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Lv M, Yang X, Xu C, Song Q, Zhao H, Sun T, Liu J, Zhang Y, Sun G, Xue Y, Zhang Z. SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2412553. [PMID: 40298941 DOI: 10.1002/advs.202412553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 03/13/2025] [Indexed: 04/30/2025]
Abstract
Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage-gated calcium channel subunit α2δ1-mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1-positive pancreatic tumor-initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA-binding capacity, enhanced glycolytic substrate 2-PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1-K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1-mediated calcium signaling to SIRT4-mediated histone lactylation epigenetic reprogramming in promoting the stem cell-like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer.
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Affiliation(s)
- Mengzhu Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Xiaodan Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Congcong Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
- State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China
| | - Qingru Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Hailian Zhao
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P. R. China
| | - Tianjiao Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pharmacy, Peking University Cancer Hospital and Institute, Beijing, 100142, P. R. China
| | - Yuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Guogui Sun
- Department of Chemoradiation, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei, 063000, P.R. China
| | - Yuanchao Xue
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P. R. China
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
- State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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3
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Lin J, Wang X, Ma S, Yang D, Li K, Li D, Zeng X. Calcium channels as therapeutic targets in head and neck squamous cell carcinoma: current evidence and clinical trials. Front Oncol 2024; 14:1516357. [PMID: 39759147 PMCID: PMC11695298 DOI: 10.3389/fonc.2024.1516357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) originates from the mucosal epithelium of the oral cavity, pharynx, and larynx, and is marked by high rates of recurrence and metastasis. Calcium signaling is associated with the progression of HNSCC and the development of drug resistance. Changes in calcium ion flow can trigger severe pathophysiological processes, including malignant transformation, tumor proliferation, epithelial-mesenchymal transition, and apoptosis evasion. Calcium channels regulate and facilitate these processes. Remodeling of calcium signaling has become one of the most prevalent adaptive mechanisms in cancer cells. Preclinical and clinical evidence indicates that alterations in calcium signaling are crucial for the progression of HNSCC. This review examines the role of calcium channels in HNSCC development and evaluates current clinical trials targeting these channels to assess the feasibility of calcium signaling-based therapies for HNSCC.
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Affiliation(s)
| | | | | | | | | | - Dongcai Li
- Department of Otolaryngology, Longgang Otolaryngology hospital & Shenzhen Key Laboratory of Otolaryngology, Shenzhen Institute of Otolaryngology, Shenzhen, China
| | - Xianhai Zeng
- Department of Otolaryngology, Longgang Otolaryngology hospital & Shenzhen Key Laboratory of Otolaryngology, Shenzhen Institute of Otolaryngology, Shenzhen, China
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4
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Li S, Li W, Miao Y, Gao M, Jia Y, Chen Z, Chen X, Pan T, Zhang S, Xing Z, Han S, Sun XL, Wei X, Liu Z, Zhou W, Wu W, Liu F, Han L, Zhu H, Ye H, Liu L, Li Y, Zhang P, Gong J, Tian Y, Ai Y, Cao P, Wu D, Qi X, Gui S, Wu QF. Modeling craniopharyngioma for drug screening reveals a neuronal mechanism for tumor growth. Sci Transl Med 2024; 16:eadn6763. [PMID: 39693408 DOI: 10.1126/scitranslmed.adn6763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 07/15/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024]
Abstract
Tumors occurring along the hypothalamus-pituitary axis receive axonal projection from neuroendocrine neurons, but it remains unclear whether neuroendocrine neuronal activity drives tumor expansion. Craniopharyngioma is a common suprasellar tumor with a propensity for invading the hypothalamus, leading to devastating endocrine and metabolic disorders. Here, we developed two autochthonous animal models that faithfully recapitulate the molecular pathology, clinical manifestations, and transcriptomic profiles of papillary craniopharyngioma. Using high-throughput drug screening, we identified 74 compounds with potent antitumor efficacy. The administration of (S)-amlodipine besylate achieved tumor regression in vivo, potentially by abrogating calcium transients and neuron-to-tumor chemical transmission. Chemogenetic manipulation of neuroendocrine neuronal activity bidirectionally regulated tumor cell growth in our mouse model, suggesting that craniopharyngioma hijacks hypothalamic neurons to promote tumor progression. These findings deepen our understanding of suprasellar tumor biology and offer promising avenues for clinical exploration of effective chemotherapies.
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Affiliation(s)
- Si Li
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Wei Li
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Yuqi Miao
- Department of Endocrinology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | | | - Yanfei Jia
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Zhenhua Chen
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xi Chen
- BGI Research, Beijing 102601, China
- BGI Research, Shenzhen 518083, China
| | | | - Shuangfeng Zhang
- National Institute of Biological Sciences, Beijing 102206, China
| | - Zhifang Xing
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Shuping Han
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xue-Lian Sun
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaochan Wei
- BGI Research, Shenzhen 518083, China
- BGI Research, Hangzhou 310030, China
| | - Zhiming Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Wentao Zhou
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Wentao Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Fangzheng Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Lei Han
- BGI Research, Hangzhou 310030, China
| | | | - Hongying Ye
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, China
| | | | - Yinqing Li
- IDG/McGovern Institute for Brain Research, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Peng Zhang
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing 100045, China
| | - Jian Gong
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Yongji Tian
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Youwei Ai
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Peng Cao
- National Institute of Biological Sciences, Beijing 102206, China
| | - Di Wu
- Department of Endocrinology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Xiangbing Qi
- National Institute of Biological Sciences, Beijing 102206, China
| | - Songbai Gui
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Qing-Feng Wu
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing 100045, China
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Beijing 100101, China
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Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
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Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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6
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Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
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Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
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Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
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8
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Wei Y, Chen Q, Chen J, Zhou C, Geng S, Shi D, Huang S, Liang Z, Chen X, Ren N, Jiang J. Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction. Cell Rep 2023; 42:113588. [PMID: 38117655 DOI: 10.1016/j.celrep.2023.113588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/31/2023] [Accepted: 11/30/2023] [Indexed: 12/22/2023] Open
Abstract
CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133+ cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133+ cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.
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Affiliation(s)
- Yuanyan Wei
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
| | - Qihang Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Jiayue Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Chenhao Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai 201199, P.R. China
| | - Shuting Geng
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Danfang Shi
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Sijing Huang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Zhiwei Liang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Xiaoning Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Ning Ren
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai 201199, P.R. China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, P.R. China.
| | - Jianhai Jiang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
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Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. Sniping Cancer Stem Cells with Nanomaterials. ACS NANO 2023; 17:23262-23298. [PMID: 38010076 DOI: 10.1021/acsnano.3c07828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.
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Affiliation(s)
- Wen-Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Yan-Yu Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhong-Lu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Guang-Liang Su
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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10
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Shan E, Cao YN, Zhang Y, Chen W, Ren X, Zhu S, Xi X, Mu S, Ma M, Zhi T, Li X. Integrated profiling identifies CACNG3 as a prognostic biomarker for patients with glioma. BMC Cancer 2023; 23:846. [PMID: 37697240 PMCID: PMC10494363 DOI: 10.1186/s12885-023-10896-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 04/27/2023] [Indexed: 09/13/2023] Open
Abstract
Gliomas are the most common malignant primary brain tumors in adults with poor prognoses. The purpose of this study is to explore CACNG3 as a prognostic factor that is closely related to the progression and survival outcome of gliomas and to provide a potential new molecular target for the diagnosis and treatment of glioma patients. CACNG3 expression and related clinical data were collected from three major databases of The Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO). The CGGA dataset was used as a training set, and TCGA and GEO datasets obtained from the GEO database were used for validation. CACNG3 was expressed at low levels in the tumor group, and the overall survival (OS) in patients with low CACNG3 expression is shorter. Furthermore, CACNG3 expression was negatively associated with glioma grades, which was confirmed in the IHC results of clinical samples. The expression level of CACNG3 in the IDH1 wide-type group, 1p/19q non-codel group, and mesenchymal subtype group was significantly reduced, and the results showed that CACNG3 could serve as a biomarker for the mesenchymal molecular subtype. In addition, the univariate and multivariate analysis verified the prognostic value of CACNG3 in predicting the OS of gliomas of all grades. The results of functional annotation and pathway enrichment analysis of differently expressed genes(DEGs), showed that CACNG3 might affect the development of glioma by interfering with synaptic transmission. Moreover, temozolomide (TMZ), commonly used in the treatment of glioma, increased CACNG3 expression in a dose and time-dependent manner. Therefore, CACNG3 plays a vital role in the occurrence and development of gliomas and can serve as a potential biomarker for targeted therapy and further investigation in the future.
