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Wu Y, Diao P, Peng Y, Yang Y, Wang Y, Lv P, Li J, Wang D, Cai T, Cheng J. A Hybrid Manganese Nanoparticle Simultaneously Eliminates Cancer Stem Cells and Activates STING Pathway to Potentiate Cancer Immunotherapy. ACS NANO 2025; 19:12237-12252. [PMID: 40116158 DOI: 10.1021/acsnano.5c00322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Current immunotherapies such as immune checkpoint blockades (ICBs) have revolutionized oncotherapy regime; however, their responsiveness and efficiencies among patients with head and neck squamous cell carcinoma (HNSCC) remain quite limited. The existence of therapeutic-refractory cancer stem cells (CSCs) and inadequate activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway greatly contribute to immune evasion and immunotherapeutic resistance. Herein, we sought to develop a nanocomplex for HNSCC therapy by simultaneous CSCs eradication and STING activation. PTC209/MnO2@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized via a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response. Meanwhile, PTC209 released from PMB NPs targets BMI1+ CSCs to suppress cancer stemness and epithelial-mesenchymal transition (EMT) and elicits apoptosis to further potentiate Mn-based metalloimmunotherapy. Both in vitro and in vivo experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation via metalloimmunotherapy.
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Affiliation(s)
- Yaping Wu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Pengfei Diao
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Yayun Peng
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics and Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yuhan Yang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics and Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yuhan Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Pin Lv
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jin Li
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Ting Cai
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics and Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, P. R. China
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Ibrahim JN, El-Hakim S, Semaan J, Ghosn S, El Ayoubi H, Elnar AA, Tohme N, El Boustany C. Sodium Butyrate (NaB) and Sodium Propionate (NaP) Reduce Cyclin A2 Expression, Inducing Cell Cycle Arrest and Proliferation Inhibition of Different Breast Cancer Subtypes, Leading to Apoptosis. Biomedicines 2024; 12:1779. [PMID: 39200243 PMCID: PMC11351769 DOI: 10.3390/biomedicines12081779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 07/27/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Sodium butyrate (NaB) and sodium propionate (NaP) have recently garnered attention for their role in regulating inflammation and controlling signaling pathways of cell growth and apoptosis, potentially preventing cancer development. However, their therapeutic effect and the underlying mechanisms involved remain elusive in breast cancer. This study aims at investigating the anticancer role of NaB and NaP in different types of breast cancer by assessing their antiproliferative effect on MCF-7 and MDA-MB-231 cells (through an MTT assay), as well as their ability to alter the cell cycle and cyclin expression (using flow cytometry and RT-qPCR, respectively), and to promote apoptosis (using Annexin V-FITC conjugated and sub-G1 phase techniques). MDA-MB-231 cell proliferation was inhibited by NaB and NaP in a dose- and time-dependent manner with respective IC50 values of 2.56 mM and 6.49 mM. Treatment induced cell arrest in the G1 phase which was further supported by the significant reduction in cyclin A2 and cyclin B1 expressions. Finally, NaB, and less significantly NaP, induced apoptosis in a dose-dependent manner with higher concentrations required for MDA-MB-231 than MCF-7. Our findings elucidate the cyclin-dependent inhibitory effect of NaB and NaP on the progression of different breast cancer subtypes, thus highlighting their therapeutic potential in breast cancer.
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Affiliation(s)
- José-Noel Ibrahim
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut 1102, Lebanon
| | - Sandy El-Hakim
- College of Engineering and Technology, American University of the Middle East, Egaila 54200, Kuwait;
| | - Josiane Semaan
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
| | - Stéphanie Ghosn
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
| | - Hiba El Ayoubi
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
| | - Arpiné Ardzivian Elnar
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
| | - Najat Tohme
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
| | - Charbel El Boustany
- Department of Laboratory Science, Faculty of Public Health—Branch 2, Lebanese University, Fanar 2611, Lebanon; (J.S.); (S.G.); (H.E.A.); (A.A.E.); (N.T.); (C.E.B.)
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Lv T, Liu H, Mao L, Song Y, Liao L, Zhong K, Shuai B, Luo Y, Guo T, Huang W, Zhang S. Cancer-associated fibroblast-derived extracellular vesicles promote lymph node metastases in oral cavity squamous cell carcinoma by encapsulating ITGB1 and BMI1. BMC Cancer 2024; 24:113. [PMID: 38254031 PMCID: PMC10804601 DOI: 10.1186/s12885-024-11855-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) have been revealed to facilitate the development of oral squamous cavity cell carcinoma (OCSCC), while its supporting role in lymph node metastases is under continuous investigation. This study aimed to examine the function of cancer-associated fibroblasts (CAF)-derived EVs (CAF-EVs) during lymph node metastasis in OCSCC and the mechanisms. METHODS CAF were isolated from OCSCC tissues of patients, and CAF-EVs were extracted and identified. EdU, colony formation, wound healing, and Transwell assays were performed. The OCSCC cells before and after CAF-EVs treatment were injected into mice to probe the effects of CAF-EVs on tumor growth and lymph node metastasis, respectively. The effect of CAF-EVs treatment on transcriptome changes in OCSCC cells was analyzed. Clinical data of patients with OCSCC were analyzed to determine the prognostic significance of the selected genes. Finally, loss-of-function assays were conducted to corroborate the involvement of polycomb complex protein BMI-1 (BMI1) and integrin beta1 (ITGB1). RESULTS CAF-EVs promoted the malignant behavior of OCSCC cells and accelerated tumor growth and lymph node metastasis in mice. CAF-EVs significantly increased the expression of BMI1 and ITGB1, and the expression of BMI1 and ITGB1 was negatively correlated with the overall survival and relapse-free survival of OCSCC patients. Knockdown of BMI1 or ITGB1 in OCSCC cells abated the promoting effects of CAF-EVs in vitro and in vivo. CONCLUSION CAF-EVs elicited the metastasis-promoting properties in OCSCC by elevating BMI1 and ITGB1, suggesting that BMI1 and ITGB1 could be potential biomarkers and therapeutic targets for OCSCC.
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Affiliation(s)
- Tianzhu Lv
- Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
- China-British Joint Molecular Head and Neck Cancer Research Laboratory, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Hongjing Liu
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Ling Mao
- Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
- China-British Joint Molecular Head and Neck Cancer Research Laboratory, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Yanrong Song
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Lili Liao
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Kun Zhong
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Binbin Shuai
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Yingkun Luo
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Tingting Guo
- Comprehensive Emergency Department of Stomatology, Stomatological Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, P.R. China
| | - Wentao Huang
- School of Savaid Stomatology, Hangzhou Medical College, 311399, Hangzhou, Zhejiang, P.R. China.
| | - Shenyingjie Zhang
- Medical Department, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 310006, Hangzhou, Zhejiang, P.R. China
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Ma N, Zhao S, Yang W, Wang Y. B-cell-specific Moloney murine leukemia virus integration site 1 knockdown impairs adriamycin resistance of gastric cancer cells. Arab J Gastroenterol 2023; 24:168-174. [PMID: 36878814 DOI: 10.1016/j.ajg.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 01/13/2023] [Accepted: 02/23/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND AND STUDY AIMS The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is associated with the progression of gastric cancer (GC). However, its role in drug resistance of gastric cancer stem cell (GCSC) remains unclear. This study aimed to explore the biological function of BMI-1 in GC cells and its role in drug resistance of GCSCs. PATIENTS AND METHODS We assessed BMI-1 expression in the GEPIA database and in our collected samples from patients with GC. We silenced BMI-1 using siRNA to study the cell proliferation and migration of GC cells. We also used Hoechst 33342 staining to verify the effect of adriamycin (ADR) on side population (SP) cells, and measured the effects of BMI-1 on the expression of N-cadherin, E-cadherin, and drug-resistance-related proteins (multidrug resistance mutation 1 and lung resistance-related protein). Finally, we analyzed BMI-1-related proteins uing the STRING and GEPIA databases. RESULTS BMI-1 mRNA was upregulated in GC tissues and cell lines, especially in MKN-45 and HGC-27 cells. Silencing BMI-1 reduced the proliferation and migration of GC cells. Knocking down BMI-1 significantly decreased epithelial-mesenchymal transition progression, expression levels of drug-resistant proteins, and the number of SP cells in ADR-treated GC cells. Bioinformatics analysis showed that EZH2, CBX8, CBX4, and SUZ12 were positively correlated with BMI-1 in GC tissues. CONCLUSION Our study demonstrates that BMI-1 affects the cellular activity, proliferation, migration, and invasion of GC cells. Silencing the BMI-1 gene significantly reduces the number of SP cells and the expression of drug-resistant proteins in ADR-treated GC cells. We speculate that inhibition of BMI-1 increases the drug resistance of GC cells by affecting GCSCs, and that EZH2, CBX8, CBX4, and SUZ12 may participate in BMI-1-induced enhancement of GCSC-like phenotype and viability.
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Affiliation(s)
- Ning Ma
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China.
| | - Sihui Zhao
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Wei Yang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Yongfang Wang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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Afshari K, Sohal KS. Potential Alternative Therapeutic Modalities for Management Head and Neck Squamous Cell Carcinoma: A Review. Cancer Control 2023; 30:10732748231185003. [PMID: 37328298 DOI: 10.1177/10732748231185003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) includes malignancies of the lip and oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. It is among the most common malignancy worldwide, affecting nearly 1 million people annually. The traditional treatment options for HNSCC include surgery, radiotherapy, and conventional chemotherapy. However, these treatment options have their specific sequelae, which produce high rates of recurrence and severe treatment-related disabilities. Recent technological advancements have led to tremendous progress in understanding tumor biology, and hence the emergence of several alternative therapeutic modalities for managing cancers (including HNSCC). These treatment options are stem cell targeted therapy, gene therapy, and immunotherapy. Therefore, this review article aims to provide an overview of these alternative treatments of HNSCC.
