujikawa H, Yamazaki K, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Korenaga M, Mizokami M, Kurosaki M, Sakamoto M, Narimatsu H, Izumi N. Serum Wisteria Floribunda Agglutinin-Positive Sialylated Mucin 1 as a Marker of Progenitor/Biliary Features in Hepatocellular Carcinoma. Sci Rep 2017; 7:244. [PMID: 28325920 PMCID: PMC5428232 DOI: 10.1038/s41598-017-00357-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/21/2017] [Indexed: 12/18/2022] Open
Abstract
Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 μL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1 <900. Furthermore, cumulative incidence of HCC recurrence was significantly higher in patients with WFA-sialylated MUC1 ≥900 and on multivariate analysis, serum WFA-sialylated MUC1 levels was an independent predictor of HCC recurrence. These results revealed that serum WFA-sialylated MUC1 was associated with histological feature of HCC and recurrence after curative therapy and it could be a novel marker of HPC/biliary features in HCC and of prognosis.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Atsushi Matsuda
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of medicine, Tokyo, Japan
| | - Ken Yamazaki
- Department of Pathology, Keio University School of medicine, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masaaki Korenaga
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Masashi Mizokami
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of medicine, Tokyo, Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
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25
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Novel phyto-derivative BRM270 inhibits hepatocellular carcinoma cells proliferation by inducing G2/M phase cell cycle arrest and apoptosis in xenograft mice model. Biomed Pharmacother 2017; 87:741-754. [DOI: 10.1016/j.biopha.2017.01.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/19/2016] [Accepted: 01/01/2017] [Indexed: 01/06/2023] Open
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26
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Kahraman DC, Hanquet G, Jeanmart L, Lanners S, Šramel P, Boháč A, Cetin-Atalay R. Quinoides and VEGFR2 TKIs influence the fate of hepatocellular carcinoma and its cancer stem cells. MEDCHEMCOMM 2017; 8:81-87. [PMID: 30108693 PMCID: PMC6072489 DOI: 10.1039/c6md00392c] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
Bioactivities of quinoides 1-5 and VEGFR2 TKIs 6-10 in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC50 values in μM concentrations in HCC cells. Quinoide 3 was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor DAPT. However, the more cytotoxic VEFGR TKIs (IC50: 0.4-3.0 μM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor (AF) was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.
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Affiliation(s)
| | - Gilles Hanquet
- Laboratoire Syncat , UMR CNRS 7509 , ECPM , Université de Strasbourg , 25 rue Becquerel , 67087 Strasbourg , France
| | - Loïc Jeanmart
- Department of Chemistry and Namur Medicine & Drug Innovation Center (NAMEDIC) , University of Namur , 61 rue de Bruxelles , 5000 Namur , Belgium
| | - Steve Lanners
- Department of Chemistry and Namur Medicine & Drug Innovation Center (NAMEDIC) , University of Namur , 61 rue de Bruxelles , 5000 Namur , Belgium
| | - Peter Šramel
- Faculty of Natural Sciences , Comenius University , Ilkovičova 6, Mlynskádolina and 842 15 Bratislava (PŠ, AB) , Slovakia
- Biomagi Ltd. , Mamateyova 26 , 851 04 Bratislava , Slovakia
| | - Andrej Boháč
- Faculty of Natural Sciences , Comenius University , Ilkovičova 6, Mlynskádolina and 842 15 Bratislava (PŠ, AB) , Slovakia
- Biomagi Ltd. , Mamateyova 26 , 851 04 Bratislava , Slovakia
| | - Rengul Cetin-Atalay
- Cancer Systems Biology Laboratory , Graduate School of Informatics , ODTU , Ankara , 06800 , Turkey .
