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Hushmandi K, Saadat SH, Raei M, Daneshi S, Aref AR, Nabavi N, Taheriazam A, Hashemi M. Implications of c-Myc in the pathogenesis and treatment efficacy of urological cancers. Pathol Res Pract 2024; 259:155381. [PMID: 38833803 DOI: 10.1016/j.prp.2024.155381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024]
Abstract
Urological cancers, including prostate, bladder, and renal cancers, are significant causes of death and negatively impact the quality of life for patients. The development and progression of these cancers are linked to the dysregulation of molecular pathways. c-Myc, recognized as an oncogene, exhibits abnormal levels in various types of tumors, and current evidence supports the therapeutic targeting of c-Myc in cancer treatment. This review aims to elucidate the role of c-Myc in driving the progression of urological cancers. c-Myc functions to enhance tumorigenesis and has been documented to increase growth and metastasis in prostate, bladder, and renal cancers. Furthermore, the dysregulation of c-Myc can result in a diminished response to therapy in these cancers. Non-coding RNAs, β-catenin, and XIAP are among the regulators of c-Myc in urological cancers. Targeting and suppressing c-Myc therapeutically for the treatment of these cancers has been explored. Additionally, the expression level of c-Myc may serve as a prognostic factor in clinical settings.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health,School of Health,Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Amir Reza Aref
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Wang Y, Tong H, Wang J, Hu L, Huang Z. LRRC1 knockdown downregulates MACF1 to inhibit the malignant progression of acute myeloid leukemia by inactivating β-catenin/c-Myc signaling. J Mol Histol 2024; 55:37-50. [PMID: 38165568 DOI: 10.1007/s10735-023-10170-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 10/21/2023] [Indexed: 01/04/2024]
Abstract
Acute myeloid leukemia (AML) is a hematologic disease associated with genetic abnormalities. This study aimed to explore the role of leucine-rich repeat-containing protein 1 (LRRC1) in the malignant activities of AML and to reveal the molecular mechanism related to microtubule actin cross-linking factor 1 (MACF1). GEPIA database was used to analyze the expression of LRRC1 in bone marrow tissues of AML patients and the correlation between LRRC1 expression and survival analysis. LRRC1 was knocked down to assess the change of AML cell proliferation, cell cycle and apoptosis using CCK-8 assay and flow cytometry. Besides, the contents of extracellular acidification and oxygen consumption rates were measured to evaluate the glycolysis. Additionally, the interaction between LRRC1 and MACF1 predicted by MEM database and was verified by co-immunoprecipitation (Co-IP) assay. Then, MACF1 was overexpressed to conduct the rescue experiments. Expression of proteins in β-catenin/c-Myc signaling was detected by western blot. Finally, AML xenograft mouse model was established to observe the impacts of LRRC1 silencing on the tumor development. Notably upregulated LRRC1 expression was observed in bone marrow tissues of AML patients and AML cells, and patients with the higher LRRC1 expression displayed the lower overall survival. LRRC1 depletion promoted cell cycle arrest and apoptosis and inhibited the glycolysis. Co-IP confirmed the interaction between LRRC1 and MACF1. MACF1 upregulation relieved the impacts of LRRC1 knockdown on the malignant activities of AML cells. Moreover, LRRC1 silencing inhibited the development of xenograft tumor growth of HL-60 cells in nude mice, suppressed MACF1 expression and inactivated the β-catenin/c-Myc signaling. Collectively, LRRC1 knockdown suppressed proliferation, glycolysis and promoted apoptosis in AML cells by downregulating MACF1 expression to inactivate β-catenin/c-Myc signaling.
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Affiliation(s)
- Yao Wang
- Department of Pediatric Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyue Road, Wenzhou, 325027, Zhejiang, China
| | - Hongfei Tong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Juxiang Wang
- Department of Pediatric Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyue Road, Wenzhou, 325027, Zhejiang, China
| | - Linglong Hu
- Department of Pediatric Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyue Road, Wenzhou, 325027, Zhejiang, China
| | - Zhen Huang
- Department of Pediatric Hematology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyue Road, Wenzhou, 325027, Zhejiang, China.
