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Ruan Z, Wang Y, Shi L, Yang XJ. Progress of research on glucose transporter proteins in hepatocellular carcinoma. World J Hepatol 2025; 17:104715. [DOI: 10.4254/wjh.v17.i3.104715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/02/2025] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.
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Affiliation(s)
- Zheng Ruan
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan Wang
- Division of Personnel, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
| | - Lei Shi
- Department of General Surgery, The Second people’s Hospital of Lanzhou, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Department of General Surgery, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
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2
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Li Y, Cao Q, Hu Y, He B, Cao T, Tang Y, Zhou XP, Lan XP, Liu SQ. Advances in the interaction of glycolytic reprogramming with lactylation. Biomed Pharmacother 2024; 177:116982. [PMID: 38906019 DOI: 10.1016/j.biopha.2024.116982] [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: 04/02/2024] [Revised: 06/03/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
Lactylation is a novel post-translational modification (PTM) involving proteins that is induced by lactate accumulation. Histone lysine lactylation alters chromatin spatial configuration, influencing gene transcription and regulating the expression of associated genes. This modification plays a crucial role as an epigenetic regulatory factor in the progression of various diseases. Glycolytic reprogramming is one of the most extensively studied forms of metabolic reprogramming, recognized as a key hallmark of cancer cells. It is characterized by an increase in glycolysis and the inhibition of the tricarboxylic acid (TCA) cycle, accompanied by significant lactate production and accumulation. The two processes are closely linked by lactate, which interacts in various physiological and pathological processes. On the one hand, lactylation levels generally correlate positively with the extent of glycolytic reprogramming, being directly influenced by the lactate concentration produced during glycolytic reprogramming. On the other hand, lactylation can also regulate glycolytic pathways by affecting the transcription and structural functions of essential glycolytic enzymes. This review comprehensively outlines the mechanisms of lactylation and glycolytic reprogramming and their interactions in tumor progression, immunity, and inflammation, with the aim of elucidating the relationship between glycolytic reprogramming and lactylation.
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Affiliation(s)
- Yue Li
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Qian Cao
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yibao Hu
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Bisha He
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Ting Cao
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yun Tang
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiang Ping Zhou
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiao Peng Lan
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Shuang Quan Liu
- Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Ma J, Wang PY, Zhuang J, Son AY, Karius AK, Syed AM, Nishi M, Wu Z, Mori MP, Kim YC, Hwang PM. CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise. Cell Rep 2024; 43:113626. [PMID: 38157298 PMCID: PMC10851177 DOI: 10.1016/j.celrep.2023.113626] [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: 04/05/2023] [Revised: 10/20/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024] Open
Abstract
Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.
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Affiliation(s)
- Jin Ma
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Ping-Yuan Wang
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Jie Zhuang
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA; School of Medicine, Nankai University, Tianjin 300071, China
| | - Annie Y Son
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Alexander K Karius
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Abu Mohammad Syed
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Masahiro Nishi
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Zhichao Wu
- Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA
| | - Mateus P Mori
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Young-Chae Kim
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
| | - Paul M Hwang
- Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA.
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4
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Deng Y, Liu L, Xiao X, Zhao Y. A four-gene-based methylation signature associated with lymph node metastasis predicts overall survival in lung squamous cell carcinoma. Genes Genet Syst 2023; 98:209-219. [PMID: 37839873 DOI: 10.1266/ggs.22-00111] [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] [Indexed: 10/17/2023] Open
Abstract
We aimed to identify prognostic methylation genes associated with lymph node metastasis (LNM) in lung squamous cell carcinoma (LUSC). Bioinformatics methods were used to obtain optimal prognostic genes for risk model construction using data from the Cancer Genome Atlas database. ROC curves were adopted to predict the prognostic value of the risk model. Multivariate regression was carried out to identify independent prognostic factors and construct a prognostic nomogram. The differences in overall survival, gene mutation and pathways between high- and low-risk groups were analyzed. Finally, the expression and methylation level of the optimal prognostic genes among different LNM stages were analyzed. FGA, GPR39, RRAD and TINAGL1 were identified as the optimal prognostic genes and were applied to establish a prognostic risk model. Significant differences were found among the different LNM stages. The risk model could predict overall survival, showing a moderate performance with AUC of 0.64-0.68. The model possessed independent prognostic value, and could accurately predict 1-, 3- and 5-year survival. Patients with a high risk score showed poorer survival. Lower gene mutation frequencies and enrichment of leukocyte transendothelial migration and the VEGF signaling pathway in the high-risk group may lead to the poor prognosis. This study identified several specific methylation markers associated with LNM in LUSC and generated a prognostic model to predict overall survival for LUSC patients.
