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Aitken RJ. Paternal age, de novo mutations, and offspring health? New directions for an ageing problem. Hum Reprod 2024; 39:2645-2654. [PMID: 39361588 PMCID: PMC11630042 DOI: 10.1093/humrep/deae230] [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: 04/25/2024] [Revised: 09/07/2024] [Indexed: 10/05/2024] Open
Abstract
This Directions article examines the mechanisms by which a father's age impacts the health and wellbeing of his children. Such impacts are significant and include adverse birth outcomes, dominant genetic conditions, neuropsychiatric disorders, and a variety of congenital developmental defects. As well as age, a wide variety of environmental and lifestyle factors are also known to impact offspring health via changes mediated by the male germ line. This picture of a dynamic germ line responsive to a wide range of intrinsic and extrinsic factors contrasts with the results of trio studies indicating that the incidence of mutations in the male germ line is low and exhibits a linear, monotonic increase with paternal age (∼two new mutations per year). While the traditional explanation for this pattern of mutation has been the metronomic plod of replication errors, an alternative model pivots around the 'faulty male' hypothesis. According to this concept, the genetic integrity of the male germ line can be dynamically impacted by age and a variety of other factors, and it is the aberrant repair of such damage that drives mutagenesis. Fortunately, DNA proofreading during spermatogenesis is extremely effective and these mutant cells are either repaired or deleted by apoptosis/ferroptosis. There appear to be only two mechanisms by which mutant germ cells can escape this apoptotic fate: (i) if the germ cells acquire a mutation that by enhancing proliferation or suppressing apoptosis, permits their clonal expansion (selfish selection hypothesis) or (ii) if a genetically damaged spermatozoon manages to fertilize an oocyte, which then fixes the damage as a mutation (or epimutation) as a result of defective DNA repair (oocyte collusion hypothesis). Exploration of these proposed mechanisms should not only help us better understand the aetiology of paternal age effects but also inform potential avenues of remediation.
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Affiliation(s)
- Robert John Aitken
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle, Callaghan, NSW 2308, Australia
- Infertility and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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Cherkasova V, Kovalchuk O, Kovalchuk I. Targeting carbohydrate metabolism in colorectal cancer - synergy between DNA-damaging agents, cannabinoids, and intermittent serum starvation. Oncoscience 2024; 11:99-105. [PMID: 39534512 PMCID: PMC11556254 DOI: 10.18632/oncoscience.611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Chemotherapy is a therapy of choice for many cancers. However, it is often inefficient for long-term patient survival and is usually accompanied by multiple adverse effects. The adverse effects are mainly associated with toxicity to normal cells, frequently resulting in immune system depression, nausea, loss of appetite and metabolic changes. In this respect, the combination of chemotherapy with cannabinoids, especially non-psychoactive, such as cannabidiol, cannabinol and other minor cannabinoids, as well as terpenes, may become very useful. This is especially pertinent because the mechanisms of anticancer effects of cannabinoids on cancer cells are often different from conventional chemotherapeutics. In addition, cannabinoids help alleviate chemotherapy-induced adverse effects, regulate sleep and appetite, and are shown to have analgesic properties. Another component for achieving potential anti-cancer synergism is regulating nutrient availability and metabolism by calorie restriction and intermittent fasting in cancer cells. As tumours require a lot of energy to grow and because glucose is constantly available, malignant cells often opt to use glucose as a primary source of ATP production through substrate-level phosphorylation (fermentation) rather than through oxidative phosphorylation. Thus, periodic depletion of cancer cells of primary fuel, glucose, could result in a strong synergy in killing cancer cells by chemo- and possibly radiotherapy when combined with cannabinoids. This commentary will discuss what is known about such combinatorial treatments, including potential mechanisms and future protocols.
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Affiliation(s)
- Viktoriia Cherkasova
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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Tang L, Zhu Y, Du Y, Long X, Long Y, Tang Y, Liu J. Clinicopathologic features and genomic profiling of female axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary. J Cancer Res Clin Oncol 2024; 150:256. [PMID: 38750402 PMCID: PMC11096249 DOI: 10.1007/s00432-024-05783-6] [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: 03/16/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024]
Abstract
PURPOSE Axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary (CUPAx) is a rare disease in women. This retrospective study intended to examine the clinicopathological features of CUPAx and compared CUPAx genetically with axillary lymph node metastases from breast cancer (BCAx), investigating differences in their biological behavior. METHODS We conducted the clinical and prognostic analysis of 58 CUPAx patients in West China Hospital spanning from 2009 to 2021. Gemonic profiling of 12 CUPAx patients and 16 BCAx patients was conducted by the FoundationOne CDx (F1CDx) platform. Moreover, we also compared the gene mutation spectrum and relevant pathways between the two groups and both TCGA and COSMIC databases. RESULTS The majority of the 58 CUPAx patients were HR-/HER2- subtype. Most patients received mastectomy combined radiotherapy (50 Gy/25f). CUPAx patients who received mastectomy instead of breast-conserving surgery had a more favorable overall prognosis. Radiotherapy in chest wall/breast and supraclavicular/infraclavicular fossa was the independent prognostic factor (HR = 0.05, 95%CI = 0.00-0.93, P = 0.04). In 28 sequencing samples (CUPAx, n = 12, BCAx, n = 16) and 401 TCGA-BRCA patients, IRS2 only mutated in CUPAx (33.33%) but amplified in BCAx (11.11%) and TCGA-BRCA (1.5%). Pathway analysis revealed that BCAx had more NOTCH pathway mutations than CUPAx. Enrichment analysis showed that CUPAx enriched more in mammary development and PML bodies than BCAx, but less in the positive regulation of kinase activity. CONCLUSIONS More active treatment methods, like chemotherapy, mastectomy and postoperative radiotherapy, could improve the prognosis of CUPAx. The differential mutation genes of CUPAx and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis.
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Affiliation(s)
- Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
- Biotherapy Clinical Research Center of Sichuan Province, Chengdu, 610041, China
| | - Yueting Zhu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
- Biotherapy Clinical Research Center of Sichuan Province, Chengdu, 610041, China
| | - Yang Du
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
- Biotherapy Clinical Research Center of Sichuan Province, Chengdu, 610041, China
| | - Xiangyu Long
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
- Biotherapy Clinical Research Center of Sichuan Province, Chengdu, 610041, China
| | - Yixiu Long
- Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China
| | - Yuan Tang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China.
- Biotherapy Clinical Research Center of Sichuan Province, Chengdu, 610041, China.
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Aloysius MM, Nikumbh T, Yadukumar L, Asija U, Shah NJ, Aswath G, John S, Goyal H. National Trends in the Incidence of Sporadic Malignant Colorectal Polyps in Young Patients (20-49 Years): An 18-Year SEER Database Analysis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:673. [PMID: 38674319 PMCID: PMC11052004 DOI: 10.3390/medicina60040673] [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: 01/19/2024] [Revised: 04/14/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
Background and Objectives: Conflicting guidelines exist for initiating average-risk colorectal cancer screening at the age of 45 years. The United States Preventive Services Task Force (USPSTF) changed its guidelines in 2021 to recommend initiating screening at 45 years due to an increasing incidence of young-onset colorectal cancer. However, the American College of Physicians (ACP) recently recommended not screening average-risk individuals between 45 and 49 years old. We aim to study the national trends in the incidence of sporadic malignant polyps (SMP) in patients from 20 to 49 years old. Materials and Methods: We analyzed the Surveillance, Epidemiology, and End Results database (2000-2017) on patients aged 20-49 years who underwent diagnostic colonoscopy with at least a single malignant sporadic colorectal polyp. Results: Of the 10,742 patients diagnosed with SMP, 42.9% were female. The mean age of incidence was 43.07 years (42.91-43.23, 95% CI). Approximately 50% of malignant polyps were diagnosed between 45 and 49 years of age, followed by 25-30% between 40 and 45. There was an upward trend in malignant polyps, with a decreased incidence of malignant villous adenomas and a rise in malignant adenomas and tubulovillous adenomas. Conclusions: Our findings suggest that almost half of the SMPs under 50 years occurred in individuals under age 45, younger than the current screening threshold recommended by the ACP. There has been an upward trend in malignant polyps in the last two decades. This reflects changes in tumor biology, and necessitates further research and support in the USPSTF guidelines to start screening at the age of 45 years.
