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1
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Valenti GE, Roveri A, Venerando R, Menichini P, Monti P, Tasso B, Traverso N, Domenicotti C, Marengo B. PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis. Antioxidants (Basel) 2023; 13:3. [PMID: 38275623 PMCID: PMC10812464 DOI: 10.3390/antiox13010003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 01/27/2024] Open
Abstract
Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1MET markedly reduced the expression of epithelial-mesenchymal transition proteins and limited the clonogenic potential and the cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.
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Affiliation(s)
- Giulia Elda Valenti
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Antonella Roveri
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy; (A.R.); (R.V.)
| | - Rina Venerando
- Department of Molecular Medicine, University of Padua, 35128 Padua, Italy; (A.R.); (R.V.)
| | - Paola Menichini
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.M.); (P.M.)
| | - Paola Monti
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.M.); (P.M.)
| | - Bruno Tasso
- Department of Pharmacy, University of Genoa, 16148 Genoa, Italy;
| | - Nicola Traverso
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Cinzia Domenicotti
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
| | - Barbara Marengo
- Department of Experimental Medicine, General Pathology Section, University of Genoa, 16132 Genoa, Italy; (G.E.V.); (N.T.); (B.M.)
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2
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Xu X, Zhou T, Wei X, Jiang X, Cao J. Application of mPEG-CS-cRGD/ Bmi-1RNAi-PTX nanoparticles in suppression of laryngeal cancer by targeting cancer stem cells. Drug Deliv 2023; 30:2180112. [PMID: 38095348 PMCID: PMC9946312 DOI: 10.1080/10717544.2023.2180112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/08/2023] [Indexed: 02/23/2023] Open
Abstract
Although surgery-based comprehensive therapy is becoming the main approach to treat laryngeal cancer, recurrence, metastasis, radiotherapy resistance and chemotherapy tolerance are still the main causes of death in patients. Targeted inhibition of laryngeal cancer stem cells has been considered as the consensus to cure laryngeal cancer. Our previous study has confirmed proto-oncogene Bmi-1 as a key regulator for self-renewal of laryngeal cancer stem cells. Targeted knockdown of Bmi-1 gene effectively inhibited the self-renewal and differentiation of laryngeal cancer stem cells, leading to the promoted sensitivity to chemotherapy including paclitaxel. However, due to off-target effects and quick degradation of the naked Bmi-1-RNAi small RNA oligo by nuclease in body fluids, it is urgently needed to develop a tumor-targeted delivery system with a protective shell. In this study, we designed and synthesized cRGD peptide-modified chitosan-polyethylene glycol slow-release nanoparticles (mPEG-CS-cRGD/Bmi-1RNAi-PTX) containing Bmi-1RNAi siRNA oligo and paclitaxel, which showed spherical in shape, 200 nm diameter in size, low cytotoxicity, strong DNA wrapping, resistance to nuclease degradation and high transfection efficiency to cells. Functional analysis indicated significant suppression of cell proliferation and migration and induction of apoptosis by the nanocomplex in laryngeal cancer cells in vitro. By application to the mouse model with laryngeal cancer, the nanocomplex inhibited tumor growth significantly in vivo. In addition, cRGD peptide, paclitaxel and Bmi-1 siRNA in the nanoparticles showed synergistic effects to suppress laryngeal cancer stem cells. In conclusion, this study not only developed a laryngeal tumor-targeted chemotherapeutic system, but also demonstrated a Bmi-1 RNAi-based chemotherapeutic strategy to inhibit cancer stem cells, having strong potential to treat laryngeal cancer patients suffering therapy resistance and/or tumor recurrence.