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Affiliation(s)
- Yufei Deng
- Department of Pharmacy, Wuxi No.2 People's Hospital
| | - Lifeng Liu
- Department of Pharmacy, Wuxi No.2 People's Hospital
| | - Xia Xiao
- Department of Oncology, Wuxi No.2 People's Hospital
| | - Yin Zhao
- Department of Pharmacy, Wuxi No.2 People's Hospital
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5
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Xiao J, Sharma U, Arab A, Miglani S, Bhalla S, Suguru S, Suter R, Mukherji R, Lippman ME, Pohlmann PR, Zeck JC, Marshall JL, Weinberg BA, He AR, Noel MS, Schlegel R, Goodarzi H, Agarwal S. Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis. Cancers (Basel) 2023; 15:1831. [PMID: 36980717 PMCID: PMC10046547 DOI: 10.3390/cancers15061831] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.
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Affiliation(s)
- Jerry Xiao
- School of Medicine, Georgetown University, Washington, DC 20057, USA
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Utsav Sharma
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Abolfazl Arab
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Sohit Miglani
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Sonakshi Bhalla
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Shravanthy Suguru
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Robert Suter
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Reetu Mukherji
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Marc E. Lippman
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Paula R. Pohlmann
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Jay C. Zeck
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - John L. Marshall
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Benjamin A. Weinberg
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Aiwu Ruth He
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Marcus S. Noel
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Richard Schlegel
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Hani Goodarzi
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Seema Agarwal
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
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Sun Z, Li Y, Tan X, Liu W, He X, Pan D, Li E, Xu L, Long L. Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer. Biomolecules 2023; 13:biom13030477. [PMID: 36979412 PMCID: PMC10046484 DOI: 10.3390/biom13030477] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Ras-related associated with diabetes (RRAD), a member of the Ras-related GTPase superfamily, is primarily a cytosolic protein that actives in the plasma membrane. RRAD is highly expressed in type 2 diabetes patients and as a biomarker of congestive heart failure. Mounting evidence showed that RRAD is important for the progression and metastasis of tumor cells, which play opposite roles as an oncogene or tumor suppressor gene depending on cancer and cell type. These findings are of great significance, especially given that relevant molecular mechanisms are being discovered. Being regulated in various pathways, RRAD plays wide spectrum cellular activity including tumor cell division, motility, apoptosis, and energy metabolism by modulating tumor-related gene expression and interacting with multiple downstream effectors. Additionally, RRAD in senescence may contribute to its role in cancer. Despite the twofold characters of RRAD, targeted therapies are becoming a potential therapeutic strategy to combat cancers. This review will discuss the dual identity of RRAD in specific cancer type, provides an overview of the regulation and downstream effectors of RRAD to offer valuable insights for readers, explore the intracellular role of RRAD in cancer, and give a reference for future mechanistic studies.