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Razali NN, Raja Ali RA, Muhammad Nawawi KN, Yahaya A, Mohd Rathi ND, Mokhtar NM. Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer: Impact of rs10889677 variant and buparlisib in colitis-associated cancer. World J Gastroenterol 2023; 29:5543-5556. [PMID: 37970476 PMCID: PMC10642440 DOI: 10.3748/wjg.v29.i40.5543] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/05/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Phosphatidylinositol-3-kinases (PI3K) is a well-known route in inflammation-related cancer. Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis (UC) and colorectal cancer (CRC) with colitis-associated cancer (CAC). PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes. Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth. AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis. METHODS Genomic DNA from 32 colonic samples, including CAC (n = 7), UC (n = 10) and CRC (n = 15), was sequenced for the rs10889677 mutation. The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector. The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line. CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium, then buparlisib was administered after 14 d. The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2. RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant, confirming the hypothesis that the variant disrupted miRNA binding sites, which led to an increase in IL23R expression and the activation of the PI3K signaling pathway. Furthermore, CAC-induced mice had a significantly higher disease activity index (P < 0.05). Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice (P < 0.05), reduced the percentage of proliferating cells by 5%, and increased the number of apoptotic cells. The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression. CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway, and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.
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Affiliation(s)
- Nurul Nadirah Razali
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Khairul Najmi Muhammad Nawawi
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Azyani Yahaya
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Norshafila Diana Mohd Rathi
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
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Cheng L, He Q, Liu B, Chen L, Lv F, Li X, Li Y, Liu C, Song Y, Xing Y. SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4. Cell Death Dis 2023; 14:74. [PMID: 36720852 PMCID: PMC9889330 DOI: 10.1038/s41419-023-05614-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023]
Abstract
Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.
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Affiliation(s)
- Lulin Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Qingliu He
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Bing Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Liang Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Fang Lv
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Xuexiang Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Yunxue Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Chunyu Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Yarong Song
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
| | - Yifei Xing
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
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Park CH, Moon J, Park M, Cheng H, Lee J, Chang JS. Protein Kinase SGK2 Is Induced by the β 3 Adrenergic Receptor-cAMP-PKA-PGC-1α/NT-PGC-1α Axis but Dispensable for Brown/Beige Adipose Tissue Thermogenesis. Front Physiol 2021; 12:780312. [PMID: 34899399 PMCID: PMC8657153 DOI: 10.3389/fphys.2021.780312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/29/2021] [Indexed: 11/21/2022] Open
Abstract
Brown and beige adipocytes are specialized to dissipate energy as heat. Sgk2, encoding a serine/threonine kinase, has been identified as a brown and beige adipocyte-specific gene in rodents and humans; however, its function in brown/beige adipocytes remains unraveled. Here, we examined the regulation and role of Sgk2 in brown/beige adipose tissue thermogenesis. We found that transcriptional coactivators PGC-1α and NT-PGC-1α activated by the β3 adrenergic receptor-cAMP-PKA pathway are recruited to the Sgk2 promoter, triggering Sgk2 transcription in response to cold. SGK2 elevation was closely associated with increased serine/threonine phosphorylation of proteins carrying the consensus RxRxxS/T phosphorylation site. However, despite cold-dependent activation of SGK2, mice lacking Sgk2 exhibited normal cold tolerance at 4°C. In addition, Sgk2+/+ and Sgk2−/− mice induced comparable increases in energy expenditure during pharmacological activation of brown and beige adipose tissue with a β3AR agonist. In vitro loss- and gain-of-function studies further demonstrated that Sgk2 ablation or activation does not alter thermogenic gene expression and mitochondrial respiration in brown adipocytes. Collectively, our results reveal a new signaling component SGK2, although dispensable for cold-induced thermogenesis that adds an additional layer of complexity to the β3AR signaling network in brown/beige adipose tissue.