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Affiliation(s)
- Mark M. Aloysius
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Tejas Nikumbh
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Lekha Yadukumar
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Udit Asija
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Niraj J. Shah
- Division of Gastroenterology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Ganesh Aswath
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Savio John
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Hemant Goyal
- Advanced Endoscopy, Borland Groover Owntown Office, Jacksonville, FL 32207, USA
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Leiphrakpam PD, Are C. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. Int J Mol Sci 2024; 25:3178. [PMID: 38542151 PMCID: PMC10970097 DOI: 10.3390/ijms25063178] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 11/11/2024] Open
Abstract
In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pathway altered in CRC. The aberrant activation of this pathway is associated with CRC initiation, progression, and metastasis and is critical for the development of drug resistance in CRC. Several drugs target PI3K/Akt/mTOR in clinical trials, alone or in combination, for the treatment of CRC. This review aims to provide an overview of the role of the PI3K/Akt/mTOR signaling pathway axis in driving CRC, existing PI3K/Akt/mTOR-targeted agents against CRC, their limitations, and future trends.
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Affiliation(s)
- Premila D. Leiphrakpam
- Graduate Medical Education, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chandrakanth Are
- Graduate Medical Education, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Nwaokorie A, Kolch W, Fey D. A Systems Biology Approach to Understand the Racial Disparities in Colorectal Cancer. CANCER RESEARCH COMMUNICATIONS 2024; 4:103-117. [PMID: 38051091 PMCID: PMC10785768 DOI: 10.1158/2767-9764.crc-22-0464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/04/2023] [Accepted: 11/28/2023] [Indexed: 12/07/2023]
Abstract
Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer are an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite cause other than possible sociodemographic, socioeconomic, education, nutrition, delivery of healthcare, screening, and cultural factors. A primary limitation in this field is the lack of and small sample size of Black/AA studies. Thus, this study aimed to investigate whether differences in gene expression contribute to this ongoing unanswered racial disparity issue. In this study, we examined transcriptomic data of Black/AA and White patient cohorts using a bioinformatic and systems biology approach. We performed a Kaplan-Meier overall survival analysis between both patient cohorts across critical colorectal cancer signal transduction networks (STN), to determine the differences in significant genes across each cohort. Other bioinformatic analyses performed included PROGENy (pathway responsive genes for activity inference), RNA sequencing differential expression using DESeq2, multivariable-adjusted regression, and other associated Kaplan-Meier analyses. These analyses identified novel prognostic genes independent from each cohort, 176 differentially expressed genes, and specific patient cohort STN survival associations. Despite the overarching limitation, the results revealed several novel differences in gene expression between the colorectal cancer Black/AA and White patient cohorts, which allows one to dive deeper into and understand the behavior on a systems level of what could be driving this racial difference across colorectal cancer. Concretely, this information can guide precision medicine approaches tailored specifically for colorectal cancer racial disparities. SIGNIFICANCE The purpose of this work is to investigate the racial disparities in colorectal cancer between Black/AA and White patient cohorts using a systems biology and bioinformatic approach. Our study investigates the underlying biology of each patient cohort. Concretely, the findings of this study include disparity-associated genes and pathways, which provide a tangible starting point to guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.
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Affiliation(s)
- Annabelle Nwaokorie
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, Ireland
| | - Walter Kolch
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, Ireland
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Dirk Fey
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, Ireland
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [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: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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Koubova K, Cizkova K, Burianova A, Tauber Z. PTEN and soluble epoxide hydrolase in intestinal cell differentiation. Biochim Biophys Acta Gen Subj 2023; 1867:130496. [PMID: 37866587 DOI: 10.1016/j.bbagen.2023.130496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/26/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023]
Abstract
Intestinal epithelial differentiation is a highly organised process. It is influenced by a variety of signalling pathways and enzymes, such as the PI3K pathway and soluble epoxide hydrolase (sEH) from arachidonic acid metabolism. We investigated the changes in the expression of enzymes and lipid messenger from the PI3K pathway, including PTEN, during intestinal cell differentiation in vitro using HT-29 and Caco2 cells and compared them with immunohistochemical patterns of these proteins in human colon. To investigate the possible crosstalk between the PI3K pathway and sEH, we treated HT-29 and Caco2 cells with the sEH inhibitor TPPU. Administration of TPPU to differentiated cells decreased the expression of PTEN, thus reversing the change in its expression observed during cell differentiation. In addition, multiplex immunofluorescence staining confirmed the relationship between the expression of PTEN and villin, a marker of intestinal cell differentiation, ranging from a moderate correlation in undifferentiated cells to a very strong correlation in differentiated cells treated with TPPU. Furthermore, we confirm that PTEN and sEH mirrored their expression patterns in samples of prenatal and adult human intestine compared to tumours using immunohistochemical staining. Taken together, it appears that PTEN and sEH cooperate in the process of intestinal cell differentiation. A better understanding of the crosstalk between the PI3K pathway and sEH and its consequences for cell differentiation is highly desirable, as several sEH inhibitors are under clinical investigation for the treatment of various diseases.
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Affiliation(s)
- Katerina Koubova
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic
| | - Katerina Cizkova
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic.
| | - Adela Burianova
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic
| | - Zdenek Tauber
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic
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Choudhury H, Pandey M, Saravanan V, Mun ATY, Bhattamisra SK, Parikh A, Garg S, Gorain B. Recent progress of targeted nanocarriers in diagnostic, therapeutic, and theranostic applications in colorectal cancer. BIOMATERIALS ADVANCES 2023; 153:213556. [PMID: 37478770 DOI: 10.1016/j.bioadv.2023.213556] [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: 04/18/2023] [Revised: 06/28/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023]
Abstract
Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.
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Affiliation(s)
- Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
| | - Vilashini Saravanan
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Amanda Tan Yee Mun
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ankit Parikh
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Sanjay Garg
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
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Cherkasova V, Ilnytskyy Y, Kovalchuk O, Kovalchuk I. Transcriptome Analysis of Cisplatin, Cannabidiol, and Intermittent Serum Starvation Alone and in Various Combinations on Colorectal Cancer Cells. Int J Mol Sci 2023; 24:14743. [PMID: 37834191 PMCID: PMC10572413 DOI: 10.3390/ijms241914743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer's stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
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Affiliation(s)
| | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
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Barbirou M, Miller AA, Mezlini A, Bouhaouala-Zahar B, Tonellato PJ. Variant Characterization of a Representative Large Pedigree Suggests "Variant Risk Clusters" Convey Varying Predisposition of Risk to Lynch Syndrome. Cancers (Basel) 2023; 15:4074. [PMID: 37627102 PMCID: PMC10452890 DOI: 10.3390/cancers15164074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three "variant risk clusters" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different "variant risk clusters" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.