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Affiliation(s)
- Xiaoyan Xu
- Department of E.N.T, Gansu Provincial Hospital, Lanzhou, P.R. China
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, P.R. China
| | - Tianhao Zhou
- Department of E.N.T, Gansu Provincial Hospital, Lanzhou, P.R. China
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, P.R. China
| | - Xudong Wei
- Department of E.N.T, Gansu Provincial Hospital, Lanzhou, P.R. China
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, P.R. China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, P.R. China
| | - Xuelian Jiang
- Department of E.N.T, Gansu Provincial Hospital, Lanzhou, P.R. China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, P.R. China
| | - Jiyan Cao
- Department of E.N.T, Gansu Provincial Hospital, Lanzhou, P.R. China
- Department of Clinical Medicine, Ningxia Medical University, Yinchuan, P.R. China
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3
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Xu J, Li L, Shi P, Cui H, Yang L. The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies. Int J Mol Sci 2022; 23:ijms23158231. [PMID: 35897796 PMCID: PMC9367737 DOI: 10.3390/ijms23158231] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 12/01/2022] Open
Abstract
B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.
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Affiliation(s)
- Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Lin Li
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (H.C.); (L.Y.)
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (H.C.); (L.Y.)
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4
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Wang X, Wu T, Wang P, Yang L, Li Q, Wang J, Zhao R, Zhang J, Liu M, Cao J, Tian L, Yu B, Sun Y. Circular RNA 103862 Promotes Proliferation and Invasion of Laryngeal Squamous Cell Carcinoma Cells Through the miR-493-5p/GOLM1 Axis. Front Oncol 2020; 10:1064. [PMID: 32850310 PMCID: PMC7405723 DOI: 10.3389/fonc.2020.01064] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Accumulating evidence suggests that circular RNAs (circRNAs) may be a key contributor to oncogenesis. Yet, the function of circRNAs in laryngeal squamous cell carcinoma (LSCC) is still not clear. In this study, we examined the function of circRNA_103862 in LSCC progression by analyzing the tissue specimens collected from a patient with LSCC by using different LSCC cell models in vitro and an LSCC xenograft model in nude mice. We found that circRNA_103862 was frequently upregulated in the tissues of LSCC and was correlated with metastasis and prognosis of LSCC patients. Furthermore, circRNA_103862 downregulation could reduce proliferation, migration, and invasion ability of LSCC cells. In terms of mechanism exploration, miR-493-5p was sponged by circRNA_103862. Rescue experiments also showed that circRNA_103862 could achieve a carcinogenic effect by regulating miR-493-5p. Moreover, a luciferase reporter analysis showed that Golgi membrane protein 1 (GOLM1) is a downstream effector of miR-493-5p. In conclusion, our data suggested that circRNA_103862 promotes the proliferation of LSCC through targeting the miR-493-5p/GOLM1 axis, and it might serve as a potential prognosis marker and therapy target for LSCC.
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Affiliation(s)
- Xin Wang
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Tianyi Wu
- Department of Otorhinolaryngology, Head and Neck Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, China
| | - Peng Wang
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Like Yang
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Qiuying Li
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jingting Wang
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Rui Zhao
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jiarui Zhang
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Ming Liu
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jing Cao
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Linli Tian
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Boyu Yu
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yanan Sun
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
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5
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Duz MB, Karatas OF. Expression profile of stem cell markers and ABC transporters in 5-fluorouracil resistant Hep-2 cells. Mol Biol Rep 2020; 47:5431-5438. [PMID: 32627138 DOI: 10.1007/s11033-020-05633-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023]
Abstract
Resistance of laryngeal squamous cell carcinoma cells to traditional therapeutic regimens still remains to be a major reason for therapeutic failure in patients. In this study, we aimed at investigating the expression profiles of ATP-binding cassette (ABC) transporters and stem cell markers in 5-fluorouracil (5-FU) resistant laryngeal Hep-2 cells. We treated parental Hep-2 cells, with stepwise increased doses of 5-FU for almost 1 year to develop 5-FU resistant sub-lines with resistance against varying levels of 5-FU concentrations (4 sub-lines resistant to 1, 2, 4, and eightfold of 5-FU). Then, we measured the expression levels of 10 genes from ABC transporters family and 4 stem cell associated markers using quantitative reverse transcription polymerase chain reaction (qRT-PCR) to find out a potential relationship between these markers and chemoresistance. We found that stemness-associated markers had elevated expressions from the beginning of 5-FU resistance acquisition. Their expressions elevated stepwise while parental Hep-2 cells got resistance to higher doses of 5-FU. Expressions of tested ABC transporters (ABCA5, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC5, ABCC10 and ABCF2, and ABCG2) were also deregulated in 5-FU resistant Hep-2 cells. Although their expressions remained unaltered at the beginning of acquisition of resistance, expressions of ABC transporters except from ABCB6 increased significantly when cells became resistant to higher doses of 5-FU. Our results suggest that enrichment of cells with stemness characteristics and upregulation of ABC transporters might be amongst the crucial contributors of chemoresistance in laryngeal cancer cells.