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Affiliation(s)
- Chul-Hong Park
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Jiyoung Moon
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Minsung Park
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Helia Cheng
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Jisu Lee
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Ji Suk Chang
- Gene Regulation and Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
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Pennington KL, McEwan CM, Woods J, Muir CM, Pramoda Sahankumari AG, Eastmond R, Balasooriya ER, Egbert CM, Kaur S, Heaton T, McCormack KK, Piccolo SR, Kurokawa M, Andersen JL. SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1. Mol Cancer Res 2021; 20:231-243. [PMID: 34654719 DOI: 10.1158/1541-7786.mcr-20-1076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 11/16/2022]
Abstract
PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1-14-3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3-bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1. IMPLICATIONS: These findings identify a potentially targetable mechanism that regulates the oncoprotein PTOV1.
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Affiliation(s)
- Katie L Pennington
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Colten M McEwan
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah.
| | - James Woods
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Colin M Muir
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - A G Pramoda Sahankumari
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Riley Eastmond
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Eranga R Balasooriya
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Christina M Egbert
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | - Sandeep Kaur
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Tyler Heaton
- Department of Biology, Brigham Young University, Provo, Utah
| | - Katherine K McCormack
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
| | | | - Manabu Kurokawa
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Joshua L Andersen
- The Fritz B. Burns Cancer Research Laboratory, Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah.
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Cui C, Liu Y, Gerloff D, Rohde C, Pauli C, Köhn M, Misiak D, Oellerich T, Schwartz S, Schmidt LH, Wiewrodt R, Marra A, Hillejan L, Bartel F, Wickenhauser C, Hüttelmaier S, Göllner S, Zhou F, Edemir B, Müller-Tidow C. NOP10 predicts lung cancer prognosis and its associated small nucleolar RNAs drive proliferation and migration. Oncogene 2021; 40:909-921. [PMID: 33288886 PMCID: PMC7862062 DOI: 10.1038/s41388-020-01570-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 11/10/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.
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Affiliation(s)
- Chunhong Cui
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany
- Shanghai University of Medicine and Health Sciences, Shanghai, 201318, PR China
| | - Yi Liu
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany
| | - Dennis Gerloff
- Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
- Department of Dermatology and Venereology, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Christian Rohde
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany
| | - Cornelius Pauli
- Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Marcel Köhn
- Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Danny Misiak
- Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Thomas Oellerich
- Department of Medicine II, Hematology/Oncology, Goethe University, 60590, Frankfurt, Germany
- German Cancer Consortium/German Cancer Research Center, 69120, Heidelberg, Germany
- Department of Molecular Diagnostics/Translational Proteomics, Frankfurt Cancer Institute, 60596, Frankfurt, Germany
| | | | - Lars-Henning Schmidt
- Department of Medicine A, University of Münster, 48149, Münster, Germany
- Klinik für Pneumologie, Beatmungsmedizin und Thorakale Onkologie, Klinikum Ingolstadt, 85049, Ingolstadt, Germany
| | - Rainer Wiewrodt
- Department of Medicine A, University of Münster, 48149, Münster, Germany
| | - Alessandro Marra
- Department of Surgery, Thoracic Surgery, Rems-Murr-Kliniken, 71364, Winnenden, Germany
| | - Ludger Hillejan
- Department of Thoracic Surgery, Niels-Stensen-Kliniken, 49179, Ostercappeln, Germany
| | - Frank Bartel
- Institute of Pathology, Martin-Luther-University Halle-Wittenberg, 06097, Halle (Saale), Germany
| | - Claudia Wickenhauser
- Institute of Pathology, Martin-Luther-University Halle-Wittenberg, 06097, Halle (Saale), Germany
| | - Stefan Hüttelmaier
- Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Stefanie Göllner
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany
| | - Fengbiao Zhou
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany
| | - Bayram Edemir
- Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Carsten Müller-Tidow
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany.