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Affiliation(s)
- Mouadh Barbirou
- Circulating Tumor Cell Core Laboratory, Population Science Division, Medical Oncology Department, Medical College, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
- Center for Biomedical Informatics, Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MI 65211, USA;
- Medical School, University of Tunis El Manar, Tunis 1068, Tunisia;
| | - Amanda A. Miller
- Circulating Tumor Cell Core Laboratory, Population Science Division, Medical Oncology Department, Medical College, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
- Center for Biomedical Informatics, Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MI 65211, USA;
| | - Amel Mezlini
- Medical Oncology Division, Salah Azeiz Oncology Institute, University of Tunis El Manar, Tunis 1068, Tunisia;
| | - Balkiss Bouhaouala-Zahar
- Medical School, University of Tunis El Manar, Tunis 1068, Tunisia;
- Laboratory of Venoms and Therapeutic Biomolecules, LR16IPT08 Institute Pasteur of Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Peter J. Tonellato
- Center for Biomedical Informatics, Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MI 65211, USA;
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Jung JH, Yang DQ, Song H, Wang X, Wu X, Kim KP, Pandey A, Byeon SK. Characterization of Lipid Alterations by Oncogenic PIK3CA Mutations Using Untargeted Lipidomics in Breast Cancer. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:327-335. [PMID: 37463468 PMCID: PMC10366275 DOI: 10.1089/omi.2023.0076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Lipids play crucial biological roles in health and disease, including in cancers. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal promoter of cell growth and proliferation in various types of cancer. The somatic mutations in PIK3CA, the gene coding for the catalytic subunit p110α of PI3K, are frequently present in cancer cells, including breast cancer. Although the most prominent mutants, represented by single amino acid substitutions in the helical domain in exon 9 (E545K) and the kinase domain in exon 20 (H1047R) are known to cause a gain of PI3K function, activate AKT signaling and induce oncogenic transformation, the effect of these mutations on cellular lipid profiles has not been studied. We carried out untargeted lipidomics using liquid chromatography-tandem mass spectrometry to detect the lipid alterations in mammary gland epithelial MCF10A cells with isogenic knockin of these mutations. A total of 536 species of lipids were analyzed. We found that the levels of monosialogangliosides, signaling molecules known to enhance cell motility through PI3K/AKT pathway, were significantly higher in both mutants. In addition, triglycerides and ceramides, lipid molecules known to be involved in promoting lipid droplet production, cancer cell migration and invasion, were increased, whereas lysophosphatidylcholines and phosphatidylcholines that are known to inhibit cancer cell motility were decreased in both mutants. Our results provide novel insights into a potential link between altered lipid profile and carcinogenesis caused by the PIK3CA hotspot mutations. In addition, we suggest untargeted lipidomics offers prospects for precision/personalized medicine by unpacking new molecular substrates of cancer biology.
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Affiliation(s)
- Jae Hun Jung
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Applied Chemistry, Kyung Hee University, Yongin, South Korea
| | - Da-Qing Yang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Hongming Song
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xiangyu Wang
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xinyan Wu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Kyung Hee University, Yongin, South Korea
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Manipal Academy of Higher Education, Manipal, India
| | - Seul Kee Byeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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14
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Xiang M, Gao Y, Zhou Y, Wang M, Yao X. A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer. BMC Cancer 2023; 23:595. [PMID: 37370046 DOI: 10.1186/s12885-023-11075-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Although the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients. METHODS EOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis. RESULTS The cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age. CONCLUSION In this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.
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Affiliation(s)
- Meijuan Xiang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- Department of General Surgery, Foresea Life Insurance Shaoguan Hospital, Shaoguan, 512000, China
| | - Yuan Gao
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yue Zhou
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Muqing Wang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Xueqing Yao
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
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15
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Fan JR, Chang SN, Chu CT, Chen HC. AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition. iScience 2023; 26:106992. [PMID: 37378334 PMCID: PMC10291577 DOI: 10.1016/j.isci.2023.106992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/04/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGFβ to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGFβ stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGFβ. These findings reveal a molecular mechanism for TGFβ-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition.
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Affiliation(s)
- Jia-Rong Fan
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Sung-Nian Chang
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Ching-Tung Chu
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Hong-Chen Chen
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
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16
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Luo H, Chen J, Jiang Q, Yu Y, Yang M, Luo Y, Wang X. Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets. Clin Epigenetics 2023; 15:100. [PMID: 37309005 DOI: 10.1186/s13148-023-01515-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/31/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND & AIMS The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC. METHODS We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking. RESULTS The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4+ T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC. CONCLUSIONS In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.
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Affiliation(s)
- Huiyan Luo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jixin Chen
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiyin Jiang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifan Yu
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Miaolun Yang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuehua Luo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiongwen Wang
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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17
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Katzengruber L, Sander P, Laufer S. MKK4 Inhibitors-Recent Development Status and Therapeutic Potential. Int J Mol Sci 2023; 24:ijms24087495. [PMID: 37108658 PMCID: PMC10144091 DOI: 10.3390/ijms24087495] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs.
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Affiliation(s)
- Leon Katzengruber
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
| | - Pascal Sander
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
| | - Stefan Laufer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany
- Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany
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18
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Fang H, Li H, Zhang H, Wang S, Xu S, Chang L, Yang Y, Cui R. Short-chain L-3-hydroxyacyl-CoA dehydrogenase: A novel vital oncogene or tumor suppressor gene in cancers. Front Pharmacol 2022; 13:1019312. [PMID: 36313354 PMCID: PMC9614034 DOI: 10.3389/fphar.2022.1019312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/23/2022] [Indexed: 08/22/2023] Open
Abstract
The reprogramming of cellular metabolism is frequently linked to tumorigenesis. Glucose, fatty acids, and amino acids are the specific substrates involved in how an organism maintains metabolic equilibrium. The HADH gene codes for the short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADH), a crucial enzyme in fatty acid oxidation that catalyzes the third phase of fatty acid oxidation in mitochondria. Increasing data suggest that HADH is differentially expressed in various types of malignancies and is linked to cancer development and progression. The significance of HADH expression in tumors and its potential mechanisms of action in the onset and progression of certain cancers are summarized in this article. The possible roles of HADH as a target and/or biomarker for the detection and treatment of various malignancies is also described here.
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Affiliation(s)
- He Fang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hanyang Li
- Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Shu Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Shuang Xu
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Li Chang
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Yongsheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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Lei K, Luo M, Tu Z, Lv S, Liu J, Gong C, Ye M, Wu M, Sheng Y, Long X, Li J, Zhu X, Huang K. Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer. Cancer Cell Int 2022; 22:275. [PMID: 36064705 PMCID: PMC9442929 DOI: 10.1186/s12935-022-02689-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/18/2022] [Indexed: 11/30/2022] Open
Abstract
Background The p21-activated kinase (PAK) family (PAKs) plays a key role in the formation and development of human tumors. However, a systematic analysis of PAKs in human cancers is lacking and the potential role of PAKs in cancer immunity has not been explored. Methods We used datasets from in The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression database (GTEx). Results Based on TCGA datasets most PAKs show noteworthy differences in expression between tumors and corresponding normal tissues or across different tumor tissues. Patients with high expression of PAKs often show a worse prognosis. However, copy number variation, mutation, and DNA methylation of PAKs have limited impact on tumor development. Further analysis showed that the impact of PAKs on immunity varies with the type of tumor and the respective tumor microenvironment. PAK1 and PAK4 may be stronger predictors of immune characteristics, and are more suitable as drugs and molecular therapeutic targets. Furthermore, Cox regression analysis revealed that a PAK gene signature could be used as an independent prognostic factor for lower grade glioma (LGG) and glioblastoma (GBM). Gene set enrichment analysis (GSEA) analysis indicated that PAK genes may affect the occurrence and development of GBM through the PI3K signaling pathway. Further experiments verified that PAK1 and AKT1 have a significant interaction in GBM cells, and inhibiting the overactivation of PAK1 can significantly inhibit the proliferation of GBM cells. Conclusions Our study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02689-6.