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Affiliation(s)
- Keihan Afshari
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Karpal Singh Sohal
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
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Li Z, Wu X, Li J, Yu S, Ke X, Yan T, Zhu Y, Cheng J, Yang J. HMGA2-Snai2 axis regulates tumorigenicity and stemness of head and neck squamous cell carcinoma. Exp Cell Res 2022; 418:113271. [PMID: 35764101 DOI: 10.1016/j.yexcr.2022.113271] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 11/04/2022]
Abstract
Cancer stem cells (CSCs) are a tumorigenic cell subpopulation, which contributes to treatment resistance, tumor recurrence, and metastasis. This study aimed to investigate the role and underlying molecular targets of high mobility group AT-hook 2 (HMGA2) in the progression and CSCs regulation of head and neck squamous cell carcinoma (HNSCC). HMGA2 mRNA and protein expression levels were examined in HNSCC specimens and cells by qRT-PCR, Western blot, and immunohistochemistry. The roles of HMGA2 were validated via loss-of-function and exogenous overexpression experiments in vitro and in vivo, and CSCs properties were assessed by tumorsphere formation assay. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays provided further insight into the molecular mechanisms by which HMGA2 regulates stemness. HMGA2 was abnormally overexpressed in HNSCC, and it promoted the expression of the CSCs markers including SOX2, CD133, CD44, ALDH1A1, and Bmi1. HMGA2 was correlated with stemness, malignant progression, and reduced survival in HNSCC. Luciferase reporter assay indicated that Snai2 was a direct downstream target gene of HMGA2. Mechanistically, ChIP-qPCR assay showed that HMGA2 was recruited to three binding sites on the Snai2 promoter, directly facilitating the transcription of Snai2 in HNSCC. Snai2 overexpression reversed the inhibitory effect of HMGA2 interference on the proliferation, invasion, and metastasis of HNSCC and CSC marker expression in vitro and in vivo. HMGA2 promoted the malignant progression of HNSCC and acquired CSCs properties through direct regulation of Snai2, thereby suggesting that targeting the HMGA2-Snai2 axis might be a promising therapeutic strategy for HNSCC.
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Affiliation(s)
- Zhongwu Li
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Xiang Wu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Jin Li
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Shijin Yu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Xueping Ke
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Tingyuan Yan
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Yumin Zhu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.
| | - Jianrong Yang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.
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Lima de Oliveira J, Moré Milan T, Longo Bighetti‐Trevisan R, Fernandes RR, Leopoldino AM, Almeida LO. Epithelial‐mesenchymal transition and cancer stem cells: a route to acquired cisplatin resistance through epigenetics in HNSCC. Oral Dis 2022. [DOI: 10.1111/odi.14209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/02/2022] [Accepted: 04/06/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Julia Lima de Oliveira
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Thaís Moré Milan
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Rayana Longo Bighetti‐Trevisan
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Roger Rodrigo Fernandes
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Andréia Machado Leopoldino
- Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Luciana Oliveira Almeida
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
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Yuksel B, Deveci Ozkan A, Aydın D, Betts Z. Evaluation of the antioxidative and genotoxic effects of sodium butyrate on breast cancer cells. Saudi J Biol Sci 2022; 29:1394-1401. [PMID: 35280546 PMCID: PMC8913555 DOI: 10.1016/j.sjbs.2021.12.061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/23/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Oncogenic stimulation shows a rise in reactive oxygen species (ROS), and ROS can eventually induce carcinogenesis by causing DNA damage. In this context, this study aims to evaluate some biochemical and genotoxic changes in the control of cell death caused by NaBu (Sodium butyrate). treatment in breast cancer cells. NaBu’s impact on cell proliferation was determined via WST-1 assay. The lipid peroxidation (MDA), reduced glutathione (GSH), Nitric Oxide (NO), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) enzyme levels were determined biochemically. NaBu-induced genotoxic damage was estimated via single-cell gel electrophoresis (SCGE). NaBu reduced cell viability and potentially induced GSH, but decreased SOD enzyme activity and the level of MDA and NO decreased also H2O2 decreased at different times and NaBu concentrations. Higher NaBu concentrations amplified DNA damage in MCF-7 cells compared to the control group. NaBu shows anticancer and genotoxic effects, especially through antioxidant enzymes, one of the oxidative stress parameters in breast cancer. However, the anticancer and genotoxic effects of NaBu is changed in the oxidative stress parameters with time and treatment concentration of NaBu in MCF-7 cells. Furthermore, his oxidative stress-dependent effect changes need to be clarified by further evaluation with molecular and more biochemical parameters.
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Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B, BMI-1, and CD44 in Different Tissues of HNSCC Patients. ACTA ACUST UNITED AC 2021; 28:2763-2774. [PMID: 34287293 PMCID: PMC8293237 DOI: 10.3390/curroncol28040241] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/03/2021] [Accepted: 07/11/2021] [Indexed: 12/31/2022]
Abstract
Cancer stem cells (CSCs) are accountable for the progress of head and neck squamous cell carcinoma (HNSCC). This exploratory study evaluated the expression of molecular CSC markers in different tissues of HNSCC patients. Tissue specimens of primary tumor, lymph node metastases and macroscopically healthy mucosa of 12 consecutive HNSCC patients, that were treated with surgery and adjuvant radio(chemo)therapy upon indication, were collected. Samples were assessed for the expression of p16 as a surrogate for HPV-related disease and different molecular stem cell markers (ALDH1A1, BCL11B, BMI-1, and CD44). In the cohort, seven patients had HPV-related HNSCC; six thereof were oropharyngeal squamous cell carcinoma. While expression of BMI-1 and BCL11B was significantly lower in healthy mucosa than both tumor and lymph node metastasis, there were no differences between tumor and lymph node metastasis. In the HPV-positive sub-cohort, these differences remained significant for BMI-1. However, no significant differences in these three tissues were found for ALDH1A1 and CD44. In conclusion, this exploratory study shows that CSC markers BMI-1 and BCL11B discriminate between healthy and cancerous tissue, whereas ALDH1A1 and CD44 were expressed to a comparable extent in healthy mucosa and cancerous tissues.
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Hsieh PL, Huang CC, Yu CC. Emerging Role of MicroRNA-200 Family in Dentistry. Noncoding RNA 2021; 7:35. [PMID: 34208375 PMCID: PMC8293310 DOI: 10.3390/ncrna7020035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/30/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs ~22 nucleotides in length, which have been shown to participate in various biological processes. As one of the most researched miRNAs, the miR-200 family has been found to regulate several factors that are associated with the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs) behavior. In this review, we briefly summarize the background of the miR-200 family and their implication in various dental diseases. We focus on the expression changes, biological functions, and clinical significance of the miR-200 family in oral cancer; periodontitis; oral potentially malignant disorder; gingival overgrowth; and other periodontal diseases. Additionally, we discuss the use of the miR-200 family as molecular biomarkers for diagnosis, prognostic, and therapeutic application.
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Affiliation(s)
- Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung 404333, Taiwan;
| | - Chun-Chung Huang
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
| | - Cheng-Chia Yu
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan
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12
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Podocalyxin in Normal Tissue and Epithelial Cancer. Cancers (Basel) 2021; 13:cancers13122863. [PMID: 34201212 PMCID: PMC8227556 DOI: 10.3390/cancers13122863] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/13/2022] Open
Abstract
Podocalyxin (PODXL), a glycosylated cell surface sialomucin of the CD34 family, is normally expressed in kidney podocytes, vascular endothelial cells, hematopoietic progenitors, mesothelium, as well as a subset of neurons. In the kidney, PODXL functions primarily as an antiadhesive molecule in podocyte epithelial cells, regulating adhesion and cell morphology, and playing an essential role in the development and function of the organ. Outside the kidney, PODXL plays subtle roles in tissue remodelling and development. Furthermore, many cancers, especially those that originated from the epithelium, have been reported to overexpress PODXL. Collective evidence suggests that PODXL overexpression is linked to poor prognosis, more aggressive tumour progression, unfavourable treatment outcomes, and possibly chemoresistance. This review summarises our current knowledge of PODXL in normal tissue function and epithelial cancer, with a particular focus on its underlying roles in cancer metastasis, likely involvement in chemoresistance, and potential use as a diagnostic and prognostic biomarker.
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13
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Balakrishnan I, Danis E, Pierce A, Madhavan K, Wang D, Dahl N, Sanford B, Birks DK, Davidson N, Metselaar DS, Meel MH, Lemma R, Donson A, Vijmasi T, Katagi H, Sola I, Fosmire S, Alimova I, Steiner J, Gilani A, Hulleman E, Serkova NJ, Hashizume R, Hawkins C, Carcaboso AM, Gupta N, Monje M, Jabado N, Jones K, Foreman N, Green A, Vibhakar R, Venkataraman S. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG. Cell Rep 2020; 33:108286. [PMID: 33086074 PMCID: PMC7574900 DOI: 10.1016/j.celrep.2020.108286] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 07/05/2020] [Accepted: 09/25/2020] [Indexed: 01/19/2023] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
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Affiliation(s)
- Ilango Balakrishnan
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Etienne Danis
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Angela Pierce
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Krishna Madhavan
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Dong Wang
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Nathan Dahl
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Bridget Sanford
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Diane K Birks
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Nate Davidson
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Dennis S Metselaar
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Michaël Hananja Meel
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Rakeb Lemma
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew Donson
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Trinka Vijmasi
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Hiroaki Katagi
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ismail Sola
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Susan Fosmire
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Irina Alimova
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Jenna Steiner
- Departments of Radiology, Radiation Oncology, and Anesthesiology, Colorado Animal Imaging Shared Resource (AISR), University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ahmed Gilani
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Esther Hulleman
- Princess Máxima Center for Pediatric Oncology, Utrecht and Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Natalie J Serkova
- Departments of Radiology, Radiation Oncology, and Anesthesiology, Colorado Animal Imaging Shared Resource (AISR), University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rintaro Hashizume
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Cynthia Hawkins
- Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Angel M Carcaboso
- Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain
| | - Nalin Gupta
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Michelle Monje
- Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Kenneth Jones
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Nicholas Foreman
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Adam Green
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA
| | - Rajeev Vibhakar
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
| | - Sujatha Venkataraman
- Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
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14
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Jiang X, Huang Y. Curcumin Derivative C086 Combined with Cisplatin Inhibits Proliferation of Osteosarcoma Cells. Med Sci Monit 2020; 26:e924507. [PMID: 32734935 PMCID: PMC7414526 DOI: 10.12659/msm.924507] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Curcumin derivative C086 (cur C086) is a potential chemotherapeutic agent for patients with osteosarcoma. In this study, the effects of cur C086 combined with cisplatin on the biological processes of osteosarcoma cells were investigated. Material/Methods In this study, expression of BMIL1 was detected by real-time quantitative reverse transcription polymerase chain reaction and Western blotting in MG-63 cells treated with cur C086+cisplatin. Functions of cur C086+cisplatin on proliferation ability, apoptosis response, and metastatic potential of MG-63 cells were determined by MTT, flow cytometry, Hoechst 33258 staining and Transwell assays, respectively. In additionally, expression of P16, E-cadherin, epidermal growth factor (EGFR), and Notch1 was measured by Western blotting. Results Expression of BMIL1 decreased significantly in MG-63 cells treated with cur C086 (20 μM)+cisplatin (1.28 nM). Treatment with cur C086+cisplatin considerably inhibited growth, migration, and invasion potential in MG-63 cells, whereas apoptosis was obviously upregulated. Moreover, cur C086+cisplatin suppressed BMIL1 expression or its potential downstream targets, P16, E-cadherin, EGFR, and Notch1. Conclusions The current results demonstrate that combined treatment with cur C086+cisplatin may be an effective form of chemotherapy for patients with osteosarcoma.