- National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
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8
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Lambrou GI, Adamaki M, Hatziagapiou K, Vlahopoulos S. Gene Expression and Resistance to Glucocorticoid-Induced Apoptosis in Acute Lymphoblastic Leukemia: A Brief Review and Update. Curr Drug Res Rev 2021; 12:131-149. [PMID: 32077838 DOI: 10.2174/2589977512666200220122650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/29/2019] [Accepted: 01/23/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND Resistance to glucocorticoid (GC)-induced apoptosis in Acute Lymphoblastic Leukemia (ALL), is considered one of the major prognostic factors for the disease. Prednisolone is a corticosteroid and one of the most important agents in the treatment of acute lymphoblastic leukemia. The mechanics of GC resistance are largely unknown and intense ongoing research focuses on this topic. AIM The aim of the present study is to review some aspects of GC resistance in ALL, and in particular of Prednisolone, with emphasis on previous and present knowledge on gene expression and signaling pathways playing a role in the phenomenon. METHODS An electronic literature search was conducted by the authors from 1994 to June 2019. Original articles and systematic reviews selected, and the titles and abstracts of papers screened to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. RESULTS Identification of gene targets responsible for glucocorticoid resistance may allow discovery of drugs, which in combination with glucocorticoids may increase the effectiveness of anti-leukemia therapies. The inherent plasticity of clinically evolving cancer justifies approaches to characterize and prevent undesirable activation of early oncogenic pathways. CONCLUSION Study of the pattern of intracellular signal pathway activation by anticancer drugs can lead to development of efficient treatment strategies by reducing detrimental secondary effects.
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Affiliation(s)
- George I Lambrou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Maria Adamaki
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Kyriaki Hatziagapiou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Spiros Vlahopoulos
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
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9
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Conforte AJ, Alves L, Coelho FC, Carels N, da Silva FAB. Modeling Basins of Attraction for Breast Cancer Using Hopfield Networks. Front Genet 2020; 11:314. [PMID: 32318098 PMCID: PMC7154169 DOI: 10.3389/fgene.2020.00314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/16/2020] [Indexed: 12/26/2022] Open
Abstract
Cancer is a genetic disease for which traditional treatments cause harmful side effects. After two decades of genomics technological breakthroughs, personalized medicine is being used to improve treatment outcomes and mitigate side effects. In mathematical modeling, it has been proposed that cancer matches an attractor in Waddington's epigenetic landscape. The use of Hopfield networks is an attractive modeling approach because it requires neither previous biological knowledge about protein-protein interactions nor kinetic parameters. In this report, Hopfield network modeling was used to analyze bulk RNA-Seq data of paired breast tumor and control samples from 70 patients. We characterized the control and tumor attractors with respect to their size and potential energy and correlated the Euclidean distances between the tumor samples and the control attractor with their corresponding clinical data. In addition, we developed a protocol that outlines the key genes involved in tumor state stability. We found that the tumor basin of attraction is larger than that of the control and that tumor samples are associated with a more substantial negative energy than control samples, which is in agreement with previous reports. Moreover, we found a negative correlation between the Euclidean distances from tumor samples to the control attractor and patient overall survival. The ascending order of each node's density in the weight matrix and the descending order of the number of patients that have the target active only in the tumor sample were the parameters that withdrew more tumor samples from the tumor basin of attraction with fewer gene inhibitions. The combinations of therapeutic targets were specific to each patient. We performed an initial validation through simulation of trastuzumab treatment effects in HER2+ breast cancer samples. For that, we built an energy landscape composed of single-cell and bulk RNA-Seq data from trastuzumab-treated and non-treated HER2+ samples. The trajectory from the non-treated bulk sample toward the treated bulk sample was inferred through the perturbation of differentially expressed genes between these samples. Among them, we characterized key genes involved in the trastuzumab response according to the literature.