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27
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Taniguchi H, Moriya C, Igarashi H, Saitoh A, Yamamoto H, Adachi Y, Imai K. Cancer stem cells in human gastrointestinal cancer. Cancer Sci 2016; 107:1556-1562. [PMID: 27575869 PMCID: PMC5132287 DOI: 10.1111/cas.13069] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 08/24/2016] [Accepted: 08/27/2016] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are thought to be responsible for tumor initiation, drug and radiation resistance, invasive growth, metastasis, and tumor relapse, which are the main causes of cancer-related deaths. Gastrointestinal cancers are the most common malignancies and still the most frequent cause of cancer-related mortality worldwide. Because gastrointestinal CSCs are also thought to be resistant to conventional therapies, an effective and novel cancer treatment is imperative. The first reported CSCs in a gastrointestinal tumor were found in colorectal cancer in 2007. Subsequently, CSCs were reported in other gastrointestinal cancers, such as esophagus, stomach, liver, and pancreas. Specific phenotypes could be used to distinguish CSCs from non-CSCs. For example, gastrointestinal CSCs express unique surface markers, exist in a side-population fraction, show high aldehyde dehydrogenase-1 activity, form tumorspheres when cultured in non-adherent conditions, and demonstrate high tumorigenic potential in immunocompromised mice. The signal transduction pathways in gastrointestinal CSCs are similar to those involved in normal embryonic development. Moreover, CSCs are modified by the aberrant expression of several microRNAs. Thus, it is very difficult to target gastrointestinal CSCs. This review focuses on the current research on gastrointestinal CSCs and future strategies to abolish the gastrointestinal CSC phenotype.
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Affiliation(s)
- Hiroaki Taniguchi
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Chiharu Moriya
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Hisayoshi Igarashi
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Anri Saitoh
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Hiroyuki Yamamoto
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineSt. Marianna University School of MedicineKawasakiJapan
| | - Yasushi Adachi
- Department of Gastroenterology, Rheumatology, and Clinical ImmunologySapporo Medical University School of MedicineSapporoJapan
| | - Kohzoh Imai
- The Institute of Medical ScienceThe University of TokyoTokyoJapan
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28
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Zhao ZG, Wang DQ, Hu DF, Li YS, Liu SH. Decreased FOXF1 promotes hepatocellular carcinoma tumorigenesis, invasion, and stemness and is associated with poor clinical outcome. Onco Targets Ther 2016; 9:1743-52. [PMID: 27042124 PMCID: PMC4809324 DOI: 10.2147/ott.s95002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Forkhead box F1 (FOXF1), a member of the forkhead transcription factor superfamily, plays critical roles in the progression of certain types of cancers. However, the expression and function of FOXF1 in human hepatocellular carcinoma (HCC) are still unclear. Quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry detected the relatively lower expression status of FOXF1 in HCC cases. Soft agar and transwell assays clearly demonstrated that FOXF1-knockdown cells showed significantly increased in vitro cell tumorigenesis and invasion, and FOXF1-overexpressing cells had significantly reduced growth and invasion potential. Our study also examined the role of FOXF1 in HCC cell stemness by sphere formation, aldehyde dehydrogenase (ALDH1) activity, and CD44/133-positive cell analysis. Enforced FOXF1 expression decreased HCC cell stemness, and the downregulation of FOXF1 promoted cancer cell stemness. The in vivo study showed that overexpressed FOXF1 inhibits nude mouse tumorigenicity with downregulation of CD44 and proliferating cell nuclear antigen. More importantly, loss of FOXF1 expression was linked to poor overall survival time by Kaplan–Meier analysis.
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Affiliation(s)
- Zhen-Guo Zhao
- Department of Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China; Department of General Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, People's Republic of China
| | - De-Qiang Wang
- Tumor Treatment Center, The Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China
| | - De-Fei Hu
- Clinical Laboratory, The Second People's Hospital of Huai'an, Huai'an, People's Republic of China
| | - You-Sheng Li
- Department of Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Shuang-Hai Liu
- Department of General Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, People's Republic of China
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29
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Wang R, Chen S, Li C, Ng KTP, Kong CW, Cheng J, Cheng SH, Li RA, Lo CM, Man K, Sun D. Fusion with stem cell makes the hepatocellular carcinoma cells similar to liver tumor-initiating cells. BMC Cancer 2016; 16:56. [PMID: 26846780 PMCID: PMC4743091 DOI: 10.1186/s12885-016-2094-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 01/29/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cell fusion is a fast and highly efficient technique for cells to acquire new properties. The fusion of somatic cells with stem cells can reprogram somatic cells to a pluripotent state. Our research on the fusion of stem cells and cancer cells demonstrates that the fused cells can exhibit stemness and cancer cell-like characteristics. Thus, tumor-initiating cell-like cells are generated. METHODS We employed laser-induced single-cell fusion technique to fuse the hepatocellular carcinoma cells and human embryonic stem cells (hESC). Real-time RT-PCR, flow cytometry and in vivo tumorigenicity assay were adopted to identify the gene expression difference. RESULTS We successfully produced a fused cell line that coalesces the gene expression information of hepatocellular carcinoma cells and stem cells. Experimental results showed that the fused cells expressed cancer and stemness markers as well as exhibited increased resistance to drug treatment and enhanced tumorigenesis. CONCLUSIONS Fusion with stem cells transforms liver cancer cells into tumor initiating-like cells. Results indicate that fusion between cancer cell and stem cell may generate tumor initiating-like cells.