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Affiliation(s)
- Xi Jiang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing, China (mainland)
| | - Yulin Huang
- Department of Clinical Laboratory, The Traditional Chinese Medicine Hospital of Wuxi, Chongqing, China (mainland)
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15
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Jakob M, Sharaf K, Schirmer M, Leu M, Küffer S, Bertlich M, Ihler F, Haubner F, Canis M, Kitz J. Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC. Strahlenther Onkol 2020; 197:231-245. [PMID: 32588101 PMCID: PMC7892527 DOI: 10.1007/s00066-020-01653-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022]
Abstract
Purpose Cancer stem cells (CSCs) are held accountable for the progress of head and neck squamous cell carcinoma (HNSCC). In the presented study, the authors evaluated the prognostic value of CSC markers in two particular HNSCC cohorts. Methods This two cohort study consisted of 85 patients with advanced stage HNSCC, treated with primary radio(chemo)therapy (pRCT), and 95 patients with HNSCC, treated with surgery and partially adjuvant radio(chemo)therapy. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were assessed. Samples were assessed for the expression of different molecular stem cell markers (ALDH1, BCL11B, BMI‑1, and CD44). Results In the pRCT cohort, none of the baseline patient and tumor features exhibited a statistically significant relation with survival in either the cohort or the human papillomavirus (HPV)-stratified subcohorts. High expression of BMI‑1 significantly decreased OS and DFS, while high expression of CD44 decreased all modes of survival. Multivariate analysis showed significant prognostic influence for all tested CSC markers, with high BMI‑1 and CD44 decreasing survival (BMI-1: OS, DFS, DSS; CD44: OS, DFS) and high ALDH1 and BCL11B showing a beneficial effect on survival (ALDH1: OS, DFS; BCL11B: OS, DSS). In the surgical cohort, classical prognosticators such as HPV status, R1 resection, and nodal status in HPV-negative HNSCC played a significant role, but the tested CSC markers showed no significant effect on prognosis. Conclusion Although validation in independent cohorts is still needed, testing for CSC markers in patients with advanced or late stage HNSCC might be beneficial, especially if many comorbidities exist or disease is irresectable. The findings might guide the development and earlier use of targeted therapies in the future. Electronic supplementary material The online version of this article (10.1007/s00066-020-01653-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mark Jakob
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany. .,Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.
| | - Kariem Sharaf
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.
| | - Markus Schirmer
- Department of Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Martin Leu
- Department of Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Stefan Küffer
- Department of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Mattis Bertlich
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Friedrich Ihler
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.,German Center of Vertigo and Dizziness, University Hospital, LMU Munich, Munich, Germany
| | - Frank Haubner
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Martin Canis
- Department of Otolaryngology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Julia Kitz
- Department of Pathology, University Medical Center Göttingen, Göttingen, Germany
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16
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Gaździcka J, Gołąbek K, Strzelczyk JK, Ostrowska Z. Epigenetic Modifications in Head and Neck Cancer. Biochem Genet 2019; 58:213-244. [PMID: 31712935 PMCID: PMC7113219 DOI: 10.1007/s10528-019-09941-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/24/2019] [Indexed: 12/17/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common human malignancy in the world, with high mortality and poor prognosis for patients. Among the risk factors are tobacco and alcohol intake, human papilloma virus, and also genetic and epigenetic modifications. Many studies show that epigenetic events play an important role in HNSCC development and progression, including DNA methylation, chromatin remodeling, histone posttranslational covalent modifications, and effects of non-coding RNA. Epigenetic modifications may influence silencing of tumor suppressor genes by promoter hypermethylation, regulate transcription by microRNAs and changes in chromatin structure, or induce genome instability through hypomethylation. Moreover, getting to better understand aberrant patterns of methylation may provide biomarkers for early detection and diagnosis, while knowledge about target genes of microRNAs may improve the therapy of HNSCC and extend overall survival. The aim of this review is to present recent studies which demonstrate the role of epigenetic regulation in the development of HNSCC.
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Affiliation(s)
- Jadwiga Gaździcka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Jordana 19 Str., 41-808, Zabrze, Katowice, Poland.
| | - Karolina Gołąbek
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Jordana 19 Str., 41-808, Zabrze, Katowice, Poland
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Jordana 19 Str., 41-808, Zabrze, Katowice, Poland
| | - Zofia Ostrowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Jordana 19 Str., 41-808, Zabrze, Katowice, Poland
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17
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Cancer Stem Cells and Oral Carcinogenesis; a Review Article. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2019. [DOI: 10.5812/ijcm.96139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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18
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Li J, Li Z, Wu Y, Wang Y, Wang D, Zhang W, Yuan H, Ye J, Song X, Yang J, Jiang H, Cheng J. The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma. Cell Death Dis 2019; 10:603. [PMID: 31399556 PMCID: PMC6689034 DOI: 10.1038/s41419-019-1838-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/23/2019] [Accepted: 07/26/2019] [Indexed: 01/06/2023]
Abstract
The Hippo-TAZ signaling has emerged as a fundamental regulator underlying cancer stem cells (CSCs) stemness which intricately associates with local recurrence and metastatic spreading in head neck squamous cell carcinoma (HNSCC). However, the precise downstream targets of TAZ responsible for HNSCC CSCs maintenance remain largely underexplored. Here, we identified Sex determining region Y box 2 (SOX2) as a putative downstream target of TAZ to promote CSCs maintenance and tumorigenicity in HNSCC. Both TAZ and SOX2 were significantly enriched in CSCs subpopulation (CD44+CD133+) isolated from Cal27 and Fadu cells via fluorescence-activated cell sorting. TAZ knockdown significantly reduced expression of SOX2 at both mRNA and protein levels, whereas its ectopic overexpression markedly increased its abundance in HNSCC cells. Moreover, reintroduction of ectopic SOX2 abolished, at least in part, the reduced tumorsphere formation and tumorigenicity in vivo induced by TAZ knockdown. Mechanistically, transcriptional complex formed by TAZ and TEAD4 was recruited to two binding sites in SOX2 promoter, which in turn facilitated transcription of SOX2 in HNSCC cells. In addition, the abundance of TAZ and SOX2 was positively correlated in HNSCC clinical samples, and both upregulations of TAZ and SOX2 associated with the worst survival. Taken together, our data reveal a previously unknown mechanistic linkage between TAZ and SOX2 and identify SOX2 as a direct downstream target of TAZ in modulating CSCs self-renewal and maintenance in HNSCC. These findings suggest that targeting TAZ-SOX2 axis might be a promising therapeutic strategy for HNSCC.
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Affiliation(s)
- Jin Li
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029, PR China
| | - Zhongwu Li
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029, PR China
| | - Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029, PR China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029, PR China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Wei Zhang
- Department of Oral Pathology, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Hua Yuan
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Jinhai Ye
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Xiaomeng Song
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Jianrong Yang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029, PR China.
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, PR China.
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19
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Yang H, Jin X, Dan H, Chen Q. Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders. Oral Dis 2019; 26:719-732. [PMID: 31056829 DOI: 10.1111/odi.13115] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 04/17/2019] [Accepted: 04/29/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Huamei Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Medicine of Carcinogenesis and Management West China Hospital of Stomatology, Sichuan University Chengdu China
| | - Xin Jin
- College of Stomatology Chongqing Medical University Chongqing China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences Chongqing China
| | - Hongxia Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Medicine of Carcinogenesis and Management West China Hospital of Stomatology, Sichuan University Chengdu China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Medicine of Carcinogenesis and Management West China Hospital of Stomatology, Sichuan University Chengdu China
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20
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Budach V, Tinhofer I. Novel prognostic clinical factors and biomarkers for outcome prediction in head and neck cancer: a systematic review. Lancet Oncol 2019; 20:e313-e326. [DOI: 10.1016/s1470-2045(19)30177-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 01/16/2023]
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21
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Mohamed H, Hagström J, Jouhi L, Atula T, Almangush A, Mäkitie A, Haglund C. The expression and prognostic value of stem cell markers Bmi-1, HESC5:3, and HES77 in human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma. Tumour Biol 2019; 41:1010428319840473. [PMID: 30915904 DOI: 10.1177/1010428319840473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Human papillomavirus is detected in over 50% of oropharyngeal squamous cell carcinomas. Human papillomavirus-positive oropharyngeal squamous cell carcinomas differ from human papillomavirus-negative tumors, and both expression patterns are classified as distinct entities. The Bmi-1 oncogene is a well-known member of the mammalian polycomb-group family. HESC5:3 and HES77 are newly developed monoclonal antibodies produced against undifferentiated embryonic stem cells. Our aim was to explore their roles in both human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. Our cohort comprised 202 consecutive oropharyngeal squamous cell carcinoma patients diagnosed and treated with curative intent. We used tissue microarray tumor blocks to study the immunohistochemical expression of Bmi-1, HESC5:3, and HES77. We compared the expressions of these stem cell markers with p16 immunoexpression and human papillomavirus status, as well as with other characteristics of the tumor, and with patients' clinical data and follow-up data. Human papillomavirus- and p16-positive tumors expressed less Bmi-1 and more HESC5:3 than the negative tumors. HES77 expression was high in human papillomavirus-positive oropharyngeal squamous cell carcinoma, but it did not correlate with p16 positivity. In our multivariable model, Bmi-1 and HESC5:3 were still associated with human papillomavirus, but the association between human papillomavirus and HES77 remained absent. In conclusion, Bmi-1, HESC5:3, and HES77 may have a different role in human papillomavirus-positive and human papillomavirus-negative tumors. There was no correlation between Bmi-1, HESC5:3, and HES77 expression and survival.