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Affiliation(s)
- Mehmet Bugrahan Duz
- Department of Medical Genetics, Haseki Training and Research Hospital, Health Science University, Istanbul, Turkey
| | - Omer Faruk Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey. .,High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey.
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6
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Wuputra K, Ku CC, Wu DC, Lin YC, Saito S, Yokoyama KK. Prevention of tumor risk associated with the reprogramming of human pluripotent stem cells. J Exp Clin Cancer Res 2020; 39:100. [PMID: 32493501 PMCID: PMC7268627 DOI: 10.1186/s13046-020-01584-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Human pluripotent embryonic stem cells have two special features: self-renewal and pluripotency. It is important to understand the properties of pluripotent stem cells and reprogrammed stem cells. One of the major problems is the risk of reprogrammed stem cells developing into tumors. To understand the process of differentiation through which stem cells develop into cancer cells, investigators have attempted to identify the key factors that generate tumors in humans. The most effective method for the prevention of tumorigenesis is the exclusion of cancer cells during cell reprogramming. The risk of cancer formation is dependent on mutations of oncogenes and tumor suppressor genes during the conversion of stem cells to cancer cells and on the environmental effects of pluripotent stem cells. Dissecting the processes of epigenetic regulation and chromatin regulation may be helpful for achieving correct cell reprogramming without inducing tumor formation and for developing new drugs for cancer treatment. This review focuses on the risk of tumor formation by human pluripotent stem cells, and on the possible treatment options if it occurs. Potential new techniques that target epigenetic processes and chromatin regulation provide opportunities for human cancer modeling and clinical applications of regenerative medicine.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Ying-Chu Lin
- School of Dentistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shigeo Saito
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
- Saito Laboratory of Cell Technology Institute, Yaita, Tochigi, 329-1571, Japan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
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7
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Non-coding RNAs in drug resistance of head and neck cancers: A review. Biomed Pharmacother 2020; 127:110231. [PMID: 32428836 DOI: 10.1016/j.biopha.2020.110231] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC), which includes epithelial malignancies of the upper aerodigestive tract (oral cavity, oropharynx, pharynx, hypopharynx, larynx, and thyroid), are slowly but consistently increasing, while the overall survival rate remains unsatisfactory. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient's appearance and self-image, as well as their ability to breathe, speak, and swallow. Patients with HNC require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapeutics. Chemotherapy is an important part of the comprehensive treatment of tumors, especially advanced HNC, but drug resistance is the main cause of poor clinical efficacy. The most important determinant of this phenomenon is still largely unknown. Recent studies have shown that non-coding RNAs have a crucial role in HNC drug resistance. In addition, they can serve as biomarkers in the diagnosis, treatment, and prognosis of HNCs. In this review, we summarize the relationship between non-coding RNAs and drug resistance of HNC, and discuss their potential clinical application in overcoming HNC chemoresistance.