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Affiliation(s)
- Kunjian Lei
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Min Luo
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Zewei Tu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Shigang Lv
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Junzhe Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Chuandong Gong
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Minhua Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Miaojing Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yilei Sheng
- Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Xiaoyan Long
- East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Jingying Li
- Department of Comprehensive Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Xingen Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. .,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Kai Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. .,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
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Wang H, Yang W, Qin Q, Yang X, Yang Y, Liu H, Lu W, Gu S, Cao X, Feng D, Zhang Z, He J. E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predictor for chemotherapy response in colorectal cancer. Mol Cancer 2022; 21:151. [PMID: 35864508 PMCID: PMC9306183 DOI: 10.1186/s12943-022-01622-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Background Recurrence and chemoresistance constitute the leading cause of death in colorectal cancer (CRC). Thus, it is of great significance to clarify the underlying mechanisms and identify predictors for tailoring adjuvant chemotherapy to improve the outcome of CRC. Methods By screening differentially expressed genes (DEGs), constructing random forest classification and ranking the importance of DEGs, we identified membrane associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) as an important gene in CRC recurrence. Immunohistochemical and western blot assays were employed to further detect MAGI3 expression in CRC tissues and cell lines. Cell counting kit-8, plate colony formation, flow cytometry, sub-cutaneous injection and azoxymethane plus dextran sulfate sodium induced mice CRC assays were employed to explore the effects of MAGI3 on proliferation, growth, cell cycle, apoptosis, xenograft formation and chemotherapy resistance of CRC. The underlying molecular mechanisms were further investigated through gene set enrichment analysis, quantitative real-time PCR, western blot, co-immunoprecipitation, ubiquitination, GST fusion protein pull-down and immunohistochemical staining assays. Results Our results showed that dysregulated low level of MAGI3 was correlated with recurrence and poor prognosis of CRC. MAGI3 was identified as a novel substrate-binding subunit of SKP1-Cullin E3 ligase to recognize c-Myc, and process c-Myc ubiquitination and degradation. Expression of MAGI3 in CRC cells inhibited cell growth, promoted apoptosis and chemosensitivity to fluoropyrimidine-based chemotherapy by suppressing activation of c-Myc in vitro and in vivo. In clinic, the stage II/III CRC patients with MAGI3-high had a significantly good recurrence-free survival (~ 80%, 5-year), and were not necessary for further adjuvant chemotherapy. The patients with MAGI3-medium had a robustly good response rate or recurrence-free survival with fluoropyrimidine-based chemotherapy, and were recommended to undergo fluoropyrimidine-based adjuvant chemotherapy. Conclusions MAGI3 is a novel E3 ubiquitin ligase by degradation of c-Myc to regulate CRC development and may act as a potential predictor of adjuvant chemotherapy for CRC patients. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01622-9.
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Affiliation(s)
- Haibo Wang
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Wenjing Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China
| | - Qiong Qin
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Xiaomei Yang
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Ying Yang
- Core Facilities Center, Capital Medical University, Beijing, People's Republic of China
| | - Hua Liu
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Wenxiu Lu
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Siyu Gu
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Xuedi Cao
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Duiping Feng
- Department of Interventional Radiology, First Hospital of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, No.95 Yong-anRoad, Xi-Cheng District, Beijing, 100050, People's Republic of China.
| | - Junqi He
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China.
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21
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Hu J, Li G. Recent Progress in Fluorescent Chemosensors for Protein Kinases. Chem Asian J 2022; 17:e202200182. [PMID: 35486328 DOI: 10.1002/asia.202200182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/21/2022] [Indexed: 11/10/2022]
Abstract
Protein kinases are involved in almost all biological activities. The activities of different kinases reflect the normal or abnormal status of the human body. Therefore, detecting the activities of different kinases is important for disease diagnosis and drug discovery. Fluorescent probes offer opportunities for studying kinase behaviors at different times and spatial locations. In this review, we summarize different kinds of fluorescent chemosensors that have been used to detect the activities of many different kinases.
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Affiliation(s)
- Jun Hu
- Fujian Agriculture and Forestry University, College of Life Sciences, No.15 Shangxiadian Road, Cangshan District, 350002, Fuzhou, CHINA
| | - Gao Li
- Minjiang University, College of Material and Chemical Engineering, CHINA
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22
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Therapeutic Strategies and Potential Actions of Female Sex Steroid Hormones and Their Receptors in Colon Cancer Based on Preclinical Studies. Life (Basel) 2022; 12:life12040605. [PMID: 35455096 PMCID: PMC9032023 DOI: 10.3390/life12040605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 11/17/2022] Open
Abstract
Several epidemiological studies have reported that the use of female sex steroid hormones could reduce the risk of colon cancer (CRC). This review summarizes the available data related to estradiol (E2) and progesterone (P4) single and dual treatments in CRC male and female in vitro and in vivo models, mainly from preclinical studies, alongside their potential molecular mechanisms. Most of the studies showed that E2 exogenous treatment and/or reactivation of its beta receptor (ERβ) significantly inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis by modulating several molecular pathways. Likewise, the inhibition of ERα receptors produced similar antitumorigenic actions, both in vivo and in vitro, suggesting that E2 could have dual opposing roles in CRC that are dependent on the expression profile of its nuclear receptors. The available studies on P4 are scarce, and the results revealed that in vitro and in vivo treatments with natural and synthetic progesterone were also associated with promising tumoricidal actions. Nevertheless, the combination of E2 with P4 showed enhanced anticancer activities compared with their monotherapy protocols in male–female cell lines and animals. Collectively, the studies suggested that the female sex steroid hormones could provide a novel and effective therapeutic strategy against CRC.
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23
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Lucas LM, Dwivedi V, Senfeld JI, Cullum RL, Mill CP, Piazza JT, Bryant IN, Cook LJ, Miller ST, Lott JH, Kelley CM, Knerr EL, Markham JA, Kaufmann DP, Jacobi MA, Shen J, Riese DJ. The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein. Pharmacol Rev 2022; 74:18-47. [PMID: 34987087 PMCID: PMC11060329 DOI: 10.1124/pharmrev.121.000381] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/15/2021] [Indexed: 12/11/2022] Open
Abstract
ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.
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Affiliation(s)
- Lauren M Lucas
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Vipasha Dwivedi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jared I Senfeld
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Richard L Cullum
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Christopher P Mill
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - J Tyler Piazza
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Ianthe N Bryant
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Laura J Cook
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - S Tyler Miller
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - James H Lott
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Connor M Kelley
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Elizabeth L Knerr
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jessica A Markham
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David P Kaufmann
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Megan A Jacobi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jianzhong Shen
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David J Riese
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
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Class I PI3K Biology. Curr Top Microbiol Immunol 2022; 436:3-49. [DOI: 10.1007/978-3-031-06566-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data. Cancers (Basel) 2021; 13:cancers13236018. [PMID: 34885128 PMCID: PMC8656546 DOI: 10.3390/cancers13236018] [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: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary This experimental preclinical study developed a strategy to identify signatures for the personalized treatment of colon cancer focusing on target-specific drug combinations. Tumor growth inhibition was analyzed in a preclinical phase II study using 25 patient-derived xenograft models (PDX) treated with drug combinations blocking alternatively activated oncogenic pathways. Results reveal an improved response by combinatorial treatment in some defined molecular subgroups and potential alternative treatment options in KRAS- and BRAF-mutated colon cancer. Abstract The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.
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Cherkasova V, Kovalchuk O, Kovalchuk I. Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer. Cancers (Basel) 2021; 13:4353. [PMID: 34503163 PMCID: PMC8430689 DOI: 10.3390/cancers13174353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 01/02/2023] Open
Abstract
Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world's disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
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Affiliation(s)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
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Nenkov M, Ma Y, Gaßler N, Chen Y. Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy. Int J Mol Sci 2021; 22:6262. [PMID: 34200820 PMCID: PMC8230539 DOI: 10.3390/ijms22126262] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/20/2022] Open
Abstract
Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.
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Affiliation(s)
| | | | | | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, University Hospital Jena, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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Tian J, Zhu Y, Rao M, Cai Y, Lu Z, Zou D, Peng X, Ying P, Zhang M, Niu S, Li Y, Zhong R, Chang J, Miao X. N 6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression. Gut 2020; 69:2180-2192. [PMID: 32312789 DOI: 10.1136/gutjnl-2019-320179] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear. DESIGN We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth. RESULTS We identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A 'writer' complex (METTL13/METTL14/WTAP) and the m6A 'reader' YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC. CONCLUSIONS These findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.