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Affiliation(s)
- Zhangyue Sun
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
| | - Yongkang Li
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
| | - Xiaolu Tan
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
| | - Wanyi Liu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
| | - Xinglin He
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
| | - Deyuan Pan
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
| | - Enmin Li
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
| | - Liyan Xu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
| | - Lin Long
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
- Cancer Research Center, Institute of Basic Medical Science, Shantou University Medical College, Shantou 515041, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
- Correspondence: ; Tel.: +86-754-88900460; Fax: +86-754-88900847
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7
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Functional diversity in the RAS subfamily of small GTPases. Biochem Soc Trans 2022; 50:921-933. [PMID: 35356965 DOI: 10.1042/bst20211166] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/15/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022]
Abstract
RAS small GTPases regulate important signalling pathways and are notorious drivers of cancer development and progression. While most research to date has focused on understanding and addressing the oncogenic potential of three RAS oncogenes: HRAS, KRAS, and NRAS; the full RAS subfamily is composed of 35 related GTPases with diverse cellular functions. Most remain deeply understudied despite strong evolutionary conservation. Here, we highlight a group of 17 poorly characterized RAS GTPases that are frequently down-regulated in cancer and evidence suggests may function not as oncogenes, but as tumour suppressors. These GTPases remain largely enigmatic in terms of their cellular function, regulation, and interaction with effector proteins. They cluster within two families we designate as 'distal-RAS' (D-RAS; comprised of DIRAS, RASD, and RASL10) and 'CaaX-Less RAS' (CL-RAS; comprised of RGK, NKIRAS, RERG, and RASL11/12 GTPases). Evidence of a tumour suppressive role for many of these GTPases supports the premise that RAS subfamily proteins may collectively regulate cellular proliferation.
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8
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Chang Y, Wang Y, Li B, Lu X, Wang R, Li H, Yan B, Gu A, Wang W, Huang A, Wu S, Li R. Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer. Front Genet 2021; 12:722078. [PMID: 34616428 PMCID: PMC8488217 DOI: 10.3389/fgene.2021.722078] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 01/22/2023] Open
Abstract
Circulating tumor cells (CTCs) have important applications in clinical practice on early tumor diagnosis, prognostic prediction, and treatment evaluation. Platinum-based chemotherapy is a fundamental treatment for non-small cell lung cancer (NSCLC) patients who are not suitable for targeted drug therapies. However, most patients progressed after a period of treatment. Therefore, revealing the genetic information contributing to drug resistance and tumor metastasis in CTCs is valuable for treatment adjustment. In this study, we enrolled nine NSCLC patients with platinum-based chemotherapy resistance. For each patient, 10 CTCs were isolated when progression occurred to perform single cell-level whole-exome sequencing (WES). Meanwhile the patients' paired primary-diagnosed formalin-fixed and paraffin-embedded samples and progressive biopsy specimens were also selected to perform WES. Comparisons of distinct mutation profiles between primary and progressive specimens as well as CTCs reflected different evolutionary mechanisms between CTC and lymph node metastasis, embodied in a higher proportion of mutations in CTCs shared with paired progressive lung tumor and hydrothorax specimens (4.4-33.3%) than with progressive lymphatic node samples (0.6-11.8%). Functional annotation showed that CTCs not only harbored cancer-driver gene mutations, including frequent mutations of EGFR and TP53 shared with primary and/or progressive tumors, but also particularly harbored cell cycle-regulated or stem cell-related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc., most of which derived from primary tumor samples and played crucial roles in chemo-drug resistance and metastasis for NSCLCs. Thus, detection of genetic information in CTCs is a feasible strategy for studying drug resistance and discovering new drug targets when progressive tumor specimens were unavailable.
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Affiliation(s)
- Yuanyuan Chang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yin Wang
- Berry Oncology Corporation, Beijing, China
| | - Boyi Li
- Berry Oncology Corporation, Beijing, China
| | | | - Ruiru Wang
- Berry Oncology Corporation, Beijing, China
| | - Hui Li
- Berry Oncology Corporation, Beijing, China
| | - Bo Yan
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Aiqin Gu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Weimin Wang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Aimi Huang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | | | - Rong Li
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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9
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Hähnlein JS, Nadafi R, de Jong TA, Semmelink JF, Remmerswaal EBM, Safy M, van Lienden KP, Maas M, Gerlag DM, Tak PP, Mebius RE, Wähämaa H, Catrina AI, G. M. van Baarsen L. Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis. Int J Mol Sci 2020; 21:ijms21165713. [PMID: 32784936 PMCID: PMC7460812 DOI: 10.3390/ijms21165713] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. METHOD Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). RESULTS Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. CONCLUSION Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.