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Rizzo MI, Ralli M, Nicolazzo C, Gradilone A, Carletti R, Di Gioia C, De Vincentiis M, Greco A. Detection of circulating tumor cells in patients with laryngeal cancer using ScreenCell: Comparative pre- and post-operative analysis and association with prognosis. Oncol Lett 2020; 19:4183-4188. [PMID: 32391112 DOI: 10.3892/ol.2020.11528] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 02/20/2020] [Indexed: 12/20/2022] Open
Abstract
The presence of circulating tumor cells (CTCs) in the blood of patients with metastatic breast, colorectal and prostate cancer have been widely investigated; however, few studies have examined CTCs in patients with laryngeal cancer. The present pilot study aimed to detect pre- and postoperative CTCs in the blood of patients with laryngeal cancer and evaluate the association with prognosis. Eight patients with laryngeal squamous cell carcinoma (LSCC) at stage III were included in the present study and underwent total or subtotal laryngectomy and radical bilateral neck lymph node dissection. Blood samples were collected from all patients before and after surgery at different time-points. The following processing steps were followed; preoperative blood sampling, surgery, postoperative blood sampling at 3, 6 and 12 month follow-ups, and prognostic association analysis. CTCs were retained on ScreenCell filters for cytological characterization. The presence of CTCs was associated with a less favorable prognosis, whereas a decrease of CTCs in the postoperative sampling was observed in patients who exhibited an improved therapeutic response. The results of the present pilot study revealed a possible association between the presence of CTCs and a less favorable prognosis in patients with LSCC; therefore, these preliminary findings may encourage further research into the incorporation of a liquid biopsy in the management of LSCC, as this may help identify patients with occult metastatic disease earlier and in a non-invasive manner. In addition, this approach may represent novel independent prognostic factor for use in the clinical evaluation of patients with LSCC.
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Affiliation(s)
- Maria Ida Rizzo
- Department of Surgical Science, Sapienza University of Rome, Rome 00186, Italy.,Craniofacial Center, Plastic and Maxillofacial Surgery Unit, Bambino Gesù Children Hospital, Rome 00165, Italy
| | - Massimo Ralli
- Department of Sense Organs, Sapienza University of Rome, Rome 00186, Italy
| | - Chiara Nicolazzo
- Department of Molecular Medicine-Circulating Tumor Cells Unit, Sapienza University of Rome, Rome 00186, Italy
| | - Angela Gradilone
- Department of Molecular Medicine-Circulating Tumor Cells Unit, Sapienza University of Rome, Rome 00186, Italy
| | - Raffaella Carletti
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome 00186, Italy
| | - Cira Di Gioia
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome 00186, Italy
| | - Marco De Vincentiis
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome 00186, Italy
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, Rome 00186, Italy
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9
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Huang C, Li Y, Zhao W, Zhang A, Lu C, Wang Z, Liu L. α2δ1 may be a potential marker for cancer stem cell in laryngeal squamous cell carcinoma. Cancer Biomark 2019; 24:97-107. [PMID: 30475757 PMCID: PMC6398553 DOI: 10.3233/cbm-181947] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Cancer stem cells (CSCs) have the ability to dictate tumor initiation, recurrence, and metastasis. Here, we examined the expression of aα2δ1+ in laryngeal cancer tissues and further determined the effect of α2δ1 on the migratory ability and tumorigenicity of laryngeal cancer cells. Immunofluorescence staining revealed that α2δ1 was positive in 13 (13/16, 81.25%) cases in laryngeal squamous cell carcinoma (LSCC) tissues, 7 (7/16, 43.75%) cases in paracancerous tissues and only 2 (2/16, 12.5%) cases in normal tumor tissues. Our quantitative RT-PCR assays further showed that α2δ1+ LSCC cells expressed significantly higher levels of stem cell-associated genes and drug efflux and resistance genes versusα2δ1- cells. Sphere-forming assays demonstrated higher sphere-forming efficiency in the α2δ1+versusα2δ1- subpopulation. Our Matrigel assays showed that α2δ1+ cells exhibited significantly greater invasive and migratory ability than α2δ1- cells. Furthermore, the percentage of purified α2δ1+ in TU686 and TU212 cells treated cisplatin or paclitaxel was significantly higher than that of the control group. Tumor xenograft assays revealed that the tumorigenicity of α2δ1+ cells was much higher than α2δ1- cells. In conclusion, a α2δ1+ subpopulation with CSC-like property was present in laryngeal cancer and possessed high self-renewal activity and was sufficient for tumor growth, differentiation, migration, invasion, and chemotherapeutic resistance. They could represent a promising therapeutic target for LSCC.