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Affiliation(s)
- Jianbo Tian
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Ying Zhu
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Meilin Rao
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Yimin Cai
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Zequn Lu
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Danyi Zou
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Xiating Peng
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Pingting Ying
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Ming Zhang
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Siyuan Niu
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Yue Li
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Rong Zhong
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Jiang Chang
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Xiaoping Miao
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
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Decreased concentrations of intracellular signaling proteins in colon cancer patients with BRAF mutations. Sci Rep 2020; 10:20113. [PMID: 33208845 PMCID: PMC7675974 DOI: 10.1038/s41598-020-77109-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/04/2020] [Indexed: 02/08/2023] Open
Abstract
The activation of intracellular signaling pathways plays a critical role in cancer pathogenesis. The current study aims to quantify intracellular signaling proteins in localized colon cancer tissue to investigate the prognostic value of these biomarkers and elucidate their possible relations to mutation status. Colon cancer tissue and autologous reference tissue were collected from 176 patients who underwent colon cancer surgery. Assays were developed to quantify ERK, AKT and cyclin d using single-molecule array technology. KRAS/BRAF/PIK3CA mutation status was determined using droplet digital PCR. Patients with BRAF mutations had decreased concentrations of ERK (p = 0.0003), AKT (p = 0.0001) and cyclin d (p = 0.003), while no significant differences were found between patients with KRAS mutations and wild-type patients. None of the investigated proteins were associated with disease-free survival or overall survival when all patients were included. However, when patients were stratified according to mutation status, significant correlations with overall survival were seen for patients with BRAF mutations and AKT (p = 0.002) or ERK (p = 0.03) and for KRAS mutations and cyclin d (p = 0.01). Conclusions: A strong correlation exists between intracellular signaling protein concentrations and mutational BRAF status. Overall survival in colon cancer patients depends on both gene mutation status and signaling protein concentrations.
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Weng WH, Yu KJ, Li LC, Pang YJ, Chen YT, Pang ST, Chuang CK. Low PTEN expression and overexpression of phosphorylated Akt Ser473 and Akt Thr308 are associated with poor overall survival in upper tract urothelial carcinoma. Oncol Lett 2020; 20:347. [PMID: 33123258 PMCID: PMC7583738 DOI: 10.3892/ol.2020.12210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 03/27/2020] [Indexed: 01/13/2023] Open
Abstract
The PI3K/Akt signaling pathway serves an essential role in various cellular processes, including cell growth, survival, cell motility, angiogenesis and cell metabolism. Loss of PTEN expression and hyperactivation of Akt can result in tumorigenesis. Previous studies observed expression of the Akt protein and absence of the PTEN protein in bladder cancer and non-small cell lung carcinoma tissues. The aim of the present study was to evaluate the expression status and prognostic value of PTEN and the PI3K/Akt signaling pathway in Taiwanese patients with upper tract urothelial carcinoma (UTUC). Archival formalin-fixed, paraffin-embedded (FFPE) tissues from 65 UTUC cases were stained via immunohistochemistry for PTEN, phosphorylated (p)Akt serine (Ser)473 and pAkt threonine (Thr)308. The expression levels of each protein were significantly correlated with clinicopathological parameters. PTEN, pAktSer473 and pAktThr308 protein expression levels were higher in adjacent normal tissues compared with those in tumor tissues. Cytoplasmic PTEN protein expression levels were lower in high-stage tumors compared with those in low-stage tumors, and nuclear and cytoplasmic pAktThr308 protein expression levels were higher in high-grade tumors compared with those in low-grade tumors. Univariate analysis showed that high pathological tumor stage (pT2-4) [P=0.01; hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.34-8.60], metastatic status (P=0.003; HR=3.55, 95% CI, 1.55-8.11), low cytoplasmic PTEN protein expression levels (P=0.016; HR=3.14; 95% CI, 1.24-7.95) and high cytoplasmic pAktSer473 protein expression levels (P=0.019, HR=2.71, 95% CI, 1.18-6.21) were predictive of poor overall survival. However, only metastatic status (P=0.031; HR=2.73; 95% CI, 1.10-6.78), low cytoplasmic PTEN protein expression levels (P=0.017; HR=3.29; 95% CI, 1.24-8.73) and high cytoplasmic pAktSer473 protein expression levels (P=0.027; HR=2.64; 95% CI, 1.12-6.23) remained significant in the multivariate analysis. Kaplan-Meier survival analysis showed that high T stage, metastasis, low expression levels of cytoplasmic PTEN protein and high expression levels of cytoplasmic pAktSer473 protein were significantly associated with poor survival (P=0.006, 0.001, 0.011 and 0.014, respectively). Co-expression of PTENlow/pAktSer473/high and pAktThr308/high phenotypes was associated with a less favorable overall survival (P=0.001). Overall, the present findings demonstrated that low expression levels of PTEN and high expression levels of pAktSer473 and pAktThr308 were predictors for poor overall survival in patients with UTUC.
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Affiliation(s)
- Wen-Hui Weng
- Department of Chemical Engineering and Biotechnology, Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C
| | - Kai-Jie Yu
- Department of Chemical Engineering and Biotechnology, Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C.,College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.,Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, R.O.C
| | - Liang-Chen Li
- Department of Chemical Engineering and Biotechnology, Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C
| | - Yeu-Jye Pang
- Department of Gastroenterology, Mater Misericordiae University Hospital, Dublin D07 R2WY, Ireland
| | - Ying-Tzu Chen
- Department of Chemical Engineering and Biotechnology, Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C
| | - See-Tong Pang
- College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.,Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, R.O.C
| | - Cheng-Keng Chuang
- College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.,Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, R.O.C
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31
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Li Z, Shao C, Liu X, Lu X, Jia X, Zheng X, Wang S, Zhu L, Li K, Pang Y, Xie F, Lu Y, Wang Y. Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression. Carcinogenesis 2020; 41:44-55. [PMID: 31046123 DOI: 10.1093/carcin/bgz086] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 04/19/2019] [Accepted: 04/30/2019] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with few therapeutic options, representing one of the great challenges in oncology. Activating KRAS mutation, occurring in >90% PDACs, is present in pancreatic intraepithelial neoplasia lesions, the precursor ductal lesions of PDAC, indicating additional genetic alterations contribute to the pathogenesis of PDAC. PDAC sequencing projects identify recurrent genomic ERBB2 alterations, mutations and amplifications, in 8.5% of PDAC patients, ranking as the top hit among the 100 receptor tyrosine kinases-encoding genes. Introduction of the ERBB2 mutations encoding protein variants S310F, S423R, R678Q, Q679L, E717D, L755S, V777L and V842I into human pancreatic epithelial cells causes oncogenic transformation, increasing ERBB2 signaling, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. Interestingly, in many PDACs, mutations in ERBB2 and KRAS occur together. ERBB2 activating mutants facilitate KRAS-driven oncogenic properties. Introduction of ERBB2 mutations into KRAS-mutant PDAC cells activates ERBB2 signaling, promotes tumor growth and attenuates KRAS dependency. In contrast, a CRISPR-mediated knockout (KO) of ERBB2 in ERBB2-amplified PDAC cells inhibits ERBB2 signaling, colony formation, anchorage-independent growth and tumor xenograft formation. Finally, oncogenic ERBB2 aberrations can be abrogated by treatment with small-molecule inhibitors. ERBB2 and KRAS inhibition cooperate to suppress PDAC cell growth in vitro and to promote tumor regression in nude mice, providing a rationale for testing an anti-ERBB2 drug in combination with a KRAS inhibitor in ERBB2-mutant PDAC patients that are currently untreatable.
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Affiliation(s)
- Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Chenghao Shao
- Department of Pancreatic-Biliary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaojing Lu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaona Jia
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xufen Zheng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Simin Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Li Zhu
- Department of General Surgery, PLA General Hospital, Beijing, China
| | - Ke Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuzhi Pang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feifei Xie
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuan Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SIBS-Changzheng Hospital Joint Center for Translational Medicine, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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32
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Bellier J, Nokin MJ, Caprasse M, Tiamiou A, Blomme A, Scheijen JL, Koopmansch B, MacKay GM, Chiavarina B, Costanza B, Rademaker G, Durieux F, Agirman F, Maloujahmoum N, Cusumano PG, Lovinfosse P, Leung HY, Lambert F, Bours V, Schalkwijk CG, Hustinx R, Peulen O, Castronovo V, Bellahcène A. Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab. Cell Rep 2020; 30:1400-1416.e6. [PMID: 32023458 DOI: 10.1016/j.celrep.2020.01.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 11/10/2019] [Accepted: 01/02/2020] [Indexed: 02/07/2023] Open
Abstract
The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.