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Affiliation(s)
- Enfang Shan
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Yi-Nan Cao
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
- Department of Medical Imaging, Nanjing Vocational Health School, No. 40, Xiaozhuang, Qixia District, Nanjing, Jiangsu Province, 210046, China
| | - Yang Zhang
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Wen Chen
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Xurui Ren
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Shanjie Zhu
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Xueru Xi
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China
| | - Shuai Mu
- Department of Oncology, Senior Department of Oncology, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100039, China
| | - Mian Ma
- Department of Neurosurgery, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, No.242 Guangji road, Suzhou, Jiangsu Province, 215008, China
| | - Tongle Zhi
- The First People's Hospital of Yancheng, The Fourth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, 224006, China.
| | - Xianwen Li
- School of Nursing, Nanjing Medical University, No.140 Hanzhong Road, Nanjing, Jiangsu Province, 210000, China.
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11
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Haustrate A, Shapovalov G, Spriet C, Cordier C, Kondratskyi A, Noyer L, Foulquier F, Prevarskaya N, Lehen'kyi V. TRPV6 Calcium Channel Targeting by Antibodies Raised against Extracellular Epitopes Induces Prostate Cancer Cell Apoptosis. Cancers (Basel) 2023; 15:cancers15061825. [PMID: 36980711 PMCID: PMC10046753 DOI: 10.3390/cancers15061825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/20/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
The TRPV6 calcium channel is known to be up-regulated in various tumors. The efforts to target the TRPV6 channel in vivo are still ongoing to propose an effective therapy against cancer. Here, we report the generation of two antibodies raised against extracellular epitopes corresponding to the extracellular loop between S1 and S2 (rb79) and the pore region (rb82). These antibodies generated a complex biphasic response with the transient activation of the TRPV6 channel. Store-operated calcium entry was consequently potentiated in the prostate cancer cell line LNCaP upon the treatment. Both rb79 and rb82 antibodies significantly decreased cell survival rate in a dose-dependent manner as compared to the control antibodies of the same isotype. This decrease was due to the enhanced cell death via apoptosis revealed using a sub-G1 peak in a cell cycle assay, TUNEL assay, and a Hoechst staining, having no effects in the PC3Mtrpv6-/- cell line. Moreover, all TUNEL-positive cells had TRPV6 membrane staining as compared to the control antibody treatment where TRPV6-positive cells were all TUNEL negative. These data clearly demonstrate that TRPV6 channel targeting using rb79 and rb82 antibodies is fatal and may be successfully used in the anticancer therapies.
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Affiliation(s)
- Aurélien Haustrate
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
- FONDATION ARC, 9 rue Guy Môquet, 94830 Villejuif, France
| | - George Shapovalov
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
| | - Corentin Spriet
- Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), CNRS, UMR 8576, Université de Lille, 59000 Lille, France
| | - Clément Cordier
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
| | - Artem Kondratskyi
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
| | - Lucile Noyer
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
| | - François Foulquier
- Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), CNRS, UMR 8576, Université de Lille, 59000 Lille, France
| | - Natalia Prevarskaya
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
| | - V'yacheslav Lehen'kyi
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
- FONDATION ARC, 9 rue Guy Môquet, 94830 Villejuif, France
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12
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Yan ZJ, Chen L, Wang HY. To be or not to be: The double-edged sword roles of liver progenitor cells. Biochim Biophys Acta Rev Cancer 2023; 1878:188870. [PMID: 36842766 DOI: 10.1016/j.bbcan.2023.188870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/28/2023] [Indexed: 02/28/2023]
Abstract
Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.
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Affiliation(s)
- Zi-Jun Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
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13
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Song Q, Zhang K, Sun T, Xu C, Zhao W, Zhang Z. Knockout of ENO1 leads to metabolism reprogramming and tumor retardation in pancreatic cancer. Front Oncol 2023; 13:1119886. [PMID: 36845730 PMCID: PMC9950624 DOI: 10.3389/fonc.2023.1119886] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/06/2023] [Indexed: 02/12/2023] Open
Abstract
The shift in glucose utilization from oxidative phosphorylation to glycolysis is the hallmark of tumor cells. The overexpression of ENO1, one of the key enzymes in the glycolysis process, has been identified in several cancers, however, its role in pancreatic cancer (PC) is yet unclear. This study identifies ENO1 as an indispensable factor in the progression of PC. Interestingly, ENO1-knockout could inhibit cell invasion and migration and prevent cell proliferation in pancreatic ductal adenocarcinoma (PDAC) cells (PANC-1 and MIA PaCa-2); meanwhile, tumor cell glucose uptake and lactate excretion also decreased significantly. Furthermore, ENO1-knockout reduced colony formation and tumorigenesis in both in vitro and in vivo tests. In total, after ENO1 knockout, 727 differentially expressed genes (DEGs) were identified in PDAC cells by RNA-seq. Gene Ontology enrichment analysis revealed that these DEGs are mainly associated with components such as the 'extracellular matrix' and 'endoplasmic reticulum lumen', and participate in the regulation of signal receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the identified DEGs are associated with pathways, such as 'fructose and mannose metabolism', 'pentose phosphate pathway, and 'sugar metabolism for amino and nucleotide. Gene Set Enrichment Analysis showed that ENO1 knockout promoted the upregulation of oxidative phosphorylation and lipid metabolism pathways-related genes. Altogether, these results indicated that ENO1-knockout inhibited tumorigenesis by reducing cell glycolysis and activating other metabolic pathways by altering the expression of G6PD, ALDOC, UAP1, as well as other related metabolic genes. Concisely, ENO1, which plays a vital role in the abnormal glucose metabolism in PC, can be exploited as a target to control carcinogenesis by reducing aerobic glycolysis.
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Affiliation(s)
| | | | | | | | | | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing, China
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14
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Role of the Ca2+ channel α2δ-1 auxiliary subunit in proliferation and migration of human glioblastoma cells. PLoS One 2022; 17:e0279186. [PMID: 36520928 PMCID: PMC9754164 DOI: 10.1371/journal.pone.0279186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
The overexpression of α2δ-1 is related to the development and degree of malignancy of diverse types of cancer. This protein is an auxiliary subunit of voltage-gated Ca2+ (CaV) channels, whose expression favors the trafficking of the main pore-forming subunit of the channel complex (α1) to the plasma membrane, thereby generating an increase in Ca2+ entry. Interestingly, TLR-4, a protein belonging to the family of toll-like receptors that participate in the inflammatory response and the transcription factor Sp1, have been linked to the progression of glioblastoma multiforme (GBM). Therefore, this report aimed to evaluate the role of the α2δ-1 subunit in the progression of GBM and investigate whether Sp1 regulates its expression after the activation of TLR-4. To this end, the expression of α2δ-1, TLR-4, and Sp1 was assessed in the U87 human glioblastoma cell line, and proliferation and migration assays were conducted using different agonists and antagonists. The actions of α2δ-1 were also investigated using overexpression and knockdown strategies. Initial luciferase assays and Western blot analyses showed that the activation of TLR-4 favors the transcription and expression of α2δ-1, which promoted the proliferation and migration of the U87 cells. Consistent with this, overexpression of α2δ-1, Sp1, and TLR-4 increased cell proliferation and migration, while their knockdown with specific siRNAs abrogated these actions. Our data also suggest that TLR-4-mediated regulation of α2δ-1 expression occurs through the NF-kB signaling pathway. Together, these findings strongly suggest that the activation of TLR-4 increases the expression of α2δ-1 in U87 cells, favoring their proliferative and migratory potential, which might eventually provide a theoretical basis to examine novel biomarkers and molecular targets for the diagnosis and treatment of GBM.
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15
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Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation. Int J Mol Sci 2022; 23:ijms232012327. [PMID: 36293184 PMCID: PMC9604119 DOI: 10.3390/ijms232012327] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
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Liu J, Tao M, Zhao W, Song Q, Yang X, Li M, Zhang Y, Xiu D, Zhang Z. Calcium Channel α2δ1 is Essential for Pancreatic Tumor-Initiating Cells through Sequential Phosphorylation of PKM2. Cell Mol Gastroenterol Hepatol 2022; 15:373-392. [PMID: 36244646 PMCID: PMC9791133 DOI: 10.1016/j.jcmgh.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS Tumor-initiating cells (TICs) drive pancreatic cancer tumorigenesis, therapeutic resistance, and metastasis. However, TICs are highly plastic and heterogenous, which impede the robust identification and targeted therapy of such a population. The aim of this study is to identify the surface marker and therapeutic target for pancreatic TICs. METHODS We isolated voltage-gated calcium channel α2δ1 subunit (isoform 5)-positive subpopulation from pancreatic cancer cell lines and freshly resected primary tissues by fluorescence-activated cell sorting and evaluated their TIC properties by spheroid formation and tumorigenic assays. Coimmunoprecipitation was used to identify the direct substrate of CaMKⅡδ. RESULTS We demonstrate that the voltage-gated calcium channel α2δ1 subunit (isoform 5) marks a subpopulation of pancreatic TICs with the highest TIC frequency among the known pancreatic TIC markers tested. Furthermore, α2δ1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx, which activates CaMKⅡδ to directly phosphorylate PKM2 at T454 that results in subsequent phosphorylation at Y105 to translocate into nucleus, enhancing the stem-like properties. Interestingly, blocking α2δ1 with its specific antibody has remarkably therapeutic effects on pancreatic cancer xenografts by reducing TICs. CONCLUSIONS α2δ1 promotes pancreatic TIC properties through sequential phosphorylation of PKM2 mediated by CaMKⅡδ, and targeting α2δ1 provides a therapeutic strategy against TICs for pancreatic cancer.
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Affiliation(s)
- Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China; Department of Pharmacology, Peking University Cancer Hospital and Institute, Beijing, P.R. China
| | - Ming Tao
- Department of General Surgery, Peking University Third Hospital, Beijing, P.R. China
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China
| | - Qingru Song
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China
| | - Xiaodan Yang
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China
| | - Meng Li
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China
| | - Yanhua Zhang
- Department of Pharmacology, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
| | - Dianrong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, P.R. China.
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
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17
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Li S, Lee DJ, Kim HY, Kim JY, Jung YS, Jung HS. Unraveled roles of Cav1.2 in proliferation and stemness of ameloblastoma. Cell Biosci 2022; 12:145. [PMID: 36057617 PMCID: PMC9440535 DOI: 10.1186/s13578-022-00873-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/04/2022] [Indexed: 11/24/2022] Open
Abstract
Background Transcriptome analysis has been known as a functional tool for cancer research recently. Mounting evidence indicated that calcium signaling plays several key roles in cancer progression. Despite numerous studies examining calcium signaling in cancer, calcium signaling studies in ameloblastoma are limited. Results In the present study, comparative transcriptome profiling of two representative odontogenic lesions, ameloblastoma and odontogenic keratocyst, revealed that Cav1.2 (CACNA1C, an L-type voltage-gated calcium channel) is strongly enriched in ameloblastoma. It was confirmed that the Ca2+ influx in ameloblastoma cells is mainly mediated by Cav1.2 through L-type voltage-gated calcium channel agonist and blocking reagent treatment. Overexpression and knockdown of Cav1.2 showed that Cav1.2 is directly involved in the regulation of the nuclear translocation of nuclear factor of activated T cell 1 (NFATc1), which causes cell proliferation. Furthermore, a tumoroid study indicated that Cav1.2-dependent Ca2+ entry is also associated with the maintenance of stemness of ameloblastoma cells via the enhancement of Wnt/β-catenin signaling activity. Conclusion In conclusion, Cav1.2 regulates the NFATc1 nuclear translocation to enhance ameloblastoma cell proliferation. Furthermore, Cav1.2 dependent Ca2+ influx contributes to the Wnt/β-catenin activity for the ameloblastoma cell stemness and tumorigenicity. Our fundamental findings could have a major impact in the fields of oral maxillofacial surgery, and genetic manipulation or pharmacological approaches to Cav1.2 can be considered as new therapeutic options. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00873-9.
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18
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Huang B, Miao L, Liu J, Zhang J, Li Y. A promising antitumor method: Targeting CSC with immune cells modified with CAR. Front Immunol 2022; 13:937327. [PMID: 36032145 PMCID: PMC9403009 DOI: 10.3389/fimmu.2022.937327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/20/2022] [Indexed: 11/30/2022] Open
Abstract
Tumors pose a great threat to human health; as a subgroup of tumor cells, cancer stem cells (CSCs) contribute to the genesis, development, metastasis, and recurrence of tumors because of their enhanced proliferation and multidirectional differentiation. Thus, a critical step in tumor treatment is to inhibit CSCs. Researchers have proposed many methods to inhibit or reduce CSCs, including monoclonal antibodies targeting specific surface molecules of CSCs, signal pathway inhibitors, and energy metabolic enzyme inhibitors and inducing differentiation therapy. Additionally, immunotherapy with immune cells engineered with a chimeric antigen receptor (CAR) showed favorable results. However, there are few comprehensive reviews in this area. In this review, we summarize the recent CSC targets used for CSC inhibition and the different immune effector cells (T cells, natural killer (NK) cells, and macrophages) which are engineered with CAR used for CSC therapy. Finally, we list the main challenges and options in targeting CSC with CAR-based immunotherapy. The design targeting two tumor antigens (one CSC antigen and one mature common tumor antigen) should be more reasonable and practical; meanwhile, we highlight the potential of CAR-NK in tumor treatment.
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Affiliation(s)
- Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Jie Liu
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Jiaxing Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Yumin Li,
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Zhao J, Li M, Xu J, Cheng W. The modulation of ion channels in cancer chemo-resistance. Front Oncol 2022; 12:945896. [PMID: 36033489 PMCID: PMC9399684 DOI: 10.3389/fonc.2022.945896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022] Open
Abstract
Ion channels modulate the flow of ions into and out of a cell or intracellular organelle, leading to generation of electrical or chemical signals and regulating ion homeostasis. The abundance of ion channels in the plasma and intracellular membranes are subject to physiological and pathological regulations. Abnormal and dysregulated expressions of many ion channels are found to be linked to cancer and cancer chemo-resistance. Here, we will summarize ion channels distribution in multiple tumors. And the involvement of ion channels in cancer chemo-resistance will be highlighted.
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20
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Store-Operated Calcium Entry and Its Implications in Cancer Stem Cells. Cells 2022; 11:cells11081332. [PMID: 35456011 PMCID: PMC9032688 DOI: 10.3390/cells11081332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 12/25/2022] Open
Abstract
Tumors are composed by a heterogeneous population of cells. Among them, a sub-population of cells, termed cancer stem cells, exhibit stemness features, such as self-renewal capabilities, disposition to differentiate to a more proliferative state, and chemotherapy resistance, processes that are all mediated by Ca2+. Ca2+ homeostasis is vital for several physiological processes, and alterations in the patterns of expressions of the proteins and molecules that modulate it have recently become a cancer hallmark. Store-operated Ca2+ entry is a major mechanism for Ca2+ entry from the extracellular medium in non-excitable cells that leads to increases in the cytosolic Ca2+ concentration required for several processes, including cancer stem cell properties. Here, we focus on the participation of STIM, Orai, and TRPC proteins, the store-operated Ca2+ entry key components, in cancer stem cell biology and tumorigenesis.
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Poly-dipeptides produced from C9orf72 hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS. Proc Natl Acad Sci U S A 2022; 119:e2113813119. [PMID: 35259014 PMCID: PMC8931230 DOI: 10.1073/pnas.2113813119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the C9orf72 repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of C9orf72 ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/β4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the C9orf72 mutation causes motor neuron hyperactivation that can lead to the motor neuron death in C9orf72 ALS.
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22
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Gao SH, Wang GZ, Wang LP, Feng L, Zhou YC, Yu XJ, Liang F, Yang FY, Wang Z, Sun BB, Wang D, Liang LJ, Xie DW, Zhao S, Feng HP, Li X, Li KK, Tang TS, Huang YC, Wang SQ, Zhou GB. Mutations and clinical significance of calcium voltage-gated channel subunit alpha 1E (CACNA1E) in non-small cell lung cancer. Cell Calcium 2022; 102:102527. [PMID: 35026540 DOI: 10.1016/j.ceca.2022.102527] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/02/2022] [Accepted: 01/04/2022] [Indexed: 12/14/2022]
Abstract
CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca2+ entrance, whereas calcium channel blockers inhibited NSCLC cell proliferation. These data indicate that CACNA1E is required for NSCLC cell proliferation, and blockade of this oncoprotein may have therapeutic potentials for this deadly disease.
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Affiliation(s)
- San-Hui Gao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Gui-Zhen Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Li-Peng Wang
- State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, 100091, China
| | - Lin Feng
- Department of Pathology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yong-Chun Zhou
- Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, 650106, China
| | - Xian-Jun Yu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Fan Liang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fu-Ying Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zheng Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bei-Bei Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Di Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Li-Jun Liang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Da-Wei Xie
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Song Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Hai-Ping Feng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Xueqing Li
- Computer Science Department, University of North Georgia, Dahlonega, GA, 30597, United States
| | - Keqin Kathy Li
- Computer Science Department, University of North Georgia, Dahlonega, GA, 30597, United States
| | - Tie-Shan Tang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Yun-Chao Huang
- Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, 650106, China
| | - Shi-Qiang Wang
- State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, 100091, China
| | - Guang-Biao Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Lai HT, Canoy RJ, Campanella M, Vassetzky Y, Brenner C. Ca2+ Transportome and the Interorganelle Communication in Hepatocellular Carcinoma. Cells 2022; 11:cells11050815. [PMID: 35269437 PMCID: PMC8909868 DOI: 10.3390/cells11050815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer with a poor prognosis for survival given the complications it bears on the patient. Though damages to the liver are acknowledged prodromic factors, the precise molecular aetiology remains ill-defined. However, many genes coding for proteins involved in calcium (Ca2+) homeostasis emerge as either mutated or deregulated. Ca2+ is a versatile signalling messenger that regulates functions that prime and drive oncogenesis, favouring metabolic reprogramming and gene expression. Ca2+ is present in cell compartments, between which it is trafficked through a network of transporters and exchangers, known as the Ca2+ transportome. The latter regulates and controls Ca2+ dynamics and tonicity. In HCC, the deregulation of the Ca2+ transportome contributes to tumorigenesis, the formation of metastasizing cells, and evasion of cell death. In this review, we reflect on these aspects by summarizing the current knowledge of the Ca2+ transportome and overviewing its composition in the plasma membrane, endoplasmic reticulum, and the mitochondria.
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Affiliation(s)
- Hong-Toan Lai
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
| | - Reynand Jay Canoy
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila 1000, Philippines
| | - Michelangelo Campanella
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London NW1 0TU, UK
- Consortium for Mitochondrial Research, University College London, London WC1 0TU, UK
- Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Yegor Vassetzky
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
| | - Catherine Brenner
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Correspondence:
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iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca 2+ homeostasis and control tumor growth and drug resistance. Proc Natl Acad Sci U S A 2022; 119:2111380119. [PMID: 35121659 PMCID: PMC8832991 DOI: 10.1073/pnas.2111380119] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2021] [Indexed: 12/13/2022] Open
Abstract
Accumulating preclinical and clinical evidence has supported a central role for alterations in Ca2+ homeostasis in the development of cancer. TMCO1 protein is an identified Ca2+-channel protein, while its roles in cancer remain obscure. Here, we found that TMCO1 is increased in colon cancer tissues. In addition, it is a substrate of E3 ligase Gp78. Enhanced oncogene iASPP stabilizes TMCO1 by competitively binding with Gp78. Inhibition of iASPP-TMCO1 sensitizes cancer cells’ response to Ca2+-induced apoptosis. This study has improved our fundamental understanding of the Ca2+ homeostasis in cancer cells. iASPP-TMCO1 axis may present a promising therapeutic target that can combine the conventional drugs to reinforce Ca2+-dependent apoptosis. Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca2+ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload–induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca2+ homeostasis.
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25
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Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 278] [Impact Index Per Article: 92.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
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26
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Zhao W, Lv M, Yang X, Zhou J, Xing B, Zhang Z. OUP accepted manuscript. Carcinogenesis 2022; 43:766-778. [PMID: 35436337 DOI: 10.1093/carcin/bgac035] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 03/20/2022] [Accepted: 04/14/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, P. R. China
| | - Mengzhu Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, P. R. China
| | - Xueying Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, P. R. China
| | - Jing Zhou
- Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100083, P. R. China
| | - Baocai Xing
- Department of Hepatobiliary Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, P. R. China
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, P. R. China
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27
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Liu Q, Dong Y, Yuan S, Yu M, Liu L, Zhang Q. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study. Open Med (Wars) 2021; 16:1395-1402. [PMID: 34611550 PMCID: PMC8447976 DOI: 10.1515/med-2021-0356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 11/15/2022] Open
Abstract
Voltage-dependent calcium channel subunit alpha-2/delta-1 (α2δ1) has been identified as a marker of cancer stem cells in multiple malignant tumor types. However, α2δ1’s role in the prognosis of hypopharyngeal squamous cell carcinoma (HSCC) was not reported. In our study, ten pairs of HSCC and peritumoral normal tissues were used for immunohistochemistry assessment. And α2δ1 expression levels of 34 more HSCC samples were also evaluated, represented by the integral optic density using Image-Pro Plus. Clinicopathological associations and prognostic value of α2δ1 were analyzed. As a result, α2δ1 expression was frequently increased in HSCC tissues. Although the correlation between patients’ clinicopathological characteristics and their α2δ1 expression levels was not significant, α2δ1 expression was significantly correlated with unfavorable overall survival (OS) (P = 0.018) and progression-free survival (PFS) (P = 0.023). Univariate and multivariate cox regression analyses suggested α2δ1’s prognostic role for both OS and PFS (P = 0.013 and 0.011, respectively). This study specifically demonstrated that α2δ1 regularly increased in HSCC compared with peritumoral tissues, and α2δ1 could act as a promising prognostic marker in HSCC patients.
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Affiliation(s)
- Qiang Liu
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Yanbo Dong
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shuoqing Yuan
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Minghang Yu
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Liangfa Liu
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Qing Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
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28
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Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis. Cancers (Basel) 2021; 13:cancers13133227. [PMID: 34203465 PMCID: PMC8267639 DOI: 10.3390/cancers13133227] [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: 04/18/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial-mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ-sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study's findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib's effect on sorafenib-resistant HCC cells.
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Fatma H, Siddique HR. Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer. Expert Rev Anticancer Ther 2021; 21:853-864. [PMID: 33832395 DOI: 10.1080/14737140.2021.1915137] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel-like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.Area covered: We cover recent discoveries and investigate the role of OSKM in inducing pluripotency and stem cell-like properties in various cancers with special emphasis on liver cancer. We review Yamanaka factors' role in stemness and chemoresistance of liver cancer.Expert opinion: In CSCs, including liver CSCs, the deregulation of various signaling pathways is one of the major reasons for stemness and drug resistance and is primarily due to OSKM. OSKM are responsible for tumor heterogeneity which renders targeting drug useless after a certain period. These factors can be exploited to understand the underlying mechanism of cancer stemness and resistance to chemotherapeutic drugs.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
| | - Hifzur Rahman Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
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30
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Chang Y, Roy S, Pan Z. Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers. Front Pharmacol 2021; 12:668730. [PMID: 34012400 PMCID: PMC8126661 DOI: 10.3389/fphar.2021.668730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal cancers, including tumors occurring in esophagus and stomach, usually have poor prognosis and lack effective chemotherapeutic drugs for treatment. The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging. This review summarizes the recent advances in understanding the contribution of SOCE-mediated intracellular Ca2+ signaling to gastroesophageal cancers. It assesses the pathophysiological role of each component in SOCE machinery, such as Orais and STIMs in the cancer cell proliferation, migration, and invasion as well as stemness maintenance. Lastly, it discusses efforts towards development of more specific and potent SOCE inhibitors, which may be a new set of chemotherapeutic drugs appearing at the horizon, to provide either targeted therapy or adjuvant treatment to overcome drug resistance for gastroesophageal cancers.
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Affiliation(s)
- Yan Chang
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Souvik Roy
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX, United States
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
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31
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Li M, Mu XD, Song JR, Zhai PT, Cheng Y, Le Y, Li ZB. PAF enhances cancer stem cell properties via β-catenin signaling in hepatocellular carcinoma. Cell Cycle 2021; 20:1010-1020. [PMID: 33970778 PMCID: PMC8172152 DOI: 10.1080/15384101.2021.1919826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/18/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Increasing proofs have declared that liver cancer stem cells (CSCs) are the main contributors to tumor initiation, metastasis, therapy resistance, and recurrence of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CSCs regulation remain largely unclear. Recently, PCNA-associated factor (PAF) was identified to play a key role in maintaining breast cancer cell stemness, but its role in liver cancer stem cells has not been declared yet. Herein, we found that both mRNA and protein expression levels of PAF were significantly higher in HCC tissues and cell lines than normal controls. CSC-enriched hepatoma spheres displayed an increase in PAF expression compared to monolayer-cultured cells. Both loss-of-function and gain-of-function experiments revealed that PAF enhanced sphere formation and the percentage of CD133+ or EpCAM+ cells in HCCLM3 and Huh7 cells. In the xenograft HCC tumor model, tumor initiation rates and tumor growth were suppressed by knockdown of PAF. Mechanistically, PAF can amplify the self-renewal of liver CSCs by activating β-catenin signaling. Taken together, our results demonstrate that PAF plays a crucial role in maintaining the hepatoma cell stemness by β-catenin signaling.Abbreviations: CSCs: cancer stem cells; HCC: hepatocellular carcinoma; PAF: pCNA-associated factor.
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Affiliation(s)
- Mei Li
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
| | - Xu-Dong Mu
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
| | - Juan-Rong Song
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
| | - Peng-Tao Zhai
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
| | - Yuan Cheng
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
| | - Yao Le
- Department of Infectious Diseases, Yulin First Hospital of Shaanxi Province, Yulin, China
| | - Zhu-Bin Li
- Department of Minimally Invasive Intervention, Shaanxi Provincial Cancer Hospital, Xi’an, China
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32
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Li M, Zhang W, Yang X, An G, Zhao W. The α2δ1 subunit of the voltage-gated calcium channel acts as a potential candidate for breast cancer tumor initial cells biomarker. Cancer Biomark 2021; 31:295-305. [PMID: 33896833 DOI: 10.3233/cbm-203165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The voltage-gated calcium channel subunit alpha 2 delta 1 (α2δ1) is a functional tumor initial cells (TICs) marker for some solid cancer cells. This study aimed to investigate whether α2δ1 can be used as a potential TIC marker for breast cancer cells. METHODS α2δ1+ and α2δ1- cells were identified and sorted from the breast cancer cell lines MDA-MB-231, MDA-MB-435s and ZR-75-1 by Immunofluorescence (IF) and Fluorescent-activated cell sorting (FACS) analyses. Spheroid formation in vitro and tumorigenesis in NOD/SCID mice were assessed to determine the self-renewal and serial transplantation abilities of these cells. Using a lentivirus infection system for α2δ1 in breast cancer cell lines, we determined the mRNA levels of stemnessassociated genes by quality real-time PCR (qRT-PCR). Boyden chamber and wounding assays were further performed to detect the migration of α2δ1 overexpression cells. Bioinformatics explored the relationship of molecular classification of breast cancer and drug resistance. RESULTS α2δ1 presents on the cytomembrane of breast cancer cells, with a positive rate of 1.5-3%. The α2δ1+ cells in breast cancer cell lines have a stronger self-renewal ability and tumor initiating properties in vitro and in vivo. Overexpressing α2δ1 successfully enhanced the sphere-forming efficiency, and upregulated the expression of stemness-associated genes, and increased cell migration. However, seldom significant was available between estrogen receptor +/- (ER+/-), progesterone receptor (PR+/-), and Her2+/-. CONCLUSIONS Breast cancer cells positive for the α2δ1 charactered tumor initiation, and α2δ1 is a potential TIC marker for breast cancer that further promotes the migration.
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Zhao W, Ma B, Tian Z, Han H, Tang J, Dong B, An G, Cao B, Wang B. Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. Br J Cancer 2021; 124:1237-1248. [PMID: 33473171 PMCID: PMC8007794 DOI: 10.1038/s41416-020-01240-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND This study aimed to investigate the possible role of inhibiting chromobox protein homologue 4 (CBX4) to deregulate of cancer stem cells (CSCs) and to evaluate the contribution of these molecules to sorafenib resistance in advanced hepatocellular carcinoma (HCC). METHODS HCC cell lines and a xenograft mouse model with resistance to sorafenib were employed to analyse the effects of miR424 on CSC characteristics. RNA expression was analysed by RT-PCR and next-generation sequencing in a cohort of HCC cancer patients and sorafenib-resistant (SR) cell lines, respectively, to validate the key microRNAs and targets in the network. RESULTS MicroRNA and mRNA profiles of SR cell lines identified miR424 and its direct target CBX4 as significantly associated with stem-cell-like properties, poor survival, and clinical characteristics. Functional experiments demonstrated that miR424 suppressed CBX4 and CBX4 induced nuclear translocation of YAP1 protein but was not associated with protein production. When YAP1 and CBX4 were modulated with CA3 and UNC3866, tumorigenicity and stem-like properties were extremely inhibited, thus indicating that these compounds exerted a strong anti-tumour effect in vivo against SR HCC cells. CONCLUSIONS Our results revealed that blocking CBX4 expression is critical in response to sorafenib resistance with advanced HCC.
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Affiliation(s)
- Wei Zhao
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Bo Ma
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Zhihua Tian
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Central Laboratory, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Haibo Han
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Laboratory Center, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Jintian Tang
- grid.459346.90000 0004 1758 0312Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang P.R. China
| | - Bin Dong
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Central Laboratory, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Guo An
- grid.412474.00000 0001 0027 0586Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Laboratory Animal, Peking University Cancer Hospital and Institute, 100142 Beijing, P.R. China
| | - Baoshan Cao
- grid.411642.40000 0004 0605 3760Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, 100191 Beijing, P.R. China
| | - Boqing Wang
- grid.459346.90000 0004 1758 0312Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang P.R. China
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Ma Y, Yang X, Zhao W, Yang Y, Zhang Z. Calcium channel α2δ1 subunit is a functional marker and therapeutic target for tumor-initiating cells in non-small cell lung cancer. Cell Death Dis 2021; 12:257. [PMID: 33707423 PMCID: PMC7952379 DOI: 10.1038/s41419-021-03522-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/26/2022]
Abstract
It is hypothesized that tumor-initiating cells (TICs) with stem cell-like properties constitute a sustaining force to drive tumor growth and renew fully established malignancy. However, the identification of such a population in non-small cell lung carcinoma (NSCLC) has been hindered by the lacking of reliable surface markers, and very few of the currently available surface markers are of functional significance. Here, we demonstrate that a subpopulation of TICs could be specifically defined by the voltage-gated calcium channel α2δ1 subunit from non-small cell lung carcinoma (NSCLC) cell lines and clinical specimens. The α2δ1+ NSCLC TICs are refractory to conventional chemotherapy, and own stem cell-like properties such as self-renewal, and the ability to generate heterogeneous tumors in NOD/SCID mice. Moreover, α2δ1+ NSCLC cells are more enriched for TICs than CD133+, or CD166+ cells. Interestingly, α2δ1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx into cells, which subsequently activate Calcineurin/NFATc2 signaling that directly activates the expression of NOTCH3, ABCG2. Importantly, a specific antibody against α2δ1 has remarkably therapeutic effects on NSCLC xenografts by eradicating TICs. Hence, targeting α2δ1 to prevent calcium influx provides a novel strategy for targeted therapy against TICs of NSCLC.
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MESH Headings
- A549 Cells
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Animals
- Antibodies, Monoclonal/pharmacology
- Antineoplastic Agents, Immunological/pharmacology
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Calcineurin/metabolism
- Calcium Channel Blockers/pharmacology
- Calcium Channels/drug effects
- Calcium Channels/genetics
- Calcium Channels/metabolism
- Calcium Signaling
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Proliferation
- Cell Self Renewal
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Mice, Inbred NOD
- Mice, SCID
- NFATC Transcription Factors/genetics
- NFATC Transcription Factors/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptor, Notch3/genetics
- Receptor, Notch3/metabolism
- Tumor Burden
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- Yuanyuan Ma
- Department of Thoracic Surgery Unit II, Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Xiaodan Yang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Yue Yang
- Department of Thoracic Surgery Unit II, Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
| | - Zhiqian Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
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Cao Y, Jiao N, Sun T, Ma Y, Zhang X, Chen H, Hong J, Zhang Y. CXCL11 Correlates With Antitumor Immunity and an Improved Prognosis in Colon Cancer. Front Cell Dev Biol 2021; 9:646252. [PMID: 33777950 PMCID: PMC7991085 DOI: 10.3389/fcell.2021.646252] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 02/16/2021] [Indexed: 12/11/2022] Open
Abstract
The chemokine ligand C-X-C motif chemokine ligand 11 (CXCL11) is involved in the progression of various cancers, but its biological roles in colorectal cancer (CRC) remain confused. Therefore, the prognostic value and underlying mechanism of CXCL11 in CRC were preliminarily evaluated. Three independent datasets were used for mRNA-related analysis: one dataset from the Cancer Genome Atlas (TCGA, n = 451) and two single-cell RNA sequencing (scRNA-seq) datasets from Gene Expression Omnibus (GEO): GSE146771 and GSE132465. In addition, a colon adenocarcinoma (COAD) patient cohort (the Yijishan Hospital cohort, YJSHC, n = 108) was utilized for analysis of cell infiltration by immunohistochemistry. We determined the distribution of CXCL11 in tumor tissue across all TCGA cancers and found that CXCL11 expression was significantly upregulated in both COAD and rectal adenocarcinoma (READ). However, the upregulation of CXCL11 mRNA was associated with a better prognosis in COAD, but not in READ. Within the YJSHC, the patients with a high abundance of intratumoral CXCL11+ cells had prolonged survival (p = 0.001). Furthermore, we found that the high CXCL11 expression group had a higher proportion of antitumor immune cells, and a lower proportion of protumor immune cells. Additionally, we discovered the changes of gene expression and enriched immune pathway network mediated by CXCL11. Interestingly, both cytotoxic genes (IFNG, GZMA, GZMB, GZMK, GZMM, and PRF1) and immunosuppressive molecules, including PD-L1, were positively correlated with CXCL11 expression. CXCL11, which promoted antitumor immunity to benefit survival, was identified as an independent prognostic biomarker in patients with COAD.
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Affiliation(s)
- Yingying Cao
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Nanlin Jiao
- Department of Pathology, Affiliated Yijishan Hospital, Wannan Medical College, Wuhu, China
| | - Tiantian Sun
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Yanru Ma
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Xinyu Zhang
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyan Chen
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Hong
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Youwei Zhang
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, Xuzhou, China
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Shiozaki A, Katsurahara K, Kudou M, Shimizu H, Kosuga T, Ito H, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Otsuji E. Amlodipine and Verapamil, Voltage-Gated Ca 2+ Channel Inhibitors, Suppressed the Growth of Gastric Cancer Stem Cells. Ann Surg Oncol 2021; 28:5400-5411. [PMID: 33566246 DOI: 10.1245/s10434-021-09645-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 12/06/2020] [Indexed: 11/18/2022]
Abstract
BACKGROUND The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs). METHODS Cells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis. RESULTS Among MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone. CONCLUSIONS The present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer.
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Affiliation(s)
- Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Keita Katsurahara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihiro Kudou
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Ito
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Shiozaki A, Katsurahara K, Otsuji E. ASO Author Reflections: Amlodipine and Verapamil, Voltage-Gated Ca 2+ Channel Inhibitors Suppressed the Growth of Gastric Cancer Stem Cells. Ann Surg Oncol 2021; 28:5412-5413. [PMID: 33555453 DOI: 10.1245/s10434-021-09647-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Keita Katsurahara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
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MicroRNA-107 inhibits proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1 in vitro. Anticancer Drugs 2021; 31:260-271. [PMID: 31725046 PMCID: PMC7028296 DOI: 10.1097/cad.0000000000000865] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our previous studies have confirmed that α2δ1 has the potential to function as a cancer stem cell marker, and CACNA2D1 is the coding gene of α2δ1. But it is unclear how microRNAs regulate the expression of the CACNA2D1 gene in laryngeal cancer cells. We detected the expressions of α2δ1 protein, microRNA-107, and CACNA2D1 in 40 pairs of laryngeal cancer tissues and adjacent normal tissues. Laryngeal squamous cell carcinoma cells, TU212 and TU686, were cultured and transfected in the blank control group, the agomiR negative control group, the agomiR-107 group, the antagomiR negative control group, or the antagomiR-107 group, and the dual-luciferase reporter assay was employed to assess the regulatory effect of microRNA-107 on CACNA2D1. Then, the effects of microRNA-107 on the biological function of laryngeal squamous cell carcinoma cells were detected by qRT-PCR, Western blot, MTT, cell migration/invasion assay, and cell colony-formation assay. Our data suggested that the protein level of α2δ1, encoded by CACNA2D1, in laryngeal carcinoma tissues was higher than that in adjacent normal tissues, while the expression of microRNA-107 was significantly decreased in laryngeal carcinoma tissues. The dual-luciferase reporter gene assay confirmed that microRNA-107 bound to the 3′-UTR two positions (202-209, 902-908) of CACNA2D1 mRNA. Moreover, the expression of CACNA2D1 and α2δ1 protein were significantly decreased in TU212 and TU686 cells transfected with microRNA-107 expression vectors (P < 0.05), and proliferation, clone formation, migration, and invasion of these cells were also reduced. Furthermore, after knocking down microRNA-107, exactly opposite results were obtained. Overexpression of microRNA-107 can inhibit the proliferation and invasion of laryngeal carcinoma cells in vitro.
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Hao W, Binbin J, Wei Y, Kun Y. Can Radiofrequency Ablation Replace Liver Resection for Solitary Colorectal Liver Metastasis? A Systemic Review and Meta-Analysis. Front Oncol 2020; 10:561669. [PMID: 33312946 PMCID: PMC7706822 DOI: 10.3389/fonc.2020.561669] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/24/2020] [Indexed: 12/24/2022] Open
Abstract
Radiofrequency ablation (RFA) can be a favorable option for patients with colorectal liver metastasis (CRLM). However, current reports about the therapeutic efficacy of liver resection (LR) and RFA for colorectal liver metastasis (CRLM) still remain controversial, especially for solitary CRLM. Therefore, this meta-analysis was performed to evaluate the therapeutic efficacy between LR and RFA for solitary CRLM. First, a comprehensive search for published studies was conducted using PubMed, the Cochrane Library Central, and Web of Science. Each study was reviewed and data extracted. In this meta-analysis, 10 studies (11 study arms) were finally included. The meta-analysis was performed using risk ratio (RR) and random effect model or fixed effect model, in which 95% confidence intervals (95% CI) for RR were calculated. The primary outcomes were disease-free survival (DFS) and overall survival (OS) at 1, 3, or 5 years plus complication rate. The results showed that patients treated by LR achieved better PFS and OS than those by RFA, but subgroup analysis and meta-regression displayed that the efficacy of RFA was equivalent to that of LR in solitary CRLM, when conditions were limited to tumors of ≤ 3 cm and fewer synchronous metastasis in the publication years 2011–2018. Meanwhile, RFA achieved lower complication rates when compared with LR. In conclusion, although patients treated by RFA cannot achieve better PFS and OS than those by LR, RFA can be considered a viable treatment option for solitary CRLM, with potentially lower complication rates.
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Affiliation(s)
- Wu Hao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jiang Binbin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yang Wei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yan Kun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing, China
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Evaluation of diagnostic accuracy of serum calcium channel α2δ1 subunit in hepatocellular carcinoma-related cirrhosis. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00053-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide that carries a bad prognosis particularly in Egypt due to the high prevalence of HCV burden. Late diagnosis of HCC especially in cirrhosis suffering-liver is one of the causes that worsen HCC outcome. Identification of molecular pathways of HCC will open the gate for early diagnosis and effective management. Oscillation of calcium controlled by the α2δ1 subunit has been proposed as one of the mechanisms in tumor-initiating cell properties of HCC. In this study, we aim to evaluate the serum α2δ1 subunit level as a biological marker for HCC. A total of 90 participants were enrolled, 40 patients with HCC, 40 patients with cirrhosis, and 10 healthy volunteers; serum level of α2δ1 was assessed in all participants with ELISA
Results
The mean serum levels of α2δ1 were significantly higher in HCC group (19.53 ± 6.87 ng/dL) than cirrhotic (6.24 ± 2.64 ng/dL) and control groups (0.67 ± 0.48 ng/dL) (P = 0.001). There was no significance between α2δ1 and etiology of liver disease as viral (HCV, HBV) or non-viral (P = 0.14).
Conclusion
α2δ1 subunit may serve as a potential non-invasive marker with excellent sensitivity for diagnosis of HCC regardless of the etiology of liver disease.
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Ali ES, Rychkov GY, Barritt GJ. Targeting Ca 2+ Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12102755. [PMID: 32987945 PMCID: PMC7600741 DOI: 10.3390/cancers12102755] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Liver cancer (hepatocellular carcinoma) is a significant health burden worldwide. It is often not detected until at an advanced stage when there are few treatment options available. Changes in calcium concentrations within liver cancer cells are essential for regulating their growth, death, and migration (metastasis). Our aim was to review published papers which have identified proteins involved in calcium signaling as potential drug targets for the treatment of liver cancer. About twenty calcium signaling proteins were identified, including those involved in regulating calcium concentrations in the cytoplasm, endoplasmic reticulum and mitochondria. A few of these have turned out to be sites of action of natural products previously known to inhibit liver cancer. More systematic studies are now needed to determine which calcium signaling proteins might be used clinically for treatment of liver cancer, especially advanced stage cancers and those resistant to inhibition by current drugs. Abstract Hepatocellular carcinoma (HCC) is a considerable health burden worldwide and a major contributor to cancer-related deaths. HCC is often not noticed until at an advanced stage where treatment options are limited and current systemic drugs can usually only prolong survival for a short time. Understanding the biology and pathology of HCC is a challenge, due to the cellular and anatomic complexities of the liver. While not yet fully understood, liver cancer stem cells play a central role in the initiation and progression of HCC and in resistance to drugs. There are approximately twenty Ca2+-signaling proteins identified as potential targets for therapeutic treatment at different stages of HCC. These potential targets include inhibition of the self-renewal properties of liver cancer stem cells; HCC initiation and promotion by hepatitis B and C and non-alcoholic fatty liver disease (principally involving reduction of reactive oxygen species); and cell proliferation, tumor growth, migration and metastasis. A few of these Ca2+-signaling pathways have been identified as targets for natural products previously known to reduce HCC. Promising Ca2+-signaling targets include voltage-operated Ca2+ channel proteins (liver cancer stem cells), inositol trisphosphate receptors, store-operated Ca2+ entry, TRP channels, sarco/endoplasmic reticulum (Ca2++Mg2+) ATP-ase and Ca2+/calmodulin-dependent protein kinases. However, none of these Ca2+-signaling targets has been seriously studied any further than laboratory research experiments. The future application of more systematic studies, including genomics, gene expression (RNA-seq), and improved knowledge of the fundamental biology and pathology of HCC will likely reveal new Ca2+-signaling protein targets and consolidate priorities for those already identified.
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Affiliation(s)
- Eunus S. Ali
- Department of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide 5001, South Australia, Australia;
| | - Grigori Y. Rychkov
- School of Medicine, The University of Adelaide, Adelaide 5005, South Australia, Australia;
- South Australian Health and Medical Research Institute, Adelaide 5005, South Australia, Australia
| | - Greg J. Barritt
- Department of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Adelaide 5001, South Australia, Australia;
- Correspondence: ; Tel.: +61-438-204-426
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Mou D, Yang X, Li S, Zhao W, Li M, Zhao M, Alotaibi NH, Zhang Z, Tang M, Alharbi KS, Bahman J, Bukhari SNA, Dézlla C. MG132 inhibits the expression of PBX3 through miRNAs by targeting Argonaute2 in hepatoma cells. Saudi J Biol Sci 2020; 27:2157-2163. [PMID: 32714042 PMCID: PMC7376200 DOI: 10.1016/j.sjbs.2020.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/23/2020] [Accepted: 06/05/2020] [Indexed: 11/04/2022] Open
Abstract
Cancer stem cells play important roles in the development of tumors also are important targets to therapy of cancer. Former researches had confirmed the pre-leukemia transcription factor 3 (PBX3) was involved in maintaining the characteristics of liver cancer stem cell. We found that PBX3 is an extremely unstable protein with a short half-life in hepatocellular carcinoma cells. Unstable proteins are believed to be susceptible to degradation by ubiquitin-proteasome system. However, when we treated hepatoma cells using the proteasome inhibitor MG132, found the levels of PBX3 protein and mRNA were significantly downregulated, suggesting that PBX3 protein is not degraded by the ubiquitin-proteasome system. Our study aims to investigate the mechanism of MG132 regulation of PBX3. We observed that the levels of miR-424, let-7c, miR-222, miR-200b were upregulated when hepatoma cells were treated with MG132, and this increase was negatively correlated with the levels of PBX3. Using the miRWalk algorithm, previous studies have predicted that these miRNAs target the PBX3 gene. Thus, we investigated the mechanism by which the proteasome inhibitor MG132 regulates these miRNAs. It has been reported that the Argonaute2 protein is an important component of the RNA-induced silencing complex (RISC), and it can regulate the levels of certain miRNAs. Consequently, we also investigated whether the proteasome inhibitor regulates related miRNAs by stabilizing Argonaute2. Using co-infection, co-immunoprecipitation (Co-IP), and western blot assays, we found that MG132 stabilizes the expression of the Argonuate2 protein by inhibiting its degradation via the ubiquitin-proteasome pathway. In summary, the PBX3 protein, which is closely linked to the stemness of hepatoma cells, does not undergo degradation by the ubiquitin-proteasome system (UPM).
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Affiliation(s)
- Daiyong Mou
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.,Clinical Laboratory of Nanchong Central Hospital, Nanchong 637000, China
| | - Xiaodan Yang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational. Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Sheng Li
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational. Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational. Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Meng Li
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational. Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Maoji Zhao
- Clinical Laboratory of Nanchong Central Hospital, Nanchong 637000, China
| | | | - Zhiqian Zhang
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.,Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational. Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Min Tang
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | | | - Joob Bahman
- Department of Biochemistry, Tabriz University of Medical Sciences, Tabriz 71348, Iran
| | | | - Cristina Dézlla
- Life Sciences College, Université de Picardie Jules Verne-Amiens, Amiens 49000, France
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Novel Therapeutic Approaches of Ion Channels and Transporters in Cancer. Rev Physiol Biochem Pharmacol 2020; 183:45-101. [PMID: 32715321 DOI: 10.1007/112_2020_28] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The expression and function of many ion channels and transporters in cancer cells display major differences in comparison to those from healthy cells. These differences provide the cancer cells with advantages for tumor development. Accordingly, targeting ion channels and transporters have beneficial anticancer effects including inhibition of cancer cell proliferation, migration, invasion, metastasis, tumor vascularization, and chemotherapy resistance, as well as promoting apoptosis. Some of the molecular mechanisms associating ion channels and transporters with cancer include the participation of oxidative stress, immune response, metabolic pathways, drug synergism, as well as noncanonical functions of ion channels. This diversity of mechanisms offers an exciting possibility to suggest novel and more effective therapeutic approaches to fight cancer. Here, we review and discuss most of the current knowledge suggesting novel therapeutic approaches for cancer therapy targeting ion channels and transporters. The role and regulation of ion channels and transporters in cancer provide a plethora of exceptional opportunities in drug design, as well as novel and promising therapeutic approaches that may be used for the benefit of cancer patients.
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma. Biomed Pharmacother 2020; 129:110315. [PMID: 32554246 DOI: 10.1016/j.biopha.2020.110315] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 04/16/2020] [Accepted: 05/21/2020] [Indexed: 12/16/2022] Open
Abstract
Sorafenib is a multi-kinase blocker and one of the few suggested drug treatments for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib may often occur over time and cause further tumor aggression. Recently, cancer stem cells were found in HCC and were speculated to be involved in tumor progression. SOX9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher SOX9 expression show poorer prognosis. Whether SOX9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased the proportion of SOX9 positive cells in HCC cell lines. Overexpression of exogenous SOX9 in HCC increased sorafenib resistance both in vitro and in vivo, whereas down-regulation led to inhibition of sorafenib resistance. Knock-down of SOX9 by RNA interference caused down-regulation of downstream genes, including ATP binding cassette subfamily G member 2 (ABCG2). The drug resistance to sorafenib caused by SOX9 overexpression could be ameliorated by ABCG2 inhibition in HCC cell lines. In the cohort of patients taken sorafenib, we found that patients with lower SOX9 expression had more prolonged overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox analysis shows that SOX9 expression exerts as an independent risk factor for the OS and PFS of HCC patients with sorafenib treatment. These findings demonstrate that SOX9 enhances sorafenib resistance and may regulate this process by modulating ABCG2 expression.
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Cancer stem cells and oral cancer: insights into molecular mechanisms and therapeutic approaches. Cancer Cell Int 2020; 20:113. [PMID: 32280305 PMCID: PMC7137421 DOI: 10.1186/s12935-020-01192-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) have been identified as a little population of cancer cells, which have features as the same as the cells normal stem cells. There is enough knowledge of the CSCs responsibility for metastasis, medicine resistance, and cancer outbreak. Therefore, CSCs control possibly provides an efficient treatment intervention inhibiting tumor growth and invasion. In spite of the significance of targeting CSCs in treating cancer, few study comprehensively explored the nature of oral CSCs. It has been showed that oral CSCs are able to contribute to oral cancer progression though activation/inhibition a sequences of cellular and molecular pathways (microRNA network, histone modifications and calcium regulation). Hence, more understanding about the properties of oral cancers and their behaviors will help us to develop new therapeutic platforms. Head and neck CSCs remain a viable and intriguing option for targeted therapy. Multiple investigations suggested the major contribution of the CSCs to the metastasis, tumorigenesis, and resistance to the new therapeutic regimes. Therefore, experts in the field are examining the encouraging targeted therapeutic choices. In spite of the advancements, there are not enough information in this area and thus a magic bullet for targeting and eliminating the CSCs deviated us. Hence, additional investigations on the combined therapies against the head and neck CSCs could offer considerable achievements. The present research is a review of the recent information on oral CSCs, and focused on current advancements in new signaling pathways contributed to their stemness regulation. Moreover, we highlighted various therapeutic approaches against oral CSCs.
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Lee H, Kim JW, Kim DK, Choi DK, Lee S, Yu JH, Kwon OB, Lee J, Lee DS, Kim JH, Min SH. Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells. Int J Mol Sci 2020; 21:ijms21072327. [PMID: 32230901 PMCID: PMC7177693 DOI: 10.3390/ijms21072327] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.
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Affiliation(s)
- Heejin Lee
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
| | - Jun Woo Kim
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
| | - Dae Kyung Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea;
| | - Dong Kyu Choi
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
| | - Seul Lee
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
| | - Ji Hoon Yu
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
| | - Oh-Bin Kwon
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
| | - Jungsul Lee
- 3 billion Inc., Seocho-gu, Seoul 06621, Korea;
| | - Dong-Seok Lee
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
- Correspondence: (D.-S.L.); (J.H.K.); (S.-H.M.)
| | - Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea;
- Correspondence: (D.-S.L.); (J.H.K.); (S.-H.M.)
| | - Sang-Hyun Min
- New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea; (H.L.); (J.W.K.); (D.K.C.); (J.H.Y.); (O.-B.K.)
- Correspondence: (D.-S.L.); (J.H.K.); (S.-H.M.)
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Liu S, Yang Z, Li G, Li C, Luo Y, Gong Q, Wu X, Li T, Zhang Z, Xing B, Xu X, Lu X. Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity. GENOMICS PROTEOMICS & BIOINFORMATICS 2020; 17:576-589. [PMID: 32205176 PMCID: PMC7212478 DOI: 10.1016/j.gpb.2018.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 05/29/2018] [Accepted: 07/24/2018] [Indexed: 12/27/2022]
Abstract
Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse.
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Affiliation(s)
- Sixue Liu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zuyu Yang
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (3)Invasive Pathogens Laboratory, Institute of Environmental Science and Research, Porirua 5022, Wellington, New Zealand
| | - Guanghao Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunyan Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanting Luo
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiang Gong
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xin Wu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Tao Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhiqian Zhang
- (4)Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research, Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Baocai Xing
- (5)Department of Hepatobiliary Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaolan Xu
- (6)National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Xuemei Lu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China; (7)CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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