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Affiliation(s)
- Chaoping Huang
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.,Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan, China.,Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yan Li
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.,Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Aobo Zhang
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Cheng Lu
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhenxiao Wang
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Liangfa Liu
- Department of Otolaryngology and Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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10
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Yuan Z, Xiu C, Song K, Pei R, Miao S, Mao X, Sun J, Jia S. Long non-coding RNA AFAP1-AS1/miR-320a/RBPJ axis regulates laryngeal carcinoma cell stemness and chemoresistance. J Cell Mol Med 2018; 22:4253-4262. [PMID: 29971915 PMCID: PMC6111816 DOI: 10.1111/jcmm.13707] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 04/17/2018] [Indexed: 01/04/2023] Open
Abstract
AFAP1-AS1 is a long non-coding RNA that is associated with tumorigenesis and poor prognosis in a variety of cancers. We have been suggested that AFAP1-AS1 increases tumorigenesis in laryngeal carcinoma specifically by enhancing stemness and chemoresistance. We assessed AFAP1-AS1 expression in human laryngeal specimens, paired adjacent normal tissues and human HEp-2 cells. Indeed, we found not only that AFAP1-AS1 was up-regulated in laryngeal carcinoma specimens and cells, but also that stemness-associated genes were overexpressed. Silencing of AFAP1-AS1 promoted HEp-2 cell chemoresistance under cisplatin treatment. Expression of AFAP1-AS1 was increased in drug-resistant Hep-2 cells. We then probed the mechanism of AFAP1-AS1 activity and determined that miR-320a was a potential molecular target of AFAP1-AS1. Luciferase reporter and qRT-PCR assays of AFAP1-AS1 and miR-320a levels in human specimens and cell cultures indicated that AFAP1-AS1 negatively regulates miR-320a. To discover the molecular mechanism of miR-320a, we again used the DIANA Tools algorithm to predict its genetic target, RBPJ. After cloning the 3'-untranslated regions (3'-UTR) of RBPJ into a luciferase reporter, we determined that miR-320a did in fact reduce RBPJ mRNA and protein levels. Ultimately, we determined that AFAP1-AS1 increases RBPJ expression by negatively regulating miR-320a and RBPJ overexpression rescues stemness and chemoresistance inhibited by AFAP1-AS1 silencing. Taken together, these results suggest that AFAP1-AS1 can serve as a prognostic biomarker in laryngeal carcinoma and that miR-320a has the potential to improve standard therapeutic approaches to the disease, especially for cases in which cancer cell stemness and drug resistance present significant barriers to effective treatment.
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Affiliation(s)
- Zhennan Yuan
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Cheng Xiu
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Kaibin Song
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Rong Pei
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Susheng Miao
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Xionghui Mao
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Ji Sun
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Shenshan Jia
- Department of Head and Neck SurgeryHarbin Medical University Cancer HospitalHarbinChina
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Karatas OF. Antiproliferative potential of miR-33a in laryngeal cancer Hep-2 cells via targeting PIM1. Head Neck 2018; 40:2455-2461. [PMID: 30102806 DOI: 10.1002/hed.25361] [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: 11/08/2017] [Revised: 03/21/2018] [Accepted: 05/17/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Laryngeal cancer is a frequent cause of cancer-associated mortality worldwide with an overall poor prognosis along with high mortality rates. Therefore, comprehensive investigation of underlying molecular mechanisms of laryngeal carcinogenesis remains an important problem. METHODS In this study, proliferative and apoptotic features of Hep-2 cells overexpressing microRNA-33a (miR-33a) were evaluated and in silico analysis along with literature search was used to find putative targets of miR-33a. The potential of PIM1 (pim-1 oncogene) as a direct target of miR-33a was tested using quantitative real-time polymerase chain reaction, Western blot, and luciferase assay. RESULTS Induced miR-33a expression significantly inhibited proliferation through inducing apoptosis of Hep-2 cells. Further in vitro tests showed downregulation of PIM1 in messenger ribonucleic acid (mRNA) and protein level upon miR-33a overexpression and confirmed PIM1 as a direct target of miR-33a. CONCLUSIONS Mir-33a was demonstrated to act as a tumor suppressor in larnygeal cancer via directly targeting the 3' untranslated region of PIM1.