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Affiliation(s)
- Ran Wang
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China.
| | - Shuxun Chen
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China.
| | - Changxian Li
- Department of Surgery, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Kevin Tak Pan Ng
- Department of Surgery, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Chi-wing Kong
- Stem Cell and Regenerative Medicine Consortium, and Departments of Medicine and Physiology, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Jinping Cheng
- Environmental Science Program, School of Science, Hong Kong University of Science and Technology, Hong Kong, China.
| | - Shuk Han Cheng
- Department of Biomedical Science, City University of Hong Kong, Hong Kong, China.
| | - Ronald A Li
- Stem Cell and Regenerative Medicine Consortium, and Departments of Medicine and Physiology, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Chung Mau Lo
- Department of Surgery, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Kwan Man
- Department of Surgery, Li Ka-Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Dong Sun
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China.
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30
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Sukowati CHC, El-Khobar KE, Ie SI, Anfuso B, Muljono DH, Tiribelli C. Significance of hepatitis virus infection in the oncogenic initiation of hepatocellular carcinoma. World J Gastroenterol 2016; 22:1497-1512. [PMID: 26819517 PMCID: PMC4721983 DOI: 10.3748/wjg.v22.i4.1497] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/06/2015] [Accepted: 10/12/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, and DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Viral
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Viral
- Genotype
- Hepacivirus/genetics
- Hepacivirus/pathogenicity
- Hepatitis B virus/genetics
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Liver Neoplasms/epidemiology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/virology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/virology
- Oncogenes
- Risk Factors
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Marrone AK, Shpyleva S, Chappell G, Tryndyak V, Uehara T, Tsuchiya M, Beland FA, Rusyn I, Pogribny IP. Differentially expressed MicroRNAs provide mechanistic insight into fibrosis-associated liver carcinogenesis in mice. Mol Carcinog 2015; 55:808-17. [PMID: 25865624 DOI: 10.1002/mc.22323] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 03/16/2015] [Accepted: 03/16/2015] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, with a rising incidence worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected molecular alterations with mounting evidence indicating an important role of microRNAs (miRNAs) in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with liver cirrhosis. To study fibrosis-associated liver carcinogenesis, we used a mouse model designed to emulate the development of HCC in cirrhotic liver. Specifically, we were interested in evaluating the role of miRNAs in the molecular pathogenesis of liver carcinogenesis in male B6C3F1/J mice treated with N-nitrosodiethylamine (DEN) or carbon tetrachloride (CCl4 ) alone or a combination of DEN and CCl4 and characterized by a differential tumor incidence that increased in the following order: DEN<CCl4 <DEN+CCl4 . Treatment with DEN alone had negligible effect on hepatic miRNA expression. In contrast, treatment with either CCl4 alone or a combination of DEN and CCl4 resulted in major changes in miRNA expression. The analysis of miRNA profiles demonstrated an involvement of dysregulated miRNAs in major processes associated with the development of liver tumors, including inflammation, fibrosis, and stem cell activation. Importantly, the greatest incidence of liver tumors in mice treated with DEN+CCl4 was accompanied by a distinct over-expression of miRNAs suggesting that miRNA alterations may be responsible, at least in part, for the high tumor incidence.
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Affiliation(s)
- April K Marrone
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas
| | - Svitlana Shpyleva
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas
| | - Grace Chappell
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Volodymyr Tryndyak
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas
| | - Takeki Uehara
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Masato Tsuchiya
- First Department of Surgery, University of Yamanashi, Chuo, Japan
| | - Frederick A Beland
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas
| | - Ivan Rusyn
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Igor P Pogribny
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas
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