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Affiliation(s)
- Justine Bellier
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Marie-Julie Nokin
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Maurine Caprasse
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Assia Tiamiou
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Arnaud Blomme
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Jean L Scheijen
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands
| | | | | | - Barbara Chiavarina
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Brunella Costanza
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Gilles Rademaker
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Florence Durieux
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Ferman Agirman
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Naïma Maloujahmoum
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Pino G Cusumano
- Department of Senology, Liège University Hospital, University of Liège, Liège, Belgium
| | - Pierre Lovinfosse
- Oncology Imaging Division, Liège University Hospital, University of Liège, Liège, Belgium
| | - Hing Y Leung
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Frédéric Lambert
- Department of Human Genetics, Liège University Hospital, Liege, Belgium
| | - Vincent Bours
- Department of Human Genetics, Liège University Hospital, Liege, Belgium
| | - Casper G Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands
| | - Roland Hustinx
- Oncology Imaging Division, Liège University Hospital, University of Liège, Liège, Belgium
| | - Olivier Peulen
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Vincent Castronovo
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Akeila Bellahcène
- Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium.
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33
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Zhu Y, Du Y, Zhang Y. DHX33 promotes colon cancer development downstream of Wnt signaling. Gene 2020; 735:144402. [PMID: 32004669 DOI: 10.1016/j.gene.2020.144402] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 01/23/2020] [Accepted: 01/24/2020] [Indexed: 02/05/2023]
Abstract
Colon cancer is one of the most common malignancies in the world; there is no effective therapeutic treatment after surgery. Our previous studies indicate that RNA helicase DHX33 plays a critical role in cell proliferation and cell growth. Here in this study, DHX33 is found to be highly expressed in colon cancer tissues and colon cancer cell lines. Knockdown of DHX33 significantly decreased cell proliferation and triggered apoptosis. Mechanistically, DHX33 was found to transcriptionally control multiple critical genes involved in cell cycle, apoptosis and migration. DHX33 deficiency caused decreased tumor growth for colon cancer cells in a xenograft model in vivo. With Wnt/β-cateninactivator and inhibitors, we further discovered that Wnt/β-catenin pathway regulates DHX33 transcriptionally. This study for the first time demonstratesthe important role of DHX33 in colon cancer development and reveals the underlying molecular mechanism. We also provide the initial evidence for the relationship between DHX33 and Wnt/β-catenin signaling pathway in colon cancer development.
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Affiliation(s)
- Yaju Zhu
- Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Yichen Du
- Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Yandong Zhang
- Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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34
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Yen YT, Chien M, Lai YC, Chen DP, Chuong CM, Hung MC, Hung SC. PP2A Deficiency Enhances Carcinogenesis of Lgr5 + Intestinal Stem Cells Both in Organoids and In Vivo. Cells 2019; 9:cells9010090. [PMID: 31905853 PMCID: PMC7017129 DOI: 10.3390/cells9010090] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 12/27/2019] [Accepted: 12/28/2019] [Indexed: 12/19/2022] Open
Abstract
In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5+ intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis.
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Affiliation(s)
- Yu-Ting Yen
- Drug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan; (Y.-T.Y.); (M.C.)
- Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan; (Y.-C.L.); (C.-M.C.)
| | - May Chien
- Drug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan; (Y.-T.Y.); (M.C.)
- Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan; (Y.-C.L.); (C.-M.C.)
| | - Yung-Chih Lai
- Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan; (Y.-C.L.); (C.-M.C.)
| | - Dao-Peng Chen
- Kim Forest Enterprise Co., Ltd., Taipei 22175, Taiwan;
| | - Cheng-Ming Chuong
- Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan; (Y.-C.L.); (C.-M.C.)
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Mien-Chie Hung
- Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan;
- Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shih-Chieh Hung
- Drug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan; (Y.-T.Y.); (M.C.)
- Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan; (Y.-C.L.); (C.-M.C.)
- Department of Orthopaedics, China Medical University Hospital, Taichung 40402, Taiwan
- Correspondence:
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35
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Ronen J, Hayat S, Akalin A. Evaluation of colorectal cancer subtypes and cell lines using deep learning. Life Sci Alliance 2019; 2:e201900517. [PMID: 31792061 PMCID: PMC6892438 DOI: 10.26508/lsa.201900517] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer (CRC) is a common cancer with a high mortality rate and a rising incidence rate in the developed world. Molecular profiling techniques have been used to better understand the variability between tumors and disease models such as cell lines. To maximize the translatability and clinical relevance of in vitro studies, the selection of optimal cancer models is imperative. We have developed a deep learning-based method to measure the similarity between CRC tumors and disease models such as cancer cell lines. Our method efficiently leverages multiomics data sets containing copy number alterations, gene expression, and point mutations and learns latent factors that describe data in lower dimensions. These latent factors represent the patterns that are clinically relevant and explain the variability of molecular profiles across tumors and cell lines. Using these, we propose refined CRC subtypes and provide best-matching cell lines to different subtypes. These findings are relevant to patient stratification and selection of cell lines for early-stage drug discovery pipelines, biomarker discovery, and target identification.
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Affiliation(s)
- Jonathan Ronen
- Max-Delbrück-Centrum für Molekulare Medizin, BIMSB, Berlin, Germany
- Humboldt Universität zu Berlin, Berlin, Germany
| | | | - Altuna Akalin
- Max-Delbrück-Centrum für Molekulare Medizin, BIMSB, Berlin, Germany
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36
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Mutation Profiling of Premalignant Colorectal Neoplasia. Gastroenterol Res Pract 2019; 2019:2542640. [PMID: 31781186 PMCID: PMC6875414 DOI: 10.1155/2019/2542640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 10/16/2019] [Indexed: 02/06/2023] Open
Abstract
Accumulation of allelic variants in genes that regulate cellular proliferation, differentiation, and apoptosis may result in expansion of the aberrant intestinal epithelium, generating adenomas. Herein, we compared the mutation profiles of conventional colorectal adenomas (CNADs) across stages of progression towards early carcinoma. DNA was isolated from 17 invasive adenocarcinomas (ACs) and 58 large CNADs, including 19 with low-grade dysplasia (LGD), 21 with LGD adjacent to areas of high-grade dysplasia and/or carcinoma (LGD-H), and 28 with high-grade dysplasia (HGD). Ion AmpliSeq Comprehensive Cancer Panel libraries were prepared and sequenced on the Ion Proton. We identified 956 unique allelic variants; of these, 499 were considered nonsynonymous variants. Eleven genes (APC, KRAS, SYNE1, NOTCH4, BLNK, FBXW7, GNAS, KMT2D, TAF1L, TCF7L2, and TP53) were mutated in at least 15% of all samples. Out of frequently mutated genes, TP53 and BCL2 had a consistent trend in mutation prevalence towards malignancy, while two other genes (HNF1A and FBXW7) exhibited the opposite trend. HGD adenomas had significantly higher mutation rates than LGD adenomas, while LGD-H adenomas exhibited mutation frequencies similar to those of LGD adenomas. A significant increase in copy number variant frequency was observed from LGD through HGD to malignant samples. The profiling of advanced CNADs demonstrated variations in mutation patterns among colorectal premalignancies. Only limited numbers of genes were repeatedly mutated while the majority were altered in single cases. Most genetic alterations in adenomas can be considered early contributors to colorectal carcinogenesis.
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37
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Piper AJ, Clark JL, Mercado-Matos J, Matthew-Onabanjo AN, Hsieh CC, Akalin A, Shaw LM. Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC). PLoS One 2019; 14:e0220567. [PMID: 31393907 PMCID: PMC6687170 DOI: 10.1371/journal.pone.0220567] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 07/18/2019] [Indexed: 11/22/2022] Open
Abstract
The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression.