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Affiliation(s)
- Alessandra Jordano Conforte
- Laboratory of Biological Systems Modeling, Center for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,Laboratory of Computational Modeling of Biological Systems, Scientific Computing Program, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Leon Alves
- Applied Math School, Getúlio Vargas Foundation, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Nicolas Carels
- Laboratory of Biological Systems Modeling, Center for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Fabrício Alves Barbosa da Silva
- Laboratory of Computational Modeling of Biological Systems, Scientific Computing Program, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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10
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Wang H, Qiao Y, Liu J, Jiang B, Zhang G, Zhang C, Liu X. Experimental study of the difference in deformation between normal and pathological, renal and bladder, cells induced by acoustic radiation force. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2020; 49:155-161. [PMID: 32006056 DOI: 10.1007/s00249-020-01422-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/06/2020] [Accepted: 01/14/2020] [Indexed: 11/28/2022]
Abstract
Previous studies have shown that alterations in the mechanical properties of cells may be associated with the onset and progression of some forms of pathology. In this paper, an experimental study of two types of cells, renal (cancer) and bladder (cancer) cells, is described which used acoustic radiation force (ARF) generated by a high-frequency ultrasound focusing transducer and performed on the operating platform of an inverted light microscope. Comparing images of cancer cells with those of normal cells of the same kind, we find that the cancer cells are more prone to deform than normal cells of the same kind under the same ARF. In addition, cancer cells with higher malignancy are more deformable than those with lower malignancy. This means that the deformability of cells may be used to distinguish diseased cells from normal ones, and more aggressive cells from less aggressive ones, which may provide a more rapid and accurate method for clinical diagnosis of urological disease in the future.
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Affiliation(s)
- Haibin Wang
- Key Laboratory of Modern Acoustics, Institute of Acoustics, Nanjing University, Nanjing, 210093, China
- School of Science, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu, China
| | - Yupei Qiao
- Key Laboratory of Modern Acoustics, Institute of Acoustics, Nanjing University, Nanjing, 210093, China
| | - Jiehui Liu
- Key Laboratory of Modern Acoustics, Institute of Acoustics, Nanjing University, Nanjing, 210093, China
| | - Bo Jiang
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China
| | - Gutian Zhang
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China
| | - Chengwei Zhang
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China
| | - Xiaozhou Liu
- Key Laboratory of Modern Acoustics, Institute of Acoustics, Nanjing University, Nanjing, 210093, China.
- State Key Laboratory of Acoustics, Institute of Acoustics, Chinese Academy of Sciences, Beijing, 100190, China.
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Ruan H, Li Y, Wang X, Sun B, Fang W, Jiang S, Liang C. CRYAB inhibits migration and invasion of bladder cancer cells through the PI3K/AKT and ERK pathways. Jpn J Clin Oncol 2019; 50:254-260. [PMID: 31829429 DOI: 10.1093/jjco/hyz172] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/24/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
Bladder cancer is a common malignancy characterized by a high recurrence rate and the development of drug resistance. Frequent mutations and gene expression alterations in the PI3K/AKT and mitogen-activated protein kinase-ERK pathways lead to deregulated cell growth and the acquisition of invasive properties, which facilitates tumour progression and confers resistance to chemotherapy. Therefore, identification of the underlying mechanisms that trigger the activation of these signalling pathways and control the invasive phenotype of tumour cells is of urgent need.
Methods
We utilized publicly available gene expression databases (GEO and TCGA) and bioinformatics analysis to identify key gene expression changes in human bladder cancer . The key gene expression was detected using BC tissue microarrays. Cell proliferation, apoptosis, migration, invasion and related signalling pathways were analysed flowing transfection with key gene overexpression plasmids.
Results
The analysis revealed that inhibited expression of the alpha-crystallin B chain was a common feature in all analysed datasets. The decrease in alpha-crystallin B expression was further confirmed at the protein level using BC tissue microarrays. Overexpression of alpha-crystallin B in T24 and J82 BC cell lines resulted in significant inhibition of tumour cell migration and invasion, which was associated with a decrease in PI3K, AKT and ERK activation. Moreover, alpha-crystallin B overexpression increased the expression of E-cadherin, while reducing the expression of N-cadherin, which indicated suppression of the epithelial–mesenchymal transition.
Conclusions
Overall, the results of our study suggested that alpha-crystallin B may function as a tumour-suppressive factor in bladder cancer.
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Affiliation(s)
- Houxin Ruan
- Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, AHMU, Hefei, China
| | - Yang Li
- Department of Gastroenterolog y, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xu Wang
- Department of Gastroenterolog y, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bin Sun
- Department of Gastroenterolog y, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | | | | | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, AHMU, Hefei, China
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