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Affiliation(s)
- Hesham Mohamed
- 1 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,2 Department of Histology, Omar Al-Mukhtar University, El-Beida, Libya
| | - Jaana Hagström
- 1 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,3 Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Lauri Jouhi
- 4 Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Timo Atula
- 4 Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Alhadi Almangush
- 1 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Antti Mäkitie
- 4 Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,5 Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology and Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.,6 Research Programme in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- 3 Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,7 Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Zhang W, Li J, Wu Y, Ge H, Song Y, Wang D, Yuan H, Jiang H, Wang Y, Cheng J. TEAD4 overexpression promotes epithelial-mesenchymal transition and associates with aggressiveness and adverse prognosis in head neck squamous cell carcinoma. Cancer Cell Int 2018; 18:178. [PMID: 30459528 PMCID: PMC6233371 DOI: 10.1186/s12935-018-0675-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/01/2018] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Deregulated Hippo signaling has been uncovered to be intricately involved in tumorigenesis. Transcriptional factor TEADs serve as key mediators of Hippo signaling and have been increasingly appreciated as putative oncogenes driving cancer initiation and progression. However, its expression pattern and oncogenic role of TEAD4 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. METHODS TEAD4 mRNA expression in HNSCC was determined by data mining and analyses from TCGA dataset and four independent cohorts with transcriptional profiling data publically available. The protein abundance of TEAD4 was measured by immunohistochemistry in 105 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The oncogenic roles of TEAD4 was further determined by 4-nitroquinoline 1-oxide (4NQO)-induced animal model, both knockdown/overexpression assay and TGF-β1-induced epithelia-mesenchymal transition (EMT) in vitro. RESULTS Both mRNA and protein abundance of TEAD4 were significantly increased in HNSCC as compared to its non-tumor counterparts. Overexpression of TEAD4 significantly associated with high pathological grade, cervical node metastasis, advanced clinical stage and reduced overall and disease-free survival. In the 4NQO-induced HNSCC mouse model, increased TEAD4 immunostaining was found associated with disease progression. TEAD4 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells, while its overexpression resulted in opposite effects and EMT. Moreover, TEAD4 was critically involved in TGF-β1-induced EMT in HNSCC cells. CONCLUSIONS Our findings reveal that TEAD4 serves as a novel prognostic biomarker and putative oncogene for HNSCC by promoting cell proliferation, migration and invasion, and EMT.
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Affiliation(s)
- Wei Zhang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
| | - Jin Li
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
| | - Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
| | - Han Ge
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
| | - Yue Song
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
| | - Hua Yuan
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Jiangsu, 210029 People’s Republic of China
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 People’s Republic of China
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23
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Wang X, Wu K, Xiao LK, Wu XY. ShRNA-mediated BMI-1 gene silencing inhibits gastrointestinal stromal tumor cell telomerase activity and enhances apoptosis. Kaohsiung J Med Sci 2018; 34:606-615. [PMID: 30392567 DOI: 10.1016/j.kjms.2018.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 11/15/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most frequently occurring mesenchymal tumors of the gastrointestinal tract. Telomerase activity is well acknowledged as a critical factor in oncogenesis. The objective of the present study is to evaluate the effect of BMI gene silencing on proliferation, apoptosis and telomerase activity in human GIST882 cells. GIST882 cells were transfected with a eukaryotic expression vector of an shRNA fragment. The silencing efficiency in the GIST882 cells was determined by RT-qPCR and a western blot analysis. After the shRNA-BMI-1 plasmid was transfected into the GIST882 cells and nude mice, a cell counting kit-8 (CCK-8) assay and flow cytometry were utilized to detect the GIST882 cell proliferation, the apoptosis rate and the cell cycle. Tumor growth was observed by tumor xenograft in nude mice. Telomerase activity and telomere length were detected by a Southern blot and a target region amplified polymorphism. The shRNA-BMI-1 recombinant plasmid was successfully constructed. The mRNA and protein expression of the BMI-1 gene in GIST882 cells was suppressed by the shRNA-BMI-1 recombinant plasmid. Meanwhile, BMI-1 gene silencing inhibited the cell proliferation, tumor growth, and cell cycle in the GIST882 cells. However, cell apoptosis was increased and telomerase activity was decreased with the silencing of the BMI-1 gene. Collectively, the results of this study suggest that silencing the BMI-1 gene may provide a new target for the treatment of GISTs.
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Affiliation(s)
- Xin Wang
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China.
| | - Kun Wu
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China
| | - Lin-Kang Xiao
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China
| | - Xing-Ye Wu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
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24
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Liu P, Zhang M, Niu Q, Zhang F, Yang Y, Jiang X. Knockdown of long non-coding RNA ANRIL inhibits tumorigenesis in human gastric cancer cells via microRNA-99a-mediated down-regulation of BMI1. ACTA ACUST UNITED AC 2018; 51:e6839. [PMID: 30156609 PMCID: PMC6110352 DOI: 10.1590/1414-431x20186839] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 06/25/2018] [Indexed: 12/19/2022]
Abstract
Long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL) has been reported to promote tumorigenesis via regulating microRNA (miR)-99a in gastric cancer cells. However, the role of each component involved in it is still not well understood. This study aimed to verify the role of ANRIL in gastric cancer as well as the underlying mechanisms. ANRIL levels in clinical gastric cancer tissues and cell lines were tested by qPCR. Effects of ANRIL silence on cell viability, migration and invasion, apoptosis, and miR-99a expression in MKN-45 and SGC-7901 cells were measured using CCK-8, Transwell assay, flow cytometry, and qPCR assays, respectively. Then, effects of miR-99a inhibition on ANRIL-silenced cells were evaluated. B-lymphoma Mo-MLV insertion region 1 (BMI1) expression, after abnormal expression of ANRIL and miR-99a, was determined. Finally, expression of key proteins in the apoptotic, Notch, and mTOR pathways was assessed. ANRIL level was elevated in gastric cancer tissues and cell lines. Knockdown of ANRIL suppressed cell viability, migration, and invasion, and increased apoptosis through up-regulating miR-99a. Furthermore, ANRIL silence down-regulated BMI1 via up-regulating miR-99a. BMI1 silence down-regulated Bcl-2 and key kinases in the Notch and mTOR pathways and up-regulated p16 and cleaved caspases. We verified the tumor suppressive effects of ANRIL knockdown in gastric cancer cells via crosstalk with miR-99a. Together, we provided a novel regulatory mechanism for ANRIL in gastric cancer, in which ANRIL silence down-regulated BMI1 via miR-99a, along with activation of the apoptotic pathway and inhibition of the Notch and mTOR pathways.
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Affiliation(s)
- Pei Liu
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Mingming Zhang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Qinghui Niu
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Fengjuan Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yuling Yang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiangjun Jiang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong, China
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25
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M JR, S V. BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer. Gene 2018; 678:302-311. [PMID: 30096458 DOI: 10.1016/j.gene.2018.08.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 07/11/2018] [Accepted: 08/04/2018] [Indexed: 12/12/2022]
Abstract
BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance and cancer stemness. Overexpression is observed in various cancer types such as breast, primary hepatocellular carcinoma (HCC), gastric, ovarian, head and neck, pancreatic and lung cancer. Studies have shown that experimental reduction of BMI protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increases susceptibility to cytotoxic agents and radiation therapy. Thus, inhibition of BMI1 expression particularly in breast cancer stem cells can be used as a potential strategy for the complete elimination of tumor and to prevent disease relapse. On other hand PTEN is known to be an important tumor suppressor next to p53. In many cancers particularly in breast cancer, p53 and PTEN undergo mutations. Studies have indicated the functional and mechanistic link between the BMI-1oncoprotein and tumor suppressor PTEN in the development and progression of cancer. The current review focuses on recent findings of how oncogenicity and chemo-resistance are caused by BMI1. It also highlights the transcriptional regulation between BMI1 and PTEN that dictates the therapeutic outcome in cancers where the functional p53 is absent. Herein, we have clearly demonstrated the regulation of transcription at genomic loci of BMI1 and PTEN in cancerous tissue or cells and the possible epigenetic regulation by histone deacetylase inhibitors (HDACi) at BMI1 and PTEN loci that may provide some clue for the possible therapy against TNBC in near future.
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Affiliation(s)
- Janaki Ramaiah M
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, India.
| | - Vaishnave S
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, India
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26
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Curtarelli RB, Gonçalves JM, dos Santos LGP, Savi MG, Nör JE, Mezzomo LAM, Rodríguez Cordeiro MM. Expression of Cancer Stem Cell Biomarkers in Human Head and Neck Carcinomas: a Systematic Review. Stem Cell Rev Rep 2018; 14:769-784. [PMID: 30076557 DOI: 10.1007/s12015-018-9839-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Mishra A, Sriram H, Chandarana P, Tanavde V, Kumar RV, Gopinath A, Govindarajan R, Ramaswamy S, Sadasivam S. Decreased expression of cell adhesion genes in cancer stem-like cells isolated from primary oral squamous cell carcinomas. Tumour Biol 2018; 40:1010428318780859. [PMID: 29888653 DOI: 10.1177/1010428318780859] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The goal of this study was to isolate cancer stem-like cells marked by high expression of CD44, a putative cancer stem cell marker, from primary oral squamous cell carcinomas and identify distinctive gene expression patterns in these cells. From 1 October 2013 to 4 September 2015, 76 stage III-IV primary oral squamous cell carcinoma of the gingivobuccal sulcus were resected. In all, 13 tumours were analysed by immunohistochemistry to visualise CD44-expressing cells. Expression of CD44 within The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma RNA-sequencing data was also assessed. Seventy resected tumours were dissociated into single cells and stained with antibodies to CD44 as well as CD45 and CD31 (together referred as Lineage/Lin). From 45 of these, CD44+Lin- and CD44-Lin- subpopulations were successfully isolated using fluorescence-activated cell sorting, and good-quality RNA was obtained from 14 such sorted pairs. Libraries from five pairs were sequenced and the results analysed using bioinformatics tools. Reverse transcription quantitative polymerase chain reaction was performed to experimentally validate the differential expression of selected candidate genes identified from the transcriptome sequencing in the same 5 and an additional 9 tumours. CD44 was expressed on the surface of poorly differentiated tumour cells, and within the The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma samples, its messenger RNA levels were higher in tumours compared to normal. Transcriptomics revealed that 102 genes were upregulated and 85 genes were downregulated in CD44+Lin- compared to CD44-Lin- cells in at least 3 of the 5 tumours sequenced. The upregulated genes included those involved in immune regulation, while the downregulated genes were enriched for genes involved in cell adhesion. Decreased expression of PCDH18, MGP, SPARCL1 and KRTDAP was confirmed by reverse transcription quantitative polymerase chain reaction. Lower expression of the cell-cell adhesion molecule PCDH18 correlated with poorer overall survival in the The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma data highlighting it as a potential negative prognostic factor in this cancer.