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Affiliation(s)
- Andrew J. Piper
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Jennifer L. Clark
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Jose Mercado-Matos
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Asia N. Matthew-Onabanjo
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Chung-Cheng Hsieh
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Ali Akalin
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Leslie M. Shaw
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
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Feng Y, Li Y, Cai S, Peng J. Immunological nomograms predicting prognosis and guiding adjuvant chemotherapy in stage II colorectal cancer. Cancer Manag Res 2019; 11:7279-7294. [PMID: 31447586 PMCID: PMC6683167 DOI: 10.2147/cmar.s212094] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/18/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The type, abundance, and location of tumor-infiltrating lymphocytes (TILs) have been associated with prognosis in colorectal cancer (CRC). This study was conducted to assess the prognostic role of TILs and develop a nomogram for accurate prognostication of stage II CRC. METHODS Immunohistochemistry was conducted to assess the densities of intraepithelial and stromal CD3+, CD8+, CD45RO+, and FOXP3+ TILs, and to estimate PD-L1 expression in tumor cells for 168 patients with stage II CRC. The prognostic roles of these features were evaluated using COX regression model, and nomograms were established to stratify patients into low- and high-risk groups and compare the benefit from adjuvant chemotherapy. RESULTS In univariate analysis, patients with high intraepithelial or stromal CD3+, CD8+, CD45RO+ and FOXP3+ TILs were associated significantly with better relapse-free survival (RFS) and overall survival (OS), except for stromal CD45RO+ TILs. In multivariate analysis, patients with high intraepithelial CD3+ and stromal FOXP3+ TILs were associated with better RFS (p<0.001 and p=0.032, respectively), while only stromal FOXP3+ TILs was an independent prognostic factor for OS (p=0.031). The nomograms were well calibrated and showed a c-index of 0.751 and 0.757 for RFS and OS, respectively. After stratifying into low- and high-risk groups, the high-risk group exhibited a better OS from adjuvant chemotherapy (3-year OS of 81.9% vs 34.3%, p=0.006). CONCLUSION These results may help improve the prognostication of stage II CRC and identify a high-risk subset of patients who appeared to benefit from adjuvant chemotherapy.
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Affiliation(s)
- Yang Feng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
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Abstract
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP. Possible mechanisms by which the PI3K/AKT/mTOR axis contributes to oncogenic transformation include stimulation of proliferation, survival, metabolic reprogramming, and invasion/metastasis, as well as suppression of autophagy and senescence. These phenotypic changes are mediated by eIF4E-induced translation of a subset of mRNAs and by other downstream effectors of mTORC1 including S6K, HIF-1α, PGC-1α, SREBP, and ULK1 complex.
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Revisiting mTOR inhibitors as anticancer agents. Drug Discov Today 2019; 24:2086-2095. [PMID: 31173912 DOI: 10.1016/j.drudis.2019.05.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/04/2019] [Accepted: 05/30/2019] [Indexed: 12/20/2022]
Abstract
The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates a variety of cellular processes, influencing diverse pathological conditions including a variety of cancers. Accordingly, therapies that target mTOR as anticancer agents benefit patients in various clinical settings. It is therefore important to fully investigate mTOR signaling at a molecular level and corresponding mTOR inhibitors to identify additional clinical opportunities of targeting mTOR in cancers. In this review, we introduce the function and regulation of the mTOR signaling pathway and organize and summarize the different roles of mTOR in cancers and a variety of mTOR inhibitors that can be used as anticancer agents. This article aims to enlighten and guide the development of mTOR-targeted anticancer agents in the future.
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Revathidevi S, Munirajan AK. Akt in cancer: Mediator and more. Semin Cancer Biol 2019; 59:80-91. [PMID: 31173856 DOI: 10.1016/j.semcancer.2019.06.002] [Citation(s) in RCA: 439] [Impact Index Per Article: 73.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/29/2019] [Accepted: 06/03/2019] [Indexed: 02/06/2023]
Abstract
Akt is a serine/threonine kinase and it participates in the key role of the PI3K signaling pathway. The Akt can be activated by a wide range of growth signals and the biochemical mechanisms leading to Akt activation are well defined. Once activated, Akt modulates the function of many downstream proteins involved in cellular survival, proliferation, migration, metabolism, and angiogenesis. The Akt is a central node of many signaling pathways and it is frequently deregulated in many types of human cancers. In this review, we provide an overview of Akt function and its role in the hallmarks of human cancer. We also discussed various mechanisms of Akt dysregulation in cancers, including epigenetic modifications like methylation, post-transcriptional non-coding RNAs-mediated regulation, and the overexpression and mutation.
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Affiliation(s)
- Sundaramoorthy Revathidevi
- Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 113, Tamil Nadu, India
| | - Arasambattu Kannan Munirajan
- Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 113, Tamil Nadu, India.
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Bai R, Yuan C, Zhou F, Ni L, Gong Y, Xie C. Evaluation of the association between the -1304T>G polymorphism in the promoter of the MKK4 gene and the risk of colorectal cancer: a PRISMA-compliant meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:144. [PMID: 31157265 DOI: 10.21037/atm.2019.03.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Colorectal cancer (CRC) is one of the most common cancers in China. Mitogen-activated protein kinase kinase 4 (MKK4) regulates tumorigenesis as a component of the MKK4 pathway. A number of studies have suggested a correlation between the MKK4 -1304T>G polymorphism and the risk of CRC. However, the results are still controversial. Therefore, we conducted a meta-analysis to obtain a more accurate assessment of the association between the MKK4 -1304T>G polymorphism and the risk of CRC. Methods Systematic literature searches were performed using PubMed, Embase, Cochrane Library, and CNKI. Four trials, including 1,255 cancer cases and 1,181 controls, were recruited in our study to assess the relationship of the MKK4 -1304T>G polymorphism with the risk of CRC. Results Four studies met our inclusion criteria and were finally included in the analysis, involving 1,255 cancer patients and 1,181 controls. Our meta-analysis revealed that the MKK4 -1304T>G polymorphism could reduce the risk of CRC (G vs. T: OR, 0.60, 95% CI: 0.48-0.76, P<0.0001; GG vs. TT: OR, 0.43, 95% CI: 0.29-0.62, P<0.0001; GG vs. TT + TG: OR, 0.50, 95% CI: 0.34-0.72, P=0.0003; TG + GG vs. TT: OR, 0.62, 95% CI: 0.53-0.73, P<0.0001; and TG vs. TT + GG: OR, 0.70, 95% CI: 0.59-0.82, P<0.0001). Conclusions In conclusion, our meta-analysis showed that the MKK4 -1304T>G polymorphism was associated with the susceptibility to CRC. In the future, large and well-designed case-control studies are needed to validate our findings.
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Affiliation(s)
- Rui Bai
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Cheng Yuan
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Lihua Ni
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.,Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yan Gong
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Conghua Xie
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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Iridoids from Valeriana jatamansi induce autophagy-associated cell death via the PDK1/Akt/mTOR pathway in HCT116 human colorectal carcinoma cells. Bioorg Chem 2019; 87:136-141. [DOI: 10.1016/j.bioorg.2019.03.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/26/2019] [Accepted: 03/09/2019] [Indexed: 12/16/2022]
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Karpisheh V, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Ghalamfarsa G, Sabz G, Yousefi M, Yousefi B, Jadidi-Niaragh F. Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat 2019; 144:106338. [PMID: 31100474 DOI: 10.1016/j.prostaglandins.2019.106338] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/30/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Although colon cancer is one of the most important triggers of cancer related mortality, a few therapeutic options exist for this disease, including combination chemotherapy, anti-EGFR and anti-angiogenic agents. However, none of these therapeutics are fully effective for complete remission, and this issue needs further investigations, particularly in the patients with advanced disease. It has been shown that colon carcinogenesis process is associated with upregulation of prostaglandin (PG) levels. Moreover, conversion of pre-malignant cells to malignant was also related with increased generation of PGs in susceptible subjects. Among the prostanoids, PGE2 is the most important produced member which generated in high levels by colon tumor cells. Generation of PGE2 by action of cyclooxygenase (COX)-2 can promote growth and development, resistance to apoptosis, proliferation, invasion and metastasis, angiogenesis and drug resistance in colon cancer. Increased levels of PGE2 and COX-2 in colon cancer is reported by various investigators which was associated with disease progression. It is suggested that there is a positive feedback loop between COX-2 and PGE2, in which function of COX-2 induces generation of PGE2, and upregulation of PGE2 increases the expression of COX-2 in colon cancer. Although an existence of this feedback loop is well-documented, its precise mechanism, signaling pathways, and the particular E-type prostanoid (EP) receptor mediating this feedback are elusive. Therefore, it seems that targeting COX-2/PGE2/EP receptors may be supposed as a potent therapeutic strategy for treatment of colon cancer. In this review, we try to clarify the role of PGE2 in cancer progression and its targeting for treatment of colon cancer.