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Affiliation(s)
- Omer Faruk Karatas
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey
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12
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Kolenda T, Przybyła W, Kapałczyńska M, Teresiak A, Zajączkowska M, Bliźniak R, Lamperska KM. Tumor microenvironment - Unknown niche with powerful therapeutic potential. Rep Pract Oncol Radiother 2018; 23:143-153. [PMID: 29760589 PMCID: PMC5948324 DOI: 10.1016/j.rpor.2018.01.004] [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: 03/20/2017] [Revised: 11/20/2017] [Accepted: 01/20/2018] [Indexed: 12/25/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) are in a group of cancers that are the most resistant to treatment. The survival rate of HNSCC patients has been still very low since last 20 years. The existence of relationship between oncogenic and surrounding cells is probably the reason for a poor response to treatment. Fibroblasts are an important element of tumor stroma which increases tumor cells ability to proliferate. Another highly resistance, tumorigenic and metastatic cell population in tumor microenvironment are cancer initiating cells (CICs). The population of cancer initiating cells can be found regardless of differentiation status of cancer and they seem to be crucial for HNSCC development. In this review, we describe the current state of knowledge about HNSCC biological and physiological tumor microenvironment.
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Affiliation(s)
- Tomasz Kolenda
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Weronika Przybyła
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
- Department of Pediatric Research, Division of Pediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Marta Kapałczyńska
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
- Department of Gastroenterology and Hepatology, Charite University Medicine Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Anna Teresiak
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
| | - Maria Zajączkowska
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Renata Bliźniak
- Laboratory of Cancer Genetic, Greater Poland Cancer Centre, Poznan, Poland
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13
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Miranda A, Blanco-Prieto MJ, Sousa J, Pais A, Vitorino C. Breaching barriers in glioblastoma. Part II: Targeted drug delivery and lipid nanoparticles. Int J Pharm 2017; 531:389-410. [DOI: 10.1016/j.ijpharm.2017.07.049] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 07/13/2017] [Accepted: 07/15/2017] [Indexed: 02/07/2023]
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14
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Zhang Y, Hu H. Long non-coding RNA CCAT1/miR-218/ZFX axis modulates the progression of laryngeal squamous cell cancer. Tumour Biol 2017. [PMID: 28631575 DOI: 10.1177/1010428317699417] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Long non-coding RNAs have been proved to be closely associated with different cancers. This study was designed to elucidate the function and mechanisms of colon cancer-associated transcript-1 in the progression of human laryngeal squamous cell cancer. Expressions of colon cancer-associated transcript-1, microRNA-218, and zinc finger protein, X-linked messenger RNA were measured using quantitative real-time polymerase chain reaction, and the expression level of zinc finger protein, X-linked protein was detected using western blot. Proliferation and invasion of laryngeal squamous cell cancer cell lines were detected by Cell Counting Kit-8 assay and Transwell invasion assay, respectively. Luciferase assay was used to confirm whether microRNA-218 is a target of colon cancer-associated transcript-1 and whether microRNA-218 directly binds to 3'-untranslated region of zinc finger protein, X-linked messenger RNA. Effect of colon cancer-associated transcript-1 on tumor growth was observed through xenograft mice models in vivo. The results showed that expressions of colon cancer-associated transcript-1 and zinc finger protein, X-linked were significantly higher while microRNA-218 expression was significantly lower in the laryngeal squamous cell cancer tissues than those in the adjacent normal