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Affiliation(s)
- Amrendra Mishra
- 1 Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, UAS-GKVK Campus, Bengaluru, India
- 2 Hannover Biomedical Research School, Hannover Medical School, Hannover, Germany
| | - Harshini Sriram
- 1 Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, UAS-GKVK Campus, Bengaluru, India
| | | | - Vivek Tanavde
- 3 iBioAnalysis Pvt. Ltd., Ahmedabad, India
- 4 Division of Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, India
- 5 Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), Singapore
| | - Rekha V Kumar
- 6 Kidwai Memorial Institute of Oncology, Bengaluru, India
| | | | | | - S Ramaswamy
- 1 Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, UAS-GKVK Campus, Bengaluru, India
| | - Subhashini Sadasivam
- 1 Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, UAS-GKVK Campus, Bengaluru, India
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28
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Wu Y, Hu H, Zhang W, Li Z, Diao P, Wang D, Zhang W, Wang Y, Yang J, Cheng J. SUZ12 is a novel putative oncogene promoting tumorigenesis in head and neck squamous cell carcinoma. J Cell Mol Med 2018; 22:3582-3594. [PMID: 29667751 PMCID: PMC6010759 DOI: 10.1111/jcmm.13638] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 03/08/2018] [Indexed: 12/16/2022] Open
Abstract
The suppressor of zest 12 (SUZ12), one of the core polycomb repressive complex 2 (PRC2) components, has increasingly appreciated as a key mediator during human tumorigenesis. However, its expression pattern and oncogenic roles in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored yet. Here, we sought to determine its expression pattern, clinicopathological significance and biological roles in HNSCC. Through data mining and interrogation from multiple publicly available databases, our bioinformatics analyses revealed that SUZ12 mRNA was significantly overexpressed in multiple HNSCC patient cohorts. Moreover, SUZ12 protein was markedly up‐regulated in primary HNSCC samples from our patient cohort as assessed by immunohistochemical staining and its overexpression significantly associated with cervical node metastasis and reduced overall and disease‐free survival. In the 4‐nitroquinoline 1‐oxide (4NQO)‐induced HNSCC mouse model, increased SUZ12 immunostaining was observed along with disease progression from epithelial hyperplasia to squamous cell carcinoma in tongue. Furthermore, shRNA‐mediated SUZ12 knock‐down significantly inhibited cell proliferation, migration and invasion in HNSCC cells, and resulted in compromised tumour growth in vivo. Collectively, our data reveal that SUZ12 might serve as a putative oncogene by promoting cell proliferation, migration and invasion, and also a novel biomarker with diagnostic and prognostic significance for HNSCC.
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Affiliation(s)
- Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
| | - Huijun Hu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China
| | - Wei Zhang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China
| | - Zhongwu Li
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
| | - Pengfei Diao
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
| | - Wei Zhang
- Department of Oral Pathology, School of Stomatology, Nanjing Medical University, Jiangsu, China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China
| | - Jianrong Yang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China
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29
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Wu Y, Diao P, Li Z, Zhang W, Wang D, Wang Y, Cheng J. Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma. J Oral Pathol Med 2018; 47:502-510. [PMID: 29569374 DOI: 10.1111/jop.12708] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND WD repeat domain 5 (WDR5), a core member of Mixed lineage leukemia (MLL) and SET1 histone H3 lysine 4 (H3K4) methyltransferase complexes, is involved in multiple biological and pathological processes. Its deregulation in cancer and pro-tumorigenic roles has been increasingly appreciated. However, the expression pattern of WDR5 and its biological functions in head neck squamous cell carcinoma (HNSCC) have not been well established. METHODS The expression of WDR5 mRNA in HNSCC was determined by data mining and interrogation using publicly available databases. Its protein expression was measured by immunohistochemistry in a retrospective cohort of primary HNSCC samples. Moreover, the associations between WDR5 expression and various clinicopathological parameters and patient survival were assessed. The pro-tumorigenic roles of WDR5 in HNSCC were further delineated in vitro by loss-of-function assay. RESULTS Our bioinformatics analyses revealed that WDR5 mRNA was significantly overexpressed in 3 HNSCC cohorts. WDR5 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with large tumor size, advanced clinical stage (chi-square test, P = .048, .006) and reduced overall and disease-free survival (Kaplan-Mier analyses, Log-rank test, P = .0137, .0154). Univariate and multivariate survival analyses further revealed WDR5 protein abundance as an independent prognostic factor for patients' overall survival. Moreover, WDR5 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells. CONCLUSIONS Our findings reveal that WDR5 is aberrantly overexpressed in HNSCC and associates with aggressiveness and unfavorable prognosis, thus representing a novel diagnostic and prognostic biomarker for HNSCC.
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Affiliation(s)
- Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Pengfei Diao
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Zhongwu Li
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, China
| | - Wei Zhang
- Department of Oral Pathology, School of Stomatology, Nanjing Medical University, Nanjing, China
| | - Dongmiao Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
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30
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Rodrigues MFSD, Xavier FCDA, Andrade NP, Lopes C, Miguita Luiz L, Sedassari BT, Ibarra AMC, López RVM, Kliemann Schmerling C, Moyses RA, Tajara da Silva EE, Nunes FD. Prognostic implications of CD44, NANOG, OCT4, and BMI1 expression in tongue squamous cell carcinoma. Head Neck 2018; 40:1759-1773. [PMID: 29607565 DOI: 10.1002/hed.25158] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 12/23/2017] [Accepted: 02/08/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Tongue squamous cell carcinoma (SCC) contains a cell subpopulation referred to as cancer stem cells (CSCs), which are responsible for tumor growth, metastasis, and resistance to chemotherapy and radiotherapy. The CSC markers have been used to isolate these cells and as biomarkers to predict overall survival. METHODS The CSC markers CD44, NANOG, OCT4, and BMI1 were investigated using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry and correlated with clinicopathological parameters. RESULTS The CD44 overexpression was associated with disease-related death (P = 0.02) and worst prognosis. NANOG was upregulated in nontumoral margins and associated with T1/T2 classification, lymph node metastasis, and worst prognosis. OCT4 was associated with lymph node metastasis and worst overall survival. BMI1 and CD44v3 were overexpressed in tongue SCC. Coexpression of CD44++ /NANOG++ was associated with worst overall survival when compared with patients with CD44-/+ /NANOG-/+ . CONCLUSION The CSC markers might play an important role not only in CSC trait acquisition but also in tongue SCC development and progression.
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Affiliation(s)
- Maria Fernanda Setúbal Destro Rodrigues
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil.,Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University (UNINOVE), São Paulo, São Paulo, Brazil
| | | | - Nathália Paiva Andrade
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Camila Lopes
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Lucyene Miguita Luiz
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Bruno Tavares Sedassari
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Ana Melissa Ccopa Ibarra
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University (UNINOVE), São Paulo, São Paulo, Brazil
| | | | - Claudia Kliemann Schmerling
- Department of Molecular Biology, São José do Rio Preto School of Medicine, São José do Rio Preto, São Paulo, Brazil
| | - Raquel Ajub Moyses
- Department of Molecular Biology, São José do Rio Preto School of Medicine, São José do Rio Preto, São Paulo, Brazil
| | | | - Fabio Daumas Nunes
- Oral and Maxillofacial Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
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31
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Hu Q, Wu T, Chen X, Li H, Du Z, Hao Y, Peng J, Tai S, Song M, Cheng B. The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation. Cancer Med 2018; 7:1056-1069. [PMID: 29479858 PMCID: PMC5911571 DOI: 10.1002/cam4.1348] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 12/25/2017] [Accepted: 12/26/2017] [Indexed: 12/14/2022] Open
Abstract
Radiotherapy for nasopharyngeal carcinoma has been reported to cause second primary oral squamous cell carcinoma (s-OSCC). The prognosis and pathologic characteristic of s-OSCC are largely unknown. Bmi1 was associated with the repair of radiation-induced DNA damage, suggesting its possible involvement in the pathologic process of s-OSCC. Herein, we compared the prognosis between s-OSCC and primary OSCC (p-OSCC) and explored the involvement of Bmi1 in s-OSCC development. In this retrospective study, s-OSCC and p-OSCC patients were matched by propensity scores. Their outcomes were compared by univariate and multivariate analyses. The expression of Bmi1 in s-OSCC and p-OSCC was detected by immunohistochemistry (IHC). Radiation-induced Bmi1 alteration in early-stage was explored in a rat model and HaCaT cells. After matching, 116 pairs of patients with highly balanced characteristics were included. In univariate analysis, the overall survival (OS), disease-specific survival (DSS), and local recurrence-free survival (LRFS) were poorer in s-OSCC than in p-OSCC (P < 0.05), while their regional metastasis-free survival (RMFS) was parallel (P = 0.112). Multivariate analysis further revealed that radiotherapy history was an independent risk factor for OS, DSS, and LRFS (P < 0.05). IHC results showed that the positive rate of Bmi1 was higher in s-OSCC (P = 0.0027). In a rat model of radiotherapy-induced mucositis, Bmi1 upregulation was observed 8 days after irradiation. Consistently, Bmi1 was upregulated in HaCaT cells 1 h after irradiation, and its upregulation was in accord with X-ray exposure duration. In conclusion, the prognosis of s-OSCC is poorer as compared to p-OSCC, which may be attributed to Bmi1 upregulation.