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Affiliation(s)
- Vahid Karpisheh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Nikkhoo
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Afshin Namdar
- Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2E1 Canada
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Gholamabas Sabz
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Elbadawy M, Usui T, Yamawaki H, Sasaki K. Emerging Roles of C-Myc in Cancer Stem Cell-Related Signaling and Resistance to Cancer Chemotherapy: A Potential Therapeutic Target Against Colorectal Cancer. Int J Mol Sci 2019; 20:E2340. [PMID: 31083525 PMCID: PMC6539579 DOI: 10.3390/ijms20092340] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 04/29/2019] [Accepted: 05/09/2019] [Indexed: 12/24/2022] Open
Abstract
Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to be responsible for the therapeutic resistance. In the previous study, we demonstrated that c-Myc mediates drug resistance of colorectal CSCs using a patient-derived primary three-dimensional (3D) organoid culture. In this review, we mainly focus on the roles of c-Myc-related signaling in the regulation of CSCs, chemotherapy resistance, and colorectal cancer organoids. Finally, we introduce the various types of c-Myc inhibitors and propose the possibility of c-Myc as a therapeutic target against colorectal cancer.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
- Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt.
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
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Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene 2019; 698:120-128. [PMID: 30849534 DOI: 10.1016/j.gene.2019.02.076] [Citation(s) in RCA: 357] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/08/2019] [Accepted: 02/17/2019] [Indexed: 12/19/2022]
Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to the extracellular stimulators. Hyperactivation of PI3K signalling cascades is one among the most ordinary events in human cancers. Focusing on the PI3K pathway remains both a chance and a challenge for cancer therapy. The high recurrence of phosphoinositide 3-kinase (PI3K) pathway adjustments in cancer has led to a surge in the progression of PI3K inhibitors. Recent developments incorporate a re-assessment of the oncogenic mechanisms behind PI3K pathway modifications. Receptor tyrosine kinases upstream of PI3K, the p110a catalytic fractional unit of PI3K, the downstream kinase, AKT, and therefore the negative regulator, PTEN, are all often altered in cancer. In this review, we consider about the phosphoinositide 3-kinases family and mechanisms of PI3K-Akt stimulation in cancer.
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Affiliation(s)
- Saeed Noorolyai
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Shajari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Callegari E, Domenicali M, Shankaraiah RC, D'Abundo L, Guerriero P, Giannone F, Baldassarre M, Bassi C, Elamin BK, Zagatti B, Ferracin M, Fornari F, Altavilla G, Blandamura S, Silini EM, Gramantieri L, Sabbioni S, Negrini M. MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 14:239-250. [PMID: 30641476 PMCID: PMC6330511 DOI: 10.1016/j.omtn.2018.11.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/26/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023]
Abstract
Most hepatocellular carcinomas (HCCs) arise in the context of chronic liver disease and/or cirrhosis. Thus, chemoprevention in individuals at risk represents an important but yet unproven approach. In this study, we investigated the ability of microRNA (miRNA)-based molecules to prevent liver cancer development in a cirrhotic model. To this end, we developed a mouse model able to recapitulate the natural progression from fibrosis to HCC, and then we tested the prophylactic activity of an miRNA-based approach in the model. The experiments were carried out in the TG221 transgenic mouse, characterized by the overexpression of miR-221 in the liver and predisposed to the development of liver tumors. TG221 as well as wild-type mice were exposed to the hepatotoxin carbon tetrachloride (CCl4) to induce chronic liver damage. All mice developed liver cirrhosis, but only TG221 mice developed nodular lesions in 100% of cases within 6 months of age. The spectrum of lesions ranged from dysplastic foci to carcinomas. To investigate miRNA-based prophylactic approaches, anti-miR-221 oligonucleotides or miR-199a-3p mimics were administered to TG221 CCl4-treated mice. Compared to control animals, a significant reduction in number, size, and, most significantly, malignant phenotype of liver nodules was observed, thus demonstrating an important prophylactic action of miRNA-based molecules. In summary, in this article, we not only report a simple model of liver cancer in a cirrhotic background but also provide evidence for a potential miRNA-based approach to reduce the risk of HCC development.
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Affiliation(s)
- Elisa Callegari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Marco Domenicali
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
| | - Ram Charan Shankaraiah
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Lucilla D'Abundo
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Paola Guerriero
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Ferdinando Giannone
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
| | - Maurizio Baldassarre
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
| | - Cristian Bassi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Bahaeldin K Elamin
- Department of Basic Sciences, College of Medicine, University of Bisha, 61922 Bisha, Saudi Arabia; Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, 11115 Khartoum, Sudan
| | - Barbara Zagatti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy
| | - Francesca Fornari
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
| | | | - Stella Blandamura
- Department of Medicine DIMED, University of Padova, 35121 Padova, Italy
| | - Enrico Maria Silini
- Section of Anatomy and Pathology, University Hospital of Parma, 43121 Parma, Italy
| | - Laura Gramantieri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy
| | - Silvia Sabbioni
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy
| | - Massimo Negrini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
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Li W, Qiu T, Guo L, Ying J, Zhou A. NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction. Pathol Res Pract 2019; 215:483-489. [DOI: 10.1016/j.prp.2018.12.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/10/2018] [Accepted: 12/30/2018] [Indexed: 12/16/2022]
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Tian T, Li X, Zhang J. mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int J Mol Sci 2019; 20:ijms20030755. [PMID: 30754640 PMCID: PMC6387042 DOI: 10.3390/ijms20030755] [Citation(s) in RCA: 403] [Impact Index Per Article: 67.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/12/2022] Open
Abstract
The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.
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Affiliation(s)
- Tian Tian
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
| | - Xiaoyi Li
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
| | - Jinhua Zhang
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
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An E, Brognard J. Orange is the new black: Kinases are the new master regulators of tumor suppression. IUBMB Life 2018; 71:738-748. [PMID: 30548122 PMCID: PMC6563145 DOI: 10.1002/iub.1981] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 12/16/2022]
Abstract
For many decades, kinases have predominantly been characterized as oncogenes and drivers of tumorigenesis, because activating mutations in kinases occur in cancer with high frequency. The oncogenic functions of kinases relate to their roles as growth factor receptors and as critical mediators of mitogen-activated pathways. Indeed, some of the most promising cancer therapeutic agents are kinase inhibitors. However, cancer genomics studies, especially screens that utilize high-throughput identification of loss-of-function somatic mutations, are beginning to shed light on a widespread role for kinases as tumor suppressors. The initial characterization of tumor-suppressing kinases- in particular members of the protein kinase C (PKC) family, MKK4 of the mitogen-activated protein kinase kinase family, and DAPK3 of the death-associated protein kinase family- laid the foundation for bioinformatic approaches that enable the identification of other tumor-suppressing kinases. In this review, we discuss the important role that kinases play as tumor suppressors, using several examples to illustrate the history of their discovery and highlight the modern approaches that presently aid in the identification of tumor-suppressing kinases. © 2018 IUBMB Life, 71(6):738-748, 2019.
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Affiliation(s)
- Elvira An
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD
| | - John Brognard
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD
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