tissues. MicroRNA-218 overexpression or zinc finger protein, X-linked silencing significantly suppressed proliferation and invasion of laryngeal squamous cell cancer cells. Moreover, knockdown of colon cancer-associated transcript-1 significantly inhibited proliferation and invasion of laryngeal squamous cell cancer cells, which were reversed by microRNA-218 downregulation or zinc finger protein, X-linked upregulation. Finally, colon cancer-associated transcript-1 silencing inhibited xenograft tumor growth of laryngeal squamous cell cancer in vivo. In conclusion, colon cancer-associated transcript-1 knockdown inhibits proliferation and invasion of laryngeal squamous cell cancer cells through enhancing zinc finger protein, X-linked by sponging microRNA-218, elucidating a novel colon cancer-associated transcript-1-microRNA-218-zinc finger protein, X-linked regulatory axis in laryngeal squamous cell cancer and providing a promising therapeutic target for laryngeal squamous cell cancer patients.
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Affiliation(s)
- Yaming Zhang
- Department of Otolaryngology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Haili Hu
- Department of Otolaryngology, Huaihe Hospital of Henan University, Kaifeng, China
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15
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Peng HX, Liu XD, Luo ZY, Zhang XH, Luo XQ, Chen X, Jiang H, Xu L. Upregulation of the proto-oncogene Bmi-1 predicts a poor prognosis in pediatric acute lymphoblastic leukemia. BMC Cancer 2017; 17:76. [PMID: 28122538 PMCID: PMC5264321 DOI: 10.1186/s12885-017-3049-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 01/09/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Bmi-1, the B cell-specific moloney murine leukemia virus insertion site 1, is a member of the Polycomb-group (PcG) family and acts as an oncogene in various tumors; however, its expression related to the prognosis of pediatric patients with acute lymphoblastic leukemia (ALL) has not been well studied. METHODS The Bmi-1 expression levels in the bone marrow of 104 pediatric ALL patients and 18 normal control subjects were determined by using qRT-PCR. The association between the Bmi-1 expression and the clinicopathological characteristics of pediatric ALL patients was analyzed, and the correlation between Bmi-1 and the prognosis of pediatric ALL was calculated according to the Kaplan-Meier method. Furthermore, the association between Bmi-1 expression and its transcriptional regulator Sall4 was investigated. RESULTS Compared to normal control subjects, patients with primary pediatric ALL exhibited upregulated levels of Bmi-1. However, these levels were sharply decreased in patients who achieved complete remission. A significant positive association between elevated Bmi-1 levels and a poor response to prednisone as well as an increased clinical risk was observed. Patients who overexpressed Bmi-1 at the time of diagnosis had a lower relapse-free survival (RFS) rate (75.8%), whereas patients with lower Bmi-1 expression had an RFS of 94.1%. Furthermore, in ALL patients, the mRNA expression of Bmi-1 was positively correlated to the mRNA expression of Sall4a. CONCLUSIONS Taken together, these data suggest that Bmi-1 could serve as a novel prognostic biomarker in pediatric primary ALL and may be partially regulated by Sall4a. Our study also showed that Bmi-1 could serve as a new therapeutic target for the treatment of pediatric ALL.
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Affiliation(s)
- Hong-Xia Peng
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong, 510623, China
| | - Xiao-Dan Liu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Zi-Yan Luo
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong, 510623, China
| | - Xiao-Hong Zhang
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong, 510623, China
| | - Xue-Qun Luo
- Department of Pediatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiao Chen
- Department of Pediatrics, Zhuzhou Central Hospital, Zhuzhou, China
| | - Hua Jiang
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong, 510623, China.
| | - Ling Xu
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong, 510623, China.
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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