|
1
|
Zhang H, Tang J, Cao H, Wang C, Shen C, Liu J. Effect and mechanism of Magnolia officinalis in colorectal cancer: Multi-component-multi-target approach. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119007. [PMID: 39471878 DOI: 10.1016/j.jep.2024.119007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/13/2024] [Accepted: 10/26/2024] [Indexed: 11/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Traditional Chinese medicine (TCM) has a long history of treating CRC, with advantages such as effectiveness, multi-target, multi-pathway, and minimal side effects. TCM Magnolia officinalis (M. officinalis) refers to the dried bark, root bark, and branch bark of either Magnolia officinalis Rehd.et Wils. or Magnolia officinalis Rehd.et Wils. var. biloba Rehd.et Wils. It is commonly utilized to alleviate the side effects of chemotherapy for CRC, owing to its anti-inflammatory and anti-tumor properties. However, current research primarily focuses on the individual components and does not take into consideration the characteristics of multi-component-multi-target action. AIM OF THE STUDY Our aim is to study the new action characteristics of M. officinalis in the treatment of CRC. MATERIALS AND METHODS Utilizing network pharmacology to identify potential active ingredients, key targets, and main signaling pathways of M. officinalis for the treatment of CRC. The binding effect was further validated through molecular docking analysis. Furthermore, the aforementioned components were identified using liquid chromatography-mass spectrometry (LC-MS), and the cleavage pathways of the main components were analyzed. Subsequently, both in vitro and in vivo experiments were carried out to investigate the anti-CRC effect of the active ingredients of M. officinalis and its potential mechanism. RESULTS Network pharmacology and Molecular docking identified 5 main active ingredients and 6 core targets of M. officinalis for the treatment of CRC. Then, LC-MS identified the active components of M. officinalis. At the same time, both in vitro and in vivo experiments have confirmed the ability of Eucalyptol (Euc) and Obovatol (Obo)to inhibit inflammation and tumor cell proliferation. The possible mechanism involved is that Euc and Obo counteract CRC by inhibiting the over-activation of NF-κBp65/JAK and Bcl-2/Caspase signaling pathways, respectively. They also play a role in the anti-CRC effect of M. officinalis. CONCLUSION Magnolol (MAG), Honokiol (HK), Euc, Obo, and Neohesperidin (NHP) in M. officinalis may be the pharmacological substance basis for its anti-cancer effect on CRC. The treatment of CRC with M. officinalis is characterized by its multi-component, multi-target, and multi-pathway approach. These findings provide a theoretical basis for further inspiring the clinical application of M. officinalis and the development of efficacy targets.
Collapse
Affiliation(s)
- He Zhang
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China
| | - Jun Tang
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China
| | - Huiliang Cao
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China
| | - Chenguang Wang
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China
| | - Chong Shen
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China.
| | - Jun Liu
- State Key Laboratory of Dynamic Measurement Technology, School of Instrument and Electronics, North University of China, Taiyuan, 030051, China.
| |
Collapse
|
|
2
|
de Moraes FCA, de Oliveira Rodrigues ALS, Priantti JN, Limachi-Choque J, Burbano RMR. Efficacy and Safety of Anti-EGFR Therapy Rechallenge in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. J Gastrointest Cancer 2024; 56:9. [PMID: 39436445 DOI: 10.1007/s12029-024-01128-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments. METHODS A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I2 statistics. R, version 4.2.3, was used for statistical analyses. RESULTS Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63 years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9 months, while the median overall survival (mOS) ranged from 5 to 17.8 months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I2, 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%). CONCLUSIONS Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.