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Affiliation(s)
- Qinchao Hu
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Tong Wu
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Xiaobing Chen
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Huan Li
- Department of Intensive Care UnitSun Yat‐sen University Cancer CenterGuangzhouChina
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouChina
| | - Zhicheng Du
- Department of Medical Statistics and EpidemiologySchool of Public HealthSun Yat‐sen UniversityGuangzhouChina
| | - Yuantao Hao
- Department of Medical Statistics and EpidemiologySchool of Public HealthSun Yat‐sen UniversityGuangzhouChina
| | - Jianmin Peng
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Shanshan Tai
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Ming Song
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Bin Cheng
- Department of Oral MedicineHospital of StomatologySun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
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Chen L, Yang R, Qiao W, Yuan X, Wang S, Goltzman D, Miao D. 1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice. Int J Cancer 2018; 143:368-382. [PMID: 29441580 DOI: 10.1002/ijc.31317] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 01/24/2018] [Accepted: 02/01/2018] [Indexed: 12/30/2022]
Abstract
Human epidemiological studies suggest that 1,25(OH)2 D3 deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)2 D3 or deficient in its receptor. In our study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)2 D3 deficient mice more than 1 year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH)2 D3 prevented spontaneous tumor development. We also demonstrated that l,25(OH)2 D3 deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH)2 D3 or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from our study suggest that 1,25(OH)2 D3 deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence-associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. Our study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH)2 D3 prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)2 D3 to prevent tumorigenesis in an aging organism.
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Affiliation(s)
- Lulu Chen
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Renlei Yang
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Wanxin Qiao
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Xiaoqin Yuan
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Shui Wang
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - David Goltzman
- Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, QC, Canada
| | - Dengshun Miao
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
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Miyazaki H, Takahashi RU, Prieto-Vila M, Kawamura Y, Kondo S, Shirota T, Ochiya T. CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells. Oncotarget 2018. [PMID: 29515788 PMCID: PMC5839369 DOI: 10.18632/oncotarget.24252] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells.
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Affiliation(s)
- Hiroaki Miyazaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.,Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo 145-8515, Japan
| | - Ryou-U Takahashi
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Marta Prieto-Vila
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Yumi Kawamura
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.,Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba 1-1-1 Tennodai, Ibaraki 305-8577, Japan
| | - Seiji Kondo
- Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo 145-8515, Japan
| | - Tatsuo Shirota
- Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo 145-8515, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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Wang Q, Li Z, Wu Y, Huang R, Zhu Y, Zhang W, Wang Y, Cheng J. Pharmacological inhibition of Bmi1 by PTC-209 impaired tumor growth in head neck squamous cell carcinoma. Cancer Cell Int 2017; 17:107. [PMID: 29200967 PMCID: PMC5697105 DOI: 10.1186/s12935-017-0481-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022] Open
Abstract
Background Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) contributes to human tumorigenesis via epigenetic transcriptional silencing and represents a novel therapeutic target with great potentials. Here we sought to determine the therapeutic efficiency of PTC-209, a potent and selective Bmi1 inhibitor, in head neck squamous cell carcinoma (HNSCC) cells and a HNSCC xenograft model. Methods The mutation pattern, mRNA level of Bmi1 in HNSCC and its associations with clinicopathological parameters were determined through comprehensive data mining and interrogation using publicly available databases GENT, cBioPortal, Oncomine and TCGA. The PTC-209, a selective and potent Bmi1 inhibitor, was exploited and its effect on Bmi1 expression was measured in two HNSCC cell lines Cal27 and FaDu. The phenotypical changes of HNSCC cells were observed upon PTC-209 treatment in vitro. Moreover, the therapeutic effects of PTC-209 for HNSCC were determined in a xenograft animal model. Results Through comprehensive data mining and interrogation, we found that Bmi1 mRNA was frequently overexpressed in a subset of HNSCC samples. Our data revealed that PTC-209 robustly reduced the expression of Bmi1 in Cal27 and FaDu cells presumably by post-transcriptional repression and ubiquitin-proteasomal degradation. PTC-209 treatment resulted in impaired cell proliferation, G1-phase cell cycle arrest, compromised migration and invasiveness, and increased cell apoptosis and chemosensitivity to 5-FU and cisplatin in vitro. Moreover, PTC-209 exposure reduced colony formation, tumorsphere formation and the percentage of ALDH1+ subpopulation in both Cal27 and FaDu cells. Importantly, in vivo PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model probably by Bmi1 inhibition and impaired cell proliferation. Conclusions Our findings indicate that pharmacological inhibition of Bmi1 is a novel therapeutic strategy for HNSCC patients, especially with those with aberrant Bmi1 overexpression. Electronic supplementary material The online version of this article (10.1186/s12935-017-0481-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qiong Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Zhongwu Li
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Rong Huang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China.,Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Yumin Zhu
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Wei Zhang
- Department of Oral Pathology, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Yanling Wang
- Department of Oral Pathology, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China.,Department of Oral Pathology, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029 Jiangsu China
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Salimi V, Shahsavari Z, Safizadeh B, Hosseini A, Khademian N, Tavakoli-Yaraki M. Sodium butyrate promotes apoptosis in breast cancer cells through reactive oxygen species (ROS) formation and mitochondrial impairment. Lipids Health Dis 2017; 16:208. [PMID: 29096636 PMCID: PMC5669027 DOI: 10.1186/s12944-017-0593-4] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 10/11/2017] [Indexed: 01/05/2023] Open
Abstract
Background Sodium butyrate (NaBu) is a short-chain fatty acid which serves as a histon deacetylase inhibitor and has received considerable interest as a possible regulator of cancer cell death. The regulatory effect of NaBu on cancer cell growth or death has yet to be illustrated in many cancers including breast cancer. This study is aimed to elucidate the possible effect of NaBu on regulation of breast cancer growth and apoptosis. Methods The cytotoxic effect of NaBu on the growth of breast cancer cells (MCF-7 and MDA-MB-468) and normal breast cells (MCF-10A) was determined using MTT assay. Annexin-V-FITC staining and PI staining were performed to detect apoptosis and cell cycle distribution using Flow cytometry, the level of mitochondrial membrane potential (Δψm), Reactive oxygen species (ROS)formation and caspase activity were determined accordingly. Results Based on our data, NaBu induced a dose and time-dependent cell toxicity in breast cancer cells which was related to the cell cycle arrest and induction of apoptosis. The impact of NaBu on MCF-10A cell toxicity, cell cycle distribution and apoptosis was inconsiderable. NaBu-elicited apoptosis was accompanied by the elevated level of ROS, increased caspase activity and reduced mitochondrial membrane potential (Δψm) in MCF-7 and MDA-MB-468 cells and with no effect on the above mentioned factors in MCF-10A cells. Conclusions Our study provided insight in to the role of NaBu on the regulation of breast cancer cell growth and lighten up the pro-apoptotic activity of NaBu.
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Affiliation(s)
- Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Shahsavari
- Department of Laboratory Medicine, Faculty of Paramedical Sciences, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
| | - Banafsheh Safizadeh
- Department of Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Ameinh Hosseini
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Narges Khademian
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Quality Assessment of Prognostic Studies Using Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma. Appl Immunohistochem Mol Morphol 2017; 26:e61-e69. [PMID: 28800012 DOI: 10.1097/pai.0000000000000569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cancer stem cells (CSC) have been investigated as prognostic markers in oral squamous cell carcinoma (OSCC). However, an assessment of the reporting quality of these studies has not been performed yet. The aim of this study was to describe the reporting quality of prognostic studies involving CSCs and OSCC, focusing mainly on the immunohistochemical reproducibility. By means a systematic review, 34 articles were selected. Analyses of both general reporting quality and immunohistochemistry technique were performed by using checklists for multiple aspects related to study reproducibility. A total of 21 different CSC markers were cited in the selected studies, evaluated by means of a wide range of antibodies, most of them (40.3%) without clone description. Discrepancies in intracellular immunolabeling were noted for some markers. The mean global score for general quality assessment revealed limits in the quality of the articles. The main problems were related to lack of report on OSCC characteristics and treatment, sample size rationale, and sensitivity analysis or internal validation of the markers. Although there was a high frequency of studies having "good or very good" score for immunohistochemistry reproducibility, the frequency of articles with "poor or very poor" score for individual items was expressive, mainly for description of immunolabeling analysis (38.2% of the studies were poorly described). In conclusion, although there is a significant range of CSC markers with promising results for prognosis of OSCC, the inadequate reporting of important sections in the published studies, including immunohistochemistry technique, may limit the quality of the investigation.
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Prognostic Value of Cancer Stem Cell Markers in Head and Neck Squamous Cell Carcinoma: a Meta-analysis. Sci Rep 2017; 7:43008. [PMID: 28220856 PMCID: PMC5318950 DOI: 10.1038/srep43008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 01/18/2017] [Indexed: 12/18/2022] Open
Abstract
Bmi-1, CD133, Nanog and Oct-4 have been reported as cancer stem cell (CSC) markers in head and neck squamous cell carcinoma (HNSCC). However, the prognostic value of them in HNSCC remains controversial. Hence, this meta-analysis was conducted to access the association between the four CSC markers and survival outcome of HNSCC patients. A total of 22 articles with 27 studies met the inclusion criteria and the combined hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated. Data analysis showed that high expression of CSC markers was associated with poor overall survival (OS) (HR = 1.93; 95% CI: 1.46–2.55, P < 0.001) and disease free survival (DFS) (HR = 4.78; 95% CI: 2.95–7.75, P < 0.001) but not disease specific survival (DSS) (HR = 1.17; 95% CI: 0.74–1.84, P = 0.50) of HNSCC patients. Subgroup analysis indicted that high expression of CD133 (HR = 2.33, 95%CI: 1.42–3.83, P < 0.001), Oct-4(HR = 2.10, 95%CI: 1.36–3.22, P = 0.007) and Nanog (HR = 2.49, 95%CI: 1.66–3.72, P < 0.001) could predict poor OS in HNSCC patients respectively whereas overexpression of Bmi-1 was not related to the reduced OS in HNSCC patients (HR = 1.32, 95%CI: 0.66–2.65, P = 0.43). Therefore, we concluded that CSC markers, especially CD133, Nanog and Oct-4, might be predictive factors in HNSCC patients.
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Overexpression of suppressor of zest 12 is associated with cervical node metastasis and unfavorable prognosis in tongue squamous cell carcinoma. Cancer Cell Int 2017; 17:26. [PMID: 28228691 PMCID: PMC5307854 DOI: 10.1186/s12935-017-0395-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 02/04/2017] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Increased expression of suppressor of zest 12 (SUZ12), a core component of the polycomb repressive complex 2, contributes to human tumorigenesis and associates with patient prognosis. In the present study, we sought to investigate the expression of SUZ12 and its clinicopathological significance in primary tongue squamous cell carcinoma (TSCC). METHODS The expression of SUZ12 protein was determined by immunohistochemistry in clinical samples from a retrospective cohort of 72 patients with primary TSCC who were treated at our institution from Jan. 2007 to Dec. 2013. The potential associations between SUZ12 abundance and multiple clinicopathological parameters were assessed by Chi square test. Moreover, the effect of SUZ12 expression on patients' survival was further estimated by Kaplan-Meier and Cox regression analyses. RESULTS Our immunohistochemical staining data revealed aberrant overexpression of SUZ12 in a large subset of TSCC as compared to normal tongue mucosa. Elevated SUZ12 was found to be significantly associated with cervical nodes metastasis (P = 0.0325) and reduced overall as well as disease-free survival (Log-rank test, P = 0.0225, 0.0179, respectively). Both univariate and multivariate Cox regression analysis identified the expression status of SUZ12 (low/high) as an important independent prognostic factor for patients' survival. CONCLUSIONS Our data reveal that aberrant SUZ12 overexpression is associated with cervical nodes metastasis and reduced survival in TSCC. These findings suggest that SUZ12 might play critical roles during tongue tumorigenesis and serve as a novel biomarker with diagnostic and prognostic significance.
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Naik PP, Das DN, Panda PK, Mukhopadhyay S, Sinha N, Praharaj PP, Agarwal R, Bhutia SK. Implications of cancer stem cells in developing therapeutic resistance in oral cancer. Oral Oncol 2016; 62:122-135. [PMID: 27865365 DOI: 10.1016/j.oraloncology.2016.10.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 10/05/2016] [Accepted: 10/15/2016] [Indexed: 12/13/2022]
Abstract
Conventional therapeutics are often frequented with recurrences, refraction and regimen resistance in oral cavity cancers which are predominantly manifested by cancer stem cells (CSCs). During oncoevolution, cancer cells may undergo structural and functional reprogramming wherein they evolve as highly tolerant CSC phenotypes with greater survival advantages. The CSCs possess inherent and exclusive properties including self-renewal, hierarchical differentiation, and tumorigenicity that serve as the basis of chemo-radio-resistance in oral cancer. However, the key mechanisms underlying the CSC-mediated therapy resistance need to be further elucidated. A spectrum of dysfunctional cellular pathways including the developmental signaling, apoptosis, autophagy, cell cycle regulation, DNA damage responses and epigenetic regulations protect the CSCs from conventional therapies. Moreover, tumor niche shelters CSCs and creates an immunosuppressive environment favoring the survival of CSCs. Maintenance of lower redox status, epithelial-to-mesenchymal transition (EMT), metabolic reprogramming and altered drug responses are the accessory features that aid in the process of chemo-radio-resistance in oral CSCs. This review deals with the functional and molecular basis of cancer cell pluripotency-associated resistance highlighting the abrupt fundamental cellular processes; targeting these events may hold a great promise in the successful treatment of oral cancer.
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Affiliation(s)
- Prajna Paramita Naik
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Durgesh Nandini Das
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Prashanta Kumar Panda
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Subhadip Mukhopadhyay
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Niharika Sinha
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | | | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States; University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO, United States.
| | - Sujit Kumar Bhutia
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India.
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Sobecka A, Barczak W, Suchorska WM. RNA interference in head and neck oncology. Oncol Lett 2016; 12:3035-3040. [PMID: 27899959 PMCID: PMC5103899 DOI: 10.3892/ol.2016.5079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 06/27/2016] [Indexed: 11/28/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide. The treatment of choice in case of head and neck cancer is surgery, followed by chemo- or/and radiotherapy. A potentially effective instrument to improve the outcome of numerous diseases, including viral infections, diabetes and cancer, is RNA interference (RNAi). It has been demonstrated that small interfering RNA and microRNA molecules are strongly involved in the regulation of various different pathological processes in cancer development. RNAi has become a valuable research tool allowing a better understanding of the mechanisms regulating cancer pathogenesis. Considering those advantages over other current therapeutics (including specificity and high efficacy), RNAi appears to be a potentially useful tool in cancer treatment. The present review discusses the current knowledge about the possibility of using RNAi in HNSCC therapy.
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Affiliation(s)
- Agnieszka Sobecka
- Department of Medical Physics, Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan University of Medical Sciences, 61-866 Poznan, Poland
| | - Wojciech Barczak
- Department of Medical Physics, Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan University of Medical Sciences, 61-866 Poznan, Poland; Department of Head and Neck Surgery, Greater Poland Cancer Centre, Poznan University of Medical Sciences, 61-866 Poznan, Poland
| | - Wiktoria Maria Suchorska
- Department of Medical Physics, Radiobiology Laboratory, Greater Poland Cancer Centre, Poznan University of Medical Sciences, 61-866 Poznan, Poland
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Ren H, Du P, Ge Z, Jin Y, Ding D, Liu X, Zou Q. TWIST1 and BMI1 in Cancer Metastasis and Chemoresistance. J Cancer 2016; 7:1074-80. [PMID: 27326250 PMCID: PMC4911874 DOI: 10.7150/jca.14031] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 03/15/2016] [Indexed: 01/07/2023] Open
Abstract
Purpose Increasing evidences revealed that cancer cells with the characteristics of epithelial-mesenchymal transition (EMT) or cancer stem cells (CSC) have high ability of progression, invasion, metastasis and chemoresistance. TWIST1 and BMI1 are crucial transcription factors required for EMT and CSC. Both TWIST1 and BMI1 are up-regulated in various cancers and have a positive correlation with poor prognosis. Although recent results showed that the two molecules function in promoting cancer metastasis and chemoresistance respectively, the correlation of TWIST1 and BMI1 is not well understood. Methods In this review, we summarize recent advance in cancer research focus on TWIST1 and BMI1 in cancer metastasis and chemoresistance, and emphasize the possible link between EMT and CSC. Results Further investigation of TWIST1 and BMI1 cooperately promote CSC proliferation due to EMT-associated effect will help to understand the mechanism of tumor cells metastasis and chemoresistance. Conclusions TWIST1 and BMI1 in cancer cells will be effective targets for treating chemoresistant metastatic lesions.
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Affiliation(s)
- Hong Ren
- 1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Peizhun Du
- 1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Zongyu Ge
- 2. Department of General Surgery, Huzhou Maternity and Child Health Care Hospital, Zhejiang Province, P.R. China
| | - Yiting Jin
- 1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Di Ding
- 3. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Xiuping Liu
- 4. Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Qiang Zou
- 1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
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Involvement of 15-lipoxygenase-1 in the regulation of breast cancer cell death induced by sodium butyrate. Cytotechnology 2016; 68:2519-2528. [PMID: 27173588 DOI: 10.1007/s10616-016-9972-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 04/18/2016] [Indexed: 01/01/2023] Open
Abstract
15-Lipoxygenase-1 (15-Lox-1) as a member of fatty acid dioxygenases family has received considerable attention as an effector of cancer cell growth. The relevance of sodium butyrate on 15-Lox-1 pathway has not been determined in breast cancer. This study is aimed to investigate the possible involvement of 15-Lox-1 in the regulation of breast cancer cell growth by sodium butyrate. MTT assay was used to assess the cytotoxicity effect and Annexin-V-FITC staining was applied for detection of apoptosis using flow cytometry. The involvement of 15-Lox-1 was examined using 15-Lox-1 specific inhibitor and enzyme gene expression level and activity was further analyzed by Real-time PCR and measurement of 13(S)-HODE. The results revealed that sodium butyrate increased the expression of 15-Lox-1 and production of 13(S)HODE. 15-Lox-1 was also involved in the sodium butyrate-induced breast cancer cell cytotoxicity and apoptosis. This study provided more evidences on the positive effectiveness of 15-Lox-1/13(S)-HODE on controlling growth of breast cancer cells.
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Newbold A, Falkenberg KJ, Prince HM, Johnstone RW. How do tumor cells respond to HDAC inhibition? FEBS J 2016; 283:4032-4046. [PMID: 27112360 DOI: 10.1111/febs.13746] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/30/2016] [Accepted: 04/22/2016] [Indexed: 02/06/2023]
Abstract
It is now well recognized that mutations, deregulated expression, and aberrant recruitment of epigenetic readers, writers, and erasers are fundamentally important processes in the onset and maintenance of many human tumors. The molecular, biological, and biochemical characteristics of a particular class of epigenetic erasers, the histone deacetylases (HDACs), have been extensively studied and small-molecule HDAC inhibitors (HDACis) have now been clinically approved for the treatment of human hemopoietic malignancies. This review explores our current understanding of the biological and molecular effects on tumor cells following HDACi treatment. The predominant responses include induction of tumor cell death and inhibition of proliferation that in experimental models have been linked to therapeutic efficacy. However, tumor cell-intrinsic responses to HDACi, including modulating tumor immunogenicity have also been described and may have substantial roles in mediating the antitumor effects of HDACi. We posit that the field has failed to fully reconcile the biological consequences of exposure to HDACis with the molecular events that underpin these responses, however progress is being made. Understanding the pleiotrophic activities of HDACis on tumor cells will hopefully fast track the development of more potent and selective HDACi that may be used alone or in combination to improve patient outcomes.
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Affiliation(s)
- Andrea Newbold
- Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia
| | | | - H Miles Prince
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia.,Division of Cancer Medicine, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia
| | - Ricky W Johnstone
- Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia
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Dvorakova M, Vanek T. Histone deacetylase inhibitors for the treatment of cancer stem cells. MEDCHEMCOMM 2016. [DOI: 10.1039/c6md00297h] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
HDAC inhibitors are a promising group of epigenetic drugs that show the ability to induce apoptosis in cancer stem cells.
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Affiliation(s)
- M. Dvorakova
- Laboratory of Plant Biotechnologies
- Institute of Experimental Botany
- Prague 6
- Czech Republic
| | - T. Vanek
- Laboratory of Plant Biotechnologies
- Institute of Experimental Botany
- Prague 6
- Czech Republic
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45
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Wang D, Zhu Y, Wang Y, Li Z, Yuan C, Zhang W, Yuan H, Ye J, Yang J, Jiang H, Cheng J. The pluripotency factor LIN28B is involved in oral carcinogenesis and associates with tumor aggressiveness and unfavorable prognosis. Cancer Cell Int 2015; 15:99. [PMID: 26478718 PMCID: PMC4608152 DOI: 10.1186/s12935-015-0252-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 10/07/2015] [Indexed: 12/14/2022] Open
Abstract
Objective LIN28B is a conserved RNA-binding protein critically involved in development, cellular metabolism and tumorigenesis. It is frequently overexpressed in human cancers and correlates with tumor aggressiveness as well as unfavorable prognosis. However, the expression pattern and oncogenic roles of LIN28B during oral squamous cell carcinoma (OSCC) development and progression has not been well established yet. Here, we sought to determine the expression of LIN28B and its clinical significance using chemical-induced OSCC animal model, cell lines and primary specimens. Method The OSCC animal model was induced using 7,12-dimethyl-1,2-bezan-tracene (DMBA) painting in the hamster buccal pouch. Buccal lesions from animals were obtained from different time points and subjected to routine histological analyses and immunohistochemical staining of LIN28B. The mRNA, protein abundance and subcellular localization of LIN28B was determined in a panel of OSCC cell lines by real-time RT-PCR, western blot and immunofluorescence. The expression levels of LIN28B in human primary OSCC samples were further evaluated by immunohistochemical staining. Moreover, the relationship between LIN28B and several clinicopathological parameters as well as patients’ prognosis were also assessed. Results Our results revealed that negative or low LIN28B expression was commonly observed in normal epithelial, whereas more LIN28B abundance was identified in epithelial dysplasia and invasive SCC in the DMBA-induced OSCC animal model. Overexpression of LIN28B was identified in a major fraction of OSCC samples(39/58) and significantly associated with tumor size (P = 0.049) and advanced clinical stages (P = 0.0286). Patients with increased LIN28B had markedly reduced overall survival as compared to those with low LIN28B. Multivariate survival analyses further indicated that LIN28B abundance served as an independent prognostic factor for patients’ overall survival. Conclusions Our findings reveal that LIN28B is critically involved in OSCC initiation and progression and aberrantly overexpressed in human OSCC. It might represent a novel diagnostic and prognostic biomarker for oral cancer.
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Affiliation(s)
- Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Yuming Zhu
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China
| | - Yanling Wang
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Zhongwu Li
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Chunping Yuan
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China
| | - Wei Zhang
- Department of Oral and Maxillofacial Pathology, Nanjing Medical University, Nanjing, 210029 China
| | - Hua Yuan
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Jinhai Ye
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Jianrong Yang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Nanjing, 210029 China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, 210029 China
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Wang W, Qin JJ, Voruganti S, Nag S, Zhou J, Zhang R. Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications. Med Res Rev 2015; 35:1220-67. [PMID: 26227500 DOI: 10.1002/med.21358] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the Pc-repressive and non-classical-Pc-functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy.
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Affiliation(s)
- Wei Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106.,Center for Cancer Biology and Therapy, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106
| | - Jiang-Jiang Qin
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106
| | - Sukesh Voruganti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106
| | - Subhasree Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, 210029, P. R. China
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106.,Center for Cancer Biology and Therapy, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106
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Wang Y, Zhang X, Zhang Y, Zhu Y, Yuan C, Qi B, Zhang W, Wang D, Ding X, Wu H, Cheng J. Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma. Cancer Biol Ther 2015; 16:839-45. [PMID: 25970228 PMCID: PMC4622565 DOI: 10.1080/15384047.2015.1030551] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 03/05/2015] [Accepted: 03/08/2015] [Indexed: 12/24/2022] Open
Abstract
Abnormal glucose metabolism mediated by pyruvate kinase M2 (PKM2) fuels cancer overgrowth and propagation. However, its expression and oncogenic roles in in oral squamous cell carcinoma (OSCC) remains incompletely known. Here, we aimed to investigate the expression of PKM2, its prognostic values and oncogenic functions using 7,12-dimethyl-1,2-bezan-tracene (DMBA)-induced hamster buccal pouch SCC model, primary OSCC specimens as well as in vitro cellular assays. We found that in DMBA-induced OSCC model, negative PKM2 expression was commonly observed in normal epithelial, while more PKM2 abundance was detected in hyperplasia, dysplasia and SCC. Overexpression of PKM2 in a major fraction of OSCC significantly associated with tumor size (P = 0.027), cervical node metastasis (P = 0.004) and clinical stages (P = 0.000). Patients with increased PKM2 had remarkably reduced overall and disease-free survival. Multivariate survival analysis further revealed that PKM served as a critical independent prognostic factor for patients' overall survival. Furthermore, impaired cell proliferation and migration, and reduced apoptosis were detected upon PKM2 knockdown in HN4 and HN12 cells. Taken together, our findings reveal that PKM2 is critically involved in OSCC initiation and progression probably by promoting cell proliferation and migration as well as reducing apoptosis. Its overexpression correlates with aggressive clinicopathological features and poor patients' outcome.
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Affiliation(s)
- Yanling Wang
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- Department of Oral and Maxillofacial Surgery; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- These authors equally contributed to this work.
| | - Xiaomin Zhang
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- Department of Oral and Maxillofacial Surgery; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- These authors equally contributed to this work.
| | - Yuchao Zhang
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- Department of Oral and Maxillofacial Surgery; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Yuming Zhu
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Chunping Yuan
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Bin Qi
- Department of Oral Pathology; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Wei Zhang
- Department of Oral Pathology; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Dongmiao Wang
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Xu Ding
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Heming Wu
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- Department of Oral and Maxillofacial Surgery; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
- Department of Oral and Maxillofacial Surgery; Affiliated Stomatological Hospital; Nanjing Medical University; Nanjing, PR China
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Bhattacharya R, Mustafi SB, Street M, Dey A, Dwivedi SKD. Bmi-1: At the crossroads of physiological and pathological biology. Genes Dis 2015; 2:225-239. [PMID: 26448339 PMCID: PMC4593320 DOI: 10.1016/j.gendis.2015.04.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells. Despite three decades of research that have elucidated the transcriptional regulation, post-translational modifications and functions of Bmi-1 in regulating the DNA damage response, cellular bioenergetics, and pathologies, the entire potential of a protein with such varied functions remains to be realized. This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer. Additionally, since cancer stem cells are emerging as a new paradigm for therapy resistance, the role of Bmi-1 in this perspective is also highlighted. The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy. Nonetheless, new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.
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Affiliation(s)
- Resham Bhattacharya
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Soumyajit Banerjee Mustafi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Mark Street
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Anindya Dey
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
| | - Shailendra Kumar Dhar Dwivedi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States of America
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Zhou Y, Zhang L, Pan H, Wang B, Yan F, Fang X, Munnee K, Tang Z. Bmi1 essentially mediates podocalyxin-enhanced Cisplatin chemoresistance in oral tongue squamous cell carcinoma. PLoS One 2015; 10:e0123208. [PMID: 25915207 PMCID: PMC4411128 DOI: 10.1371/journal.pone.0123208] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 03/01/2015] [Indexed: 11/24/2022] Open
Abstract
Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.
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Affiliation(s)
- Yueying Zhou
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Leiyi Zhang
- Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Pan
- Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China
| | - Baisheng Wang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Fei Yan
- Department of Prosthodontics, Xiangya Stomatological Hospital, Central South University, Changsha, China
| | - Xiaodan Fang
- Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China
| | - Krishna Munnee
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhangui Tang
- Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China
- * E-mail:
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50
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He Q, Liu Z, Zhao T, Zhao L, Zhou X, Wang A. Bmi1 drives stem-like properties and is associated with migration, invasion, and poor prognosis in tongue squamous cell carcinoma. Int J Biol Sci 2015; 11:1-10. [PMID: 25552924 PMCID: PMC4278249 DOI: 10.7150/ijbs.10405] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 10/17/2014] [Indexed: 11/05/2022] Open
Abstract
Bmi1 (B-cell-specific Moloney murine leukemia virus insertion site 1) had been found to involve in self -renewal of stem cells and tumorigenesis in various malignancies. The purpose of this study is to evaluate the role of Bmi1 in the development of tongue squamous cell carcinoma (TSCC) and its functional effect on the migration and invasion of TSCC. Initially, immunohistochemistry revealed that Bmi1 overexpression was a common event in premalignant dysplasia, primary TSCC, and lymph node metastases and was associated with a poor prognosis. A significant correlation between Bmi1 and SOD2 (manganese superoxide dismutase) expression was observed. Side population (SP) cells were used as cancer stem-like cells and further assessed by sphere and colony formation assays, and the expression of stem cell markers. TSCC cells with higher migration and invasion ability (UM1 cell lines) showed a higher proportion of SP cells and Bmi1 expression than TSCC cells with lower migration and invasion ability (UM2 cell lines). Knockdown of Bmi1 in UM1 or SP cells inhibited migration and invasion and decreased the sphere and colony formation, and the expression of stem cell markers and SOD2. Direct binding of C-myc to the Bmi1 promoter was demonstrated by chromatin immunoprecipitation and luciferase assays. Moreover, C-myc knockdown in SP cells inhibited their migration and invasion and decreased the expression of Bmi1 and SOD2. Our results indicate that the deregulation of Bmi1 expression is a frequent event during the progression of TSCC and may have a prognostic value for patients with this disease. The Bmi1-mediated migration and invasion of TSCC is related to cancer stem-like cells and involves the C-myc-Bmi1-SOD2 pathway.
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Affiliation(s)
- Qianting He
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhonghua Liu
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tingting Zhao
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Luodan Zhao
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaofeng Zhou
- 2. Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612-7213, USA. ; 3. Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612-7213, USA
| | - Anxun Wang
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
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