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Affiliation(s)
- Janine S. Hähnlein
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
- Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Reza Nadafi
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, VU Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; (R.N.); (R.E.M.)
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Tineke A. de Jong
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
- Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Johanna F. Semmelink
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
- Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Ester B. M. Remmerswaal
- Renal Transplant Unit, Division of Internal Medicine and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
| | - Mary Safy
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
| | - Krijn P. van Lienden
- Department of Radiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (K.P.v.L.); (M.M.)
| | - Mario Maas
- Department of Radiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (K.P.v.L.); (M.M.)
| | - Danielle M. Gerlag
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
| | - Paul P. Tak
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
- Kintai Therapeutics, Cambridge, MA 02140, USA
- Internal Medicine, Cambridge University, Cambridge, CB2 1TN, UK
- Rheumatology, Ghent University, 9000 Ghent, Belgium
| | - Reina E. Mebius
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, VU Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; (R.N.); (R.E.M.)
| | - Heidi Wähämaa
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, 17176 Stockholm, Sweden; (H.W.); (A.I.C.)
| | - Anca I. Catrina
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, 17176 Stockholm, Sweden; (H.W.); (A.I.C.)
| | - Lisa G. M. van Baarsen
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (J.S.H.); (T.A.d.J.); (J.F.S.); (M.S.); (D.M.G.); (P.P.T.)
- Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-205668043
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10
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Gibbs ZA, Reza LC, Cheng CC, Westcott JM, McGlynn K, Whitehurst AW. The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer. eLife 2020; 9:57679. [PMID: 32515734 PMCID: PMC7302877 DOI: 10.7554/elife.57679] [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: 04/08/2020] [Accepted: 06/09/2020] [Indexed: 12/19/2022] Open
Abstract
Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC.
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Affiliation(s)
- Zane A Gibbs
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
| | - Luis C Reza
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
| | - Chun-Chun Cheng
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
| | - Jill M Westcott
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, United States
| | - Kathleen McGlynn
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
| | - Angelique W Whitehurst
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
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11
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RRAD expression in gastric and colorectal cancer with peritoneal carcinomatosis. Sci Rep 2019; 9:19439. [PMID: 31857616 PMCID: PMC6923381 DOI: 10.1038/s41598-019-55767-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/30/2019] [Indexed: 12/17/2022] Open
Abstract
The role of Ras-related associated with diabetes (RRAD) in gastric cancer (GC) or colorectal cancer (CRC) has not been investigated. We aimed to investigate the biological and clinical roles of RRAD in GC and CRC and to assess RRAD as a therapeutic target. A total of 31 cancer cell lines (17 GC cell lines, 14 CRC cell lines), 59 patient-derived cells (PDCs from 48 GC patients and 11 CRC patients), and 84 matched pairs of primary cancer tissue and non-tumor tissue were used to evaluate the role of RRAD in vitro and in vivo. RRAD expression was frequently increased in GC and CRC cell lines, and siRNA/shRNA-mediated RRAD inhibition induced significant decline of tumor cell proliferation both in vitro and in vivo. A synergistic effect of RRAD inhibition was generated by combined treatment with chemotherapy. Notably, RRAD expression was markedly increased in PDCs, and RRAD inhibition suppressed PDC proliferation. RRAD inhibition also resulted in reduced cell invasion, decreased expression of EMT markers, and decreased angiogenesis and levels of associated proteins including VEGF and ANGP2. Our study suggests that RRAD could be a novel therapeutic target for treatment of GC and CRC, especially in patients with peritoneal seeding.
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12
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Ras associated with diabetes may play a role in fracture nonunion development in rats. BMC Musculoskelet Disord 2019; 20:602. [PMID: 31830958 PMCID: PMC6909478 DOI: 10.1186/s12891-019-2970-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 11/26/2019] [Indexed: 02/07/2023] Open
Abstract
Background Rad is the prototypic member of a subfamily of Ras-related small G-proteins and is highly expressed in the skeletal muscle of patients with type II diabetes. Our previous microarray analysis suggested that Rad may mediate fracture nonunion development. Thus, the present study used rat experimental models to investigate and compare the gene and protein expression patterns of both Rad and Rem1, another RGK subfamily member, in nonunions and standard healing fractures. Methods Standard healing fractures and nonunions (produced via periosteal cauterization at the fracture site) were created in the femurs of 3-month-old male Sprague-Dawley rats. At post-fracture days 7, 14, 21, and 28, the fracture callus and fibrous tissue from the standard healing fractures and nonunions, respectively, were harvested and screened (via real-time PCR) for Rad and Rem1 expression. The immunolocalization of both encoded proteins was analyzed at post-fracture days 14 and 21. At the same time points, hematoxylin and eosin staining was performed to identify the detailed tissue structures. Results Results of real-time PCR analysis showed that Rad expression increased significantly in the nonunions, compared to that in the standard healing fractures, at post-fracture days 14, 21, and 28. Conversely, immunohistochemical analysis revealed the immunolocalization of Rad to be similar to that of Rem1 in both fracture types at post-fracture days 14 and 21. Conclusions Rad may mediate nonunion development, and thus, may be a promising therapeutic target to treat these injuries.
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13
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Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept. Cells 2019; 8:cells8111330. [PMID: 31661894 PMCID: PMC6912264 DOI: 10.3390/cells8111330] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/18/2019] [Accepted: 10/23/2019] [Indexed: 12/16/2022] Open
Abstract
Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks.
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Snail-Overexpression Induces Epithelial-mesenchymal Transition and Metabolic Reprogramming in Human Pancreatic Ductal Adenocarcinoma and Non-tumorigenic Ductal Cells. J Clin Med 2019; 8:jcm8060822. [PMID: 31181802 PMCID: PMC6617272 DOI: 10.3390/jcm8060822] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 12/30/2022] Open
Abstract
The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.
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15
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Colella S, Parisot N, Simonet P, Gaget K, Duport G, Baa-Puyoulet P, Rahbé Y, Charles H, Febvay G, Callaerts P, Calevro F. Bacteriocyte Reprogramming to Cope With Nutritional Stress in a Phloem Sap Feeding Hemipteran, the Pea Aphid Acyrthosiphon pisum. Front Physiol 2018; 9:1498. [PMID: 30410449 PMCID: PMC6209921 DOI: 10.3389/fphys.2018.01498] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/04/2018] [Indexed: 11/13/2022] Open
Abstract
Nutritional symbioses play a central role in the ability of insects to thrive on unbalanced diets and in ensuring their evolutionary success. A genomic model for nutritional symbiosis comprises the hemipteran Acyrthosiphon pisum, and the gamma-3-proteobacterium, Buchnera aphidicola, with genomes encoding highly integrated metabolic pathways. A. pisum feeds exclusively on plant phloem sap, a nutritionally unbalanced diet highly variable in composition, thus raising the question of how this symbiotic system responds to nutritional stress. We addressed this by combining transcriptomic, phenotypic and life history trait analyses to determine the organismal impact of deprivation of tyrosine and phenylalanine. These two aromatic amino acids are essential for aphid development, are synthesized in a metabolic pathway for which the aphid host and the endosymbiont are interdependent, and their concentration can be highly variable in plant phloem sap. We found that this nutritional challenge does not have major phenotypic effects on the pea aphid, except for a limited weight reduction and a 2-day delay in onset of nymph laying. Transcriptomic analyses through aphid development showed a prominent response in bacteriocytes (the core symbiotic tissue which houses the symbionts), but not in gut, thus highlighting the role of bacteriocytes as major modulators of this homeostasis. This response does not involve a direct regulation of tyrosine and phenylalanine biosynthetic pathway and transporter genes. Instead, we observed an extensive transcriptional reprogramming of the bacteriocyte with a rapid down-regulation of genes encoding sugar transporters and genes required for sugar metabolism. Consistently, we observed continued overexpression of the A. pisum homolog of RRAD, a small GTPase implicated in repressing aerobic glycolysis. In addition, we found increased transcription of genes involved in proliferation, cell size control and signaling. We experimentally confirmed the significance of these gene expression changes detecting an increase in bacteriocyte number and cell size in vivo under tyrosine and phenylalanine depletion. Our results support a central role of bacteriocytes in the aphid response to amino acid deprivation: their transcriptional and cellular responses fine-tune host physiology providing the host insect with an effective way to cope with the challenges posed by the variability in composition of phloem sap.
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Affiliation(s)
- Stefano Colella
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Nicolas Parisot
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Pierre Simonet
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Karen Gaget
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Gabrielle Duport
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | | | - Yvan Rahbé
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Hubert Charles
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Gérard Febvay
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
| | - Patrick Callaerts
- Laboratory of Behavioral and Developmental Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Federica Calevro
- Univ Lyon, INSA-Lyon, INRA, BF2I, UMR0203, F-69621, Villeurbanne, France
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16
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Withers CN, Brown DM, Byiringiro I, Allen MR, Condon KW, Satin J, Andres DA. Rad GTPase is essential for the regulation of bone density and bone marrow adipose tissue in mice. Bone 2017; 103:270-280. [PMID: 28732776 PMCID: PMC6886723 DOI: 10.1016/j.bone.2017.07.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 07/12/2017] [Accepted: 07/16/2017] [Indexed: 01/03/2023]
Abstract
The small GTP-binding protein Rad (RRAD, Ras associated with diabetes) is the founding member of the RGK (Rad, Rem, Rem2, and Gem/Kir) family that regulates cardiac voltage-gated Ca2+ channel function. However, its cellular and physiological functions outside of the heart remain to be elucidated. Here we report that Rad GTPase function is required for normal bone homeostasis in mice, as Rad deletion results in significantly lower bone mass and higher bone marrow adipose tissue (BMAT) levels. Dynamic histomorphometry in vivo and primary calvarial osteoblast assays in vitro demonstrate that bone formation and osteoblast mineralization rates are depressed, while in vitro osteoclast differentiation is increased, in the absence of Rad. Microarray analysis revealed that canonical osteogenic gene expression (Runx2, osterix, etc.) is not altered in Rad-/- calvarial osteoblasts; instead robust up-regulation of matrix Gla protein (MGP, +11-fold), an inhibitor of extracellular matrix mineralization and a protein secreted during adipocyte differentiation, was observed. Strikingly, Rad deficiency also resulted in significantly higher marrow adipose tissue levels in vivo and promoted spontaneous in vitro adipogenesis of primary calvarial osteoblasts. Adipogenic differentiation of wildtype calvarial osteoblasts resulted in the loss of endogenous Rad protein, further supporting a role for Rad in the control of BMAT levels. These findings reveal a novel in vivo function for Rad and establish a role for Rad signaling in the complex physiological control of skeletal homeostasis and bone marrow adiposity.
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Affiliation(s)
- Catherine N Withers
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, BBSRB, 741 S Limestone Street, Lexington, KY 40536-0509, USA.
| | - Drew M Brown
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.
| | - Innocent Byiringiro
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.
| | - Matthew R Allen
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.
| | - Keith W Condon
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.
| | - Jonathan Satin
- Department of Physiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0298, USA.
| | - Douglas A Andres
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, BBSRB, 741 S Limestone Street, Lexington, KY 40536-0509, USA.
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17
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Abstract
Liver cancer is fundamentally physiologically different from the surrounding liver tissue. Despite multiple efforts to target the altered signaling pathways created by oncogenic mutations, not many have focused on targeting the altered metabolism that allows liver cancer to develop and grow. Still to be resolved is the question of whether the altered metabolic pathways in this cancer differ enough from the surrounding noncancerous cells to allow for the development of potent and specific compounds. Clinical studies of metabolic modulators would provide some more information with regard to the feasibility of this approach. Furthermore, as it appears that oncogenic signaling is essential to this cancer's altered metabolism, it stands to reason that targeting this altered signaling may allow the exploitation of specific metabolic vulnerabilities in combination with other drugs for enhanced efficacy. The identification of biomarkers of metabolic sensitivity will also be essential to determine whether these drugs will have the desired effect.
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Affiliation(s)
- Ali Zarrinpar
- 1 Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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18
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Yao Z, Xie F, Li M, Liang Z, Xu W, Yang J, Liu C, Li H, Zhou H, Qu LH. Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells. Cell Death Dis 2017; 8:e2633. [PMID: 28230866 PMCID: PMC5386482 DOI: 10.1038/cddis.2017.35] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 12/21/2016] [Accepted: 01/10/2017] [Indexed: 12/26/2022]
Abstract
The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells. Then miRNA profiling of SW480 cells revealed those intracellular signaling related to energy supply was affected by oridonin, suggesting that glucose metabolism is a potential target for CRC therapy. Moreover, our results indicated that oridonin induced metabolic imbalances by significantly inhibiting glucose uptake and reducing lactate export through significantly downregulating the protein levels of GLUT1 and MCT1 in vitro and vivo. However, the ATP level in oridonin-treated CRC cells was not decreased when oridonin blocked the glucose supply, indicating that oridonin induced autophagy process, an important ATP source in cancer cells. The observation was then supported by the results of LC3-II detection and transmission electron microscopy analysis, which confirmed the presence of autophagy. Furthermore, p-AMPK was rapidly deactivated following oridonin treatment, resulting in downregulation of GLUT1 and induction of autophagy in the cancer cells. Thus our finding helped to clarify the anticancer mechanisms of oridonin and suggested it could be applied as a glucose metabolism-targeting agent for cancer treatment.
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Affiliation(s)
- Zhuo Yao
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Fuhua Xie
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Min Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Zirui Liang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Wenli Xu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Jianhua Yang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Chang Liu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Hongwangwang Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Hui Zhou
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Liang-Hu Qu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
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19
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Shang RZ, Qu SB, Wang DS. Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects. World J Gastroenterol 2016; 22:9933-9943. [PMID: 28018100 PMCID: PMC5143760 DOI: 10.3748/wjg.v22.i45.9933] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 09/30/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.
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20
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Yan Y, Xie M, Zhang L, Zhou X, Xie H, Zhou L, Zheng S, Wang W. Ras-related associated with diabetes gene acts as a suppressor and inhibits Warburg effect in hepatocellular carcinoma. Onco Targets Ther 2016; 9:3925-37. [PMID: 27418837 PMCID: PMC4935086 DOI: 10.2147/ott.s106703] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide and is a prominent source of mortality. Ras-related associated with diabetes (RRAD), one of the first members of the 35–39 kDa class of novel Ras-related GTPases, is linked to several types of cancer, although its function in HCC remains unclear. In this study, we observed that RRAD was downregulated in HCC compared with adjacent normal tissues. This change was associated with a poor prognosis. Furthermore, knockdown of RRAD in SK-Hep-1 cells facilitated cell proliferation, accelerated the G1/S transition during the cell cycle, induced cell migration, and reduced apoptosis. In contrast, overexpression of RRAD in Huh7 cells had the opposite effects. Moreover, we demonstrated that RRAD induced cell proliferation through regulation of the cell cycle by downregulating cyclins and cyclin-dependent kinases. RRAD induced tumor cell apoptosis through the mitochondrial apoptosis pathway. In addition, we confirmed that knockdown of RRAD promoted aerobic glycolysis by upregulating glucose transporter 1, whereas overexpression of RRAD inhibited aerobic glycolysis. In conclusion, RRAD plays a pivotal role as a potential tumor suppressor in HCC. An improved understanding of the roles of RRAD in tumor metabolism may provide insights into its potential as a novel molecular target in HCC therapy.
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Affiliation(s)
- Yingcai Yan
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Minjie Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Linshi Zhang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Xiaohu Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Haiyang Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Lin Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Weilin Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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