Collapse
|
|
3
|
Khan S, Budamagunta V, Zhou D. Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. Adv Cancer Res 2023; 159:145-184. [PMID: 37268395 DOI: 10.1016/bs.acr.2023.02.004] [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] [Indexed: 03/12/2023]
Abstract
KRAS, a predominant member of the RAS family, is the most frequently mutated oncogene in human pancreatic cancer (∼95% of cases). Mutations in KRAS lead to its constitutive activation and activation of its downstream signaling pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR that promote cell proliferation and provide apoptosis evasion capabilities to cancer cells. KRAS had been considered 'undruggable' until the discovery of the first covalent inhibitor targeting the G12C mutation. While G12C mutations are frequently found in non-small cell lung cancer, these are relatively rare in pancreatic cancer. On the other hand, pancreatic cancer harbors other KRAS mutations such as G12D and G12V. The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking. Unfortunately, KRAS inhibitor monotherapy-associated resistance hinders their therapeutic efficacy. Therefore, various combination strategies have been tested and some yielded promising results, such as combinations with receptor tyrosine kinase, SHP2, or SOS1 inhibitors. In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-XL-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo. This is in part because KRAS-targeted therapies induce cell cycle arrest and cellular senescence, which contributes to therapeutic resistance, while their combination with DT2216 can more effectively induce apoptosis. Similar combination strategies may also work for G12D inhibitors in pancreatic cancer. This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.
Collapse
Affiliation(s)
- Sajid Khan
- Department of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
| | - Vivekananda Budamagunta
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, United States; Genetics and Genomics Graduate Program, Genetics Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Daohong Zhou
- Department of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
| |
Collapse
|
|
4
|
Zhang Q, Zheng Y, Liu J, Tang X, Wang Y, Li X, Li H, Zhou X, Tang S, Tang Y, Wang X, He H, Li T. CircIFNGR2 enhances proliferation and migration of CRC and induces cetuximab resistance by indirectly targeting KRAS via sponging to MiR-30b. Cell Death Dis 2023; 14:24. [PMID: 36639711 PMCID: PMC9839739 DOI: 10.1038/s41419-022-05536-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
Currently the clinical efficacy of colorectal cancer (CRC) which is the most common malignant tumors over the world has not reached an ideal level. Cetuximab, the monoclonal antibody targeting the extracellular domain of EGFR, has shown its great efficacy in the promotion of apoptosis and the inhibition of tumor cells-like characteristics in numerous cancers. However certain KRAS wild-type CRC patients unexpectedly show cetuximab resistance and the specific mechanism remains unclear. Circular RNAs (circRNAs) as the promising novel type of biomarkers in the cancer diagnosis and therapy, have been reported to be related with the drug resistance. In this study, with wondering the mechanism of cetuximab resistance in KRAS wild-type CRC patients, we evaluate the impact of circIFNGR2 on CRC and detect the association among circIFNGR2, miR-30b and KRAS via various experiments such as RT-qPCR, immunohistochemistry, luciferase assays, cell functional experiments and xenograft model. We conclude that circIFNGR2 induces cetuximab resistance in colorectal cancer cells by indirectly regulating target gene KRAS by sponging miR-30b at the post-transcriptional level. It is thus suggested that inhibition of circIFNGR2 can be a promising therapeutic strategy for malignant CRC patients with cetuximab resistance.
Collapse
Affiliation(s)
- Qi Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yifeng Zheng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Jiajia Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoxiao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yuan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xianzheng Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Huibin Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Xiaoying Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Shiru Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yitao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
| | - Han He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
| |
Collapse
|
|
5
|
Ton TVT, Hong HHL, Kovi RC, Shockley KR, Peddada SD, Gerrish KE, Janardhan KS, Flake G, Stout MD, Sills RC, Pandiri AR. Chronic Inhalation Exposure to Antimony Trioxide Exacerbates the MAPK Signaling in Alveolar Bronchiolar Carcinomas in B6C3F1/N Mice. Toxicol Pathol 2023; 51:39-55. [PMID: 37009983 PMCID: PMC11368139 DOI: 10.1177/01926233231157322] [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] [Indexed: 04/04/2023]
Abstract
Antimony trioxide (AT) is used as a flame retardant in fabrics and plastics. Occupational exposure in miners and smelters is mainly through inhalation and dermal contact. Chronic inhalation exposure to AT particulates in B6C3F1/N mice and Wistar Han rats resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). In this study, we demonstrated Kras (43%) and Egfr (46%) hotspot mutations in mouse lung tumors (n = 80) and only Egfr (50%) mutations in rat lung tumors (n = 26). Interestingly, there were no differences in the incidences of these mutations in ABCs from rats and mice at exposure concentrations that did and did not exceed the pulmonary overload threshold. There was increased expression of p44/42 mitogen-activated protein kinase (MAPK) (Erk1/2) protein in ABCs harboring mutations in Kras and/or Egfr, confirming the activation of MAPK signaling. Transcriptomic analysis indicated significant alterations in MAPK signaling such as ephrin receptor signaling and signaling by Rho-family GTPases in AT-exposed ABCs. In addition, there was significant overlap between transcriptomic data from mouse ABCs due to AT exposure and human pulmonary adenocarcinoma data. Collectively, these data suggest chronic AT exposure exacerbates MAPK signaling in ABCs and, thus, may be translationally relevant to human lung cancers.
Collapse
Affiliation(s)
- Thai-Vu T. Ton
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Hue-Hua L. Hong
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Ramesh C. Kovi
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Keith R. Shockley
- Biostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC 27709
| | - Shyamal D. Peddada
- Biostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC 27709
| | - Kevin E. Gerrish
- Molecular Genomics Core Laboratory, NIEHS, Research Triangle Park, NC 27709
| | - Kyathanahalli S. Janardhan
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Gordon Flake
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Mathew D. Stout
- Office of the Scientific Director, DTT, NIEHS, Research Triangle Park, NC 27709
| | - Robert C. Sills
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| | - Arun R. Pandiri
- Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology (DTT), National Institute Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709
| |
Collapse
|
|
6
|
Maximizing Small Biopsy Patient Samples: Unified RNA-Seq Platform Assessment of over 120,000 Patient Biopsies. J Pers Med 2022; 13:jpm13010024. [PMID: 36675685 PMCID: PMC9866839 DOI: 10.3390/jpm13010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Despite its wide-ranging benefits, whole-transcriptome or RNA exome profiling is challenging to implement in a clinical diagnostic setting. The Unified Assay is a comprehensive workflow wherein exome-enriched RNA-sequencing (RNA-Seq) assays are performed on clinical samples and analyzed by a series of advanced machine learning-based classifiers. Gene expression signatures and rare and/or novel genomic events, including fusions, mitochondrial variants, and loss of heterozygosity were assessed using RNA-Seq data generated from 120,313 clinical samples across three clinical indications (thyroid cancer, lung cancer, and interstitial lung disease). Since its implementation, the data derived from the Unified Assay have allowed significantly more patients to avoid unnecessary diagnostic surgery and have played an important role in guiding follow-up decisions regarding treatment. Collectively, data from the Unified Assay show the utility of RNA-Seq and RNA expression signatures in the clinical laboratory, and their importance to the future of precision medicine.
Collapse
|
|
7
|
Alfaro Alfaro ÁE, Murillo Castillo B, Cordero García E, Tascón J, Morales AI. Colon Cancer Pharmacogenetics: A Narrative Review. PHARMACY 2022; 10:95. [PMID: 36005935 PMCID: PMC9413567 DOI: 10.3390/pharmacy10040095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 12/16/2022] Open
Abstract
Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.
Collapse
Affiliation(s)
| | | | | | - Javier Tascón
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana I. Morales
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
|
8
|
Target-Based Small Molecule Drug Discovery for Colorectal Cancer: A Review of Molecular Pathways and In Silico Studies. Biomolecules 2022; 12:biom12070878. [PMID: 35883434 PMCID: PMC9312989 DOI: 10.3390/biom12070878] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/05/2022] [Accepted: 06/17/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer is one of the most prevalent cancer types. Although there have been breakthroughs in its treatments, a better understanding of the molecular mechanisms and genetic involvement in colorectal cancer will have a substantial role in producing novel and targeted treatments with better safety profiles. In this review, the main molecular pathways and driver genes that are responsible for initiating and propagating the cascade of signaling molecules reaching carcinoma and the aggressive metastatic stages of colorectal cancer were presented. Protein kinases involved in colorectal cancer, as much as other cancers, have seen much focus and committed efforts due to their crucial role in subsidizing, inhibiting, or changing the disease course. Moreover, notable improvements in colorectal cancer treatments with in silico studies and the enhanced selectivity on specific macromolecular targets were discussed. Besides, the selective multi-target agents have been made easier by employing in silico methods in molecular de novo synthesis or target identification and drug repurposing.
Collapse
|
|
9
|
Molecular Targets and Mechanisms of Hedyotis diffusa- Scutellaria barbata Herb Pair for the Treatment of Colorectal Cancer Based on Network Pharmacology and Molecular Docking. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6186662. [PMID: 35707465 PMCID: PMC9192289 DOI: 10.1155/2022/6186662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/26/2022] [Indexed: 11/29/2022]
Abstract
Objective: Hedyotis diffusa-Scutellaria barbata herb pair (HS) has therapeutic effects on a variety of cancers, and this study aims to systematically explore the multiple mechanisms of HS in the treatment of colorectal cancer (CRC). Methods. The active ingredients of HS were obtained from TCMSP, and the potential targets related to these ingredients were screened from the STITCH, SuperPred, and Swiss TargetPrediction databases. Targets associated with CRC were retrieved by Drugbank, TTD, DisGeNET, and GeneCards. We used a Venn diagram to screen the intersection targets and used Cytoscape to construct the herb-ingredient-target-disease network, and the core targets were selected. The Go analysis and KEGG pathway annotation were performed by R language software. We used PyMol and Autodock Vina to achieve molecular docking of core ingredients and targets. Results: A total of 33 active ingredients were obtained from the HS, and 762 CRC-related targets were reserved from the four databases. We got 170 intersection targets to construct the network and found that the four ingredients with the most targets were quercetin, luteolin, baicalein, and dinatin, which were the core ingredients. The PPI analysis showed that the core targets were STAT3, TP53, MAPK3, AKT1, JUN, EGFR, MYC, VEGFA, EGF, and CTNNB1. Molecular docking results showed that these core ingredients had good binding potential with core targets, especially the docking of each component with MAPK obtained the lowest binding energy. HS acts simultaneously on various signaling pathways related to CRC, including the PI3K-Akt signaling pathway, proteoglycans in cancer, and the MAPK signaling pathway. Conclusions: This study systematically analyzed the active ingredients, core targets, and central mechanisms of HS in the treatment of CRC. It reveals the role of HS targeting PI3K-Akt signaling and MAPK signaling pathways in the treatment of CRC. We hope that our research could bring a new perspective to the therapy of CRC and find new anticancer drugs.
Collapse
|
|
10
|
Luo K, Song Y, Guan Z, Ou S, Ye J, Ran S, Wang H, Tao Y, Gong Z, Ma T, Jin Y, Huang R, Gao F, Yu S. A KRAS-Associated Signature for Prognostic, Immune and Chemical Anti-Cancer Drug-Response Prediction in Colon Cancer. Front Pharmacol 2022; 13:899725. [PMID: 35774610 PMCID: PMC9237412 DOI: 10.3389/fphar.2022.899725] [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: 03/19/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background: KRAS mutation, one of the most important biological processes in colorectal cancer, leads to poor prognosis in patients. Although studies on KRAS have concentrated for a long time, there are currently no ideal drugs against KRAS mutations. Methods: Different expression analysis and weighted gene coexpression network analysis was conducted to select candidate genes. Log-rank tests and Cox regression picked out the prognostic genes to build a KRAS-related gene prognostic score (KRGPS). A nomogram based on KRGPS was built to predict survival of clinical patients. Comprehensive analysis showed the prognosis, immune microenvironment and response to immune therapy and chemotherapy in KRGPS subgroups. Results: We collected a KRGPS from the set of two genes GJB6 and NTNG1, with low-KRGSP patients having better progression-free survival (PFS). Low KRGPS is correlated with high infiltration of activated NK cells, plasma cells and activated memory CD4 T cells and that these cells benefit more from immune checkpoint inhibitor therapy. However, high KRGPS is associated with high infiltration of activated mast cells, pathways of immune dysregulation and a high ratio of TP53 and KRAS mutations. KRGPS subgroups are also sensitive to chemotherapy differently. A nomogram, established based on the KRGPS and pathological stage, predict 3- and 5-years PFS well. Conclusions: The KRAS-associated score acts as a promising signature to distinguish prognosis, molecular and immune characteristics, and benefits from immune and chemical therapy. These KRAS-associated genes could be promising targets for drug design.
Collapse
Affiliation(s)
- Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanni Song
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zilong Guan
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Suwen Ou
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinhua Ye
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Songlin Ran
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hufei Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zijian Gong
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of General Surgery, The People’s Hospital of Duerbert Mongolian Autonomous County, Harbin, China
| | - Tianyi Ma
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yinghu Jin
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Feng Gao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
11
|
de Souza Oliveira PF, Faria AVS, Clerici SP, Akagi EM, Carvalho HF, Justo GZ, Durán N, Ferreira-Halder CV. Violacein negatively modulates the colorectal cancer survival and epithelial-mesenchymal transition. J Cell Biochem 2022; 123:1247-1258. [PMID: 35661241 DOI: 10.1002/jcb.30295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/30/2022] [Accepted: 05/13/2022] [Indexed: 12/27/2022]
Abstract
Violacein is a secondary metabolite produced by several microorganisms including Chromobacterium violaceum, and it is already used in food and cosmetics. However, due to its potent anticancer and low side effects, its molecular action needs to be deeply scrutinized. Therefore, the main objective of this study was to evaluate the violacein's ability to interfere with three cancer hallmarks: growth factors receptor-dependent signaling, proliferation, and epithelial-mesenchymal transition (EMT). Violacein has been associated with the induction of apoptosis in colorectal cancer (CRC) cells. Here, we demonstrate that this molecule is also active in CRC spheroids and inhibits cell migration. Violacein treatment reduced the amount of EGFR and AXL receptors in the HT29 cell line. Accordingly, the inhibition of the AKT, ERK, and PKCδ kinases, which are downstream mediators of the signaling pathways triggered by EGFR and AXL, is detected. Another interesting finding was that even when the cells were stimulated with transforming growth factor-β, the EMT marker (N-cadherin) decreased. Therefore, this study provides further evidence that reinforces the potential of violacein as an antitumor agent, once this biomolecule can "switch off" properties associated with cancer plasticity.
Collapse
Affiliation(s)
| | - Alessandra V S Faria
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Stefano P Clerici
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Erica M Akagi
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Hernandes F Carvalho
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Giselle Z Justo
- Department of Pharmaceutical Sciences and Biochemistry, Federal University of São Paulo (UNIFESP-Diadema), São Paulo, Brazil
| | - Nelson Durán
- Laboratory of Urogenital Carcinogenesis and Immunotherapy, Department of Structural and Functional Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,Nanomedicine Research Unit (Nanomed), Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, Brazil
| | - Carmen V Ferreira-Halder
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| |
Collapse
|
|
12
|
Solís-Fernández G, Montero-Calle A, Sánchez-Martínez M, Peláez-García A, Fernández-Aceñero MJ, Pallarés P, Alonso-Navarro M, Mendiola M, Hendrix J, Hardisson D, Bartolomé RA, Hofkens J, Rocha S, Barderas R. Aryl-hydrocarbon receptor-interacting protein regulates tumorigenic and metastatic properties of colorectal cancer cells driving liver metastasis. Br J Cancer 2022. [DOI: 10.1038/s41416-022-01762-1
expr 880987936 + 827650491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
|
|
13
|
Solís-Fernández G, Montero-Calle A, Sánchez-Martínez M, Peláez-García A, Fernández-Aceñero MJ, Pallarés P, Alonso-Navarro M, Mendiola M, Hendrix J, Hardisson D, Bartolomé RA, Hofkens J, Rocha S, Barderas R. Aryl-hydrocarbon receptor-interacting protein regulates tumorigenic and metastatic properties of colorectal cancer cells driving liver metastasis. Br J Cancer 2022; 126:1604-1615. [PMID: 35347323 PMCID: PMC9130499 DOI: 10.1038/s41416-022-01762-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/07/2022] [Accepted: 02/15/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Liver metastasis is the primary cause of colorectal cancer (CRC)-associated death. Aryl-hydrocarbon receptor-interacting protein (AIP), a putative positive intermediary in aryl-hydrocarbon receptor-mediated signalling, is overexpressed in highly metastatic human KM12SM CRC cells and other highly metastatic CRC cells. METHODS Meta-analysis and immunohistochemistry were used to assess the relevance of AIP. Cellular functions and signalling mechanisms mediated by AIP were assessed by gain-of-function experiments and in vitro and in vivo experiments. RESULTS A significant association of high AIP expression with poor CRC patients' survival was observed. Gain-of-function and quantitative proteomics experiments demonstrated that AIP increased tumorigenic and metastatic properties of isogenic KM12C (poorly metastatic) and KM12SM (highly metastatic to the liver) CRC cells. AIP overexpression dysregulated epithelial-to-mesenchymal (EMT) markers and induced several transcription factors and Cadherin-17 activation. The former induced the signalling activation of AKT, SRC and JNK kinases to increase adhesion, migration and invasion of CRC cells. In vivo, AIP expressing KM12 cells induced tumour growth and liver metastasis. Furthermore, KM12C (poorly metastatic) cells ectopically expressing AIP became metastatic to the liver. CONCLUSIONS Our data reveal new roles for AIP in regulating proteins associated with cancer and metastasis to induce tumorigenic and metastatic properties in colon cancer cells driving liver metastasis.
Collapse
Affiliation(s)
- Guillermo Solís-Fernández
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
- Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium
| | - Ana Montero-Calle
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - Maricruz Sánchez-Martínez
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - Alberto Peláez-García
- Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), E-28046, Madrid, Spain
| | | | - Pilar Pallarés
- Unidades Centrales, Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - Miren Alonso-Navarro
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - Marta Mendiola
- Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), E-28046, Madrid, Spain
| | - Jelle Hendrix
- Dynamic Bioimaging Lab, Advanced Optical Microscopy Centre and Biomedical Research Institute, Hasselt University, Agoralaan C (BIOMED), 3590 Diepenbeek, Hasselt, Belgium
| | - David Hardisson
- Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), E-28046, Madrid, Spain
| | | | - Johan Hofkens
- Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany
| | - Susana Rocha
- Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium.
| | - Rodrigo Barderas
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain.
| |
Collapse
|
|
14
|
High-Throughput Profiling of Colorectal Cancer Liver Metastases Reveals Intra- and Inter-Patient Heterogeneity in the EGFR and WNT Pathways Associated with Clinical Outcome. Cancers (Basel) 2022; 14:cancers14092084. [PMID: 35565214 PMCID: PMC9104154 DOI: 10.3390/cancers14092084] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Tumor heterogeneity can greatly influence therapy outcome and patient survival. In this study, we aimed at unraveling inter- and intra-patient heterogeneity of colorectal cancer liver metastases (CRLM). To this end, we comprehensively characterized CRLM using state-of-the-art high-throughput technologies combined with bioinformatics analyses. We found a high degree of inter- and intra-patient heterogeneity among the metastases, in particular in genes of the WNT and EGFR pathways. Through analyzing the master regulators and effectors associated with the regulation of these genes, we identified a specific gene signature that was highly expressed in a large cohort of colorectal cancer patients and associated with clinical outcome. Abstract Seventy percent of patients with colorectal cancer develop liver metastases (CRLM), which are a decisive factor in cancer progression. Therapy outcome is largely influenced by tumor heterogeneity, but the intra- and inter-patient heterogeneity of CRLM has been poorly studied. In particular, the contribution of the WNT and EGFR pathways, which are both frequently deregulated in colorectal cancer, has not yet been addressed in this context. To this end, we comprehensively characterized normal liver tissue and eight CRLM from two patients by standardized histopathological, molecular, and proteomic subtyping. Suitable fresh-frozen tissue samples were profiled by transcriptome sequencing (RNA-Seq) and proteomic profiling with reverse phase protein arrays (RPPA) combined with bioinformatic analyses to assess tumor heterogeneity and identify WNT- and EGFR-related master regulators and metastatic effectors. A standardized data analysis pipeline for integrating RNA-Seq with clinical, proteomic, and genetic data was established. Dimensionality reduction of the transcriptome data revealed a distinct signature for CRLM differing from normal liver tissue and indicated a high degree of tumor heterogeneity. WNT and EGFR signaling were highly active in CRLM and the genes of both pathways were heterogeneously expressed between the two patients as well as between the synchronous metastases of a single patient. An analysis of the master regulators and metastatic effectors implicated in the regulation of these genes revealed a set of four genes (SFN, IGF2BP1, STAT1, PIK3CG) that were differentially expressed in CRLM and were associated with clinical outcome in a large cohort of colorectal cancer patients as well as CRLM samples. In conclusion, high-throughput profiling enabled us to define a CRLM-specific signature and revealed the genes of the WNT and EGFR pathways associated with inter- and intra-patient heterogeneity, which were validated as prognostic biomarkers in CRC primary tumors as well as liver metastases.
Collapse
|
|
15
|
Siu DHW, Ali A, Tjokrowidjaja A, De Silva M, Lee J, Clingan PR, Aghmesheh M, Brungs D, Mapagu C, Goldstein D, O'Neill S, Liauw WS, Sjoquist KM, Thomas D, Pavlakis N, Clarke SJ, Diakos C, Chantrill LA. Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers. Asia Pac J Clin Oncol 2022; 18:660-668. [PMID: 35098672 DOI: 10.1111/ajco.13745] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/16/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context. AIM To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival. METHODS We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018. RESULTS Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01). CONCLUSION The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.
Collapse
Affiliation(s)
- Derrick Ho Wai Siu
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,Department of Medical Oncology, St George Hospital, New South Wales, Australia.,National Health and Medical Research Council (NHMRC) Clinical Trial Centre, University of Sydney, New South Wales, Australia.,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Arwa Ali
- Department of Medical Oncology, Nelune Cancer Centre, The Prince of Wales Hospital (POWH), New South Wales, Australia.,Department of Medical Oncology, South Egypt Cancer Institute, Asyut, Egypt
| | - Angelina Tjokrowidjaja
- Department of Medical Oncology, St George Hospital, New South Wales, Australia.,National Health and Medical Research Council (NHMRC) Clinical Trial Centre, University of Sydney, New South Wales, Australia
| | - Madhawa De Silva
- Department of Medical Oncology, Royal North Shore Hospital (RNSH), New South Wales, Australia
| | - Joanna Lee
- Department of Medical Oncology, St George Hospital, New South Wales, Australia
| | - Philip R Clingan
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,School of Medicine, University of Wollongong, New South Wales, Australia
| | - Morteza Aghmesheh
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,School of Medicine, University of Wollongong, New South Wales, Australia
| | - Daniel Brungs
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,School of Medicine, University of Wollongong, New South Wales, Australia
| | - Cristina Mapagu
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,Westmead Clinical School, University of Sydney, New South Wales, Australia
| | - David Goldstein
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.,Department of Medical Oncology, Nelune Cancer Centre, The Prince of Wales Hospital (POWH), New South Wales, Australia
| | - Siobhan O'Neill
- Department of Medical Oncology, Nelune Cancer Centre, The Prince of Wales Hospital (POWH), New South Wales, Australia
| | - Winston S Liauw
- Department of Medical Oncology, St George Hospital, New South Wales, Australia.,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Katrin M Sjoquist
- Department of Medical Oncology, St George Hospital, New South Wales, Australia.,National Health and Medical Research Council (NHMRC) Clinical Trial Centre, University of Sydney, New South Wales, Australia
| | - David Thomas
- Department of Medical Oncology, St George Hospital, New South Wales, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital (RNSH), New South Wales, Australia.,Northern Clinical School, University of Sydney, New South Wales, Australia
| | - Stephen J Clarke
- Department of Medical Oncology, Royal North Shore Hospital (RNSH), New South Wales, Australia.,Northern Clinical School, University of Sydney, New South Wales, Australia
| | - Connie Diakos
- Department of Medical Oncology, Royal North Shore Hospital (RNSH), New South Wales, Australia.,Northern Clinical School, University of Sydney, New South Wales, Australia
| | - Lorraine A Chantrill
- Department of Medical Oncology, Illawarra Shoalhaven Local Health District (ISLHD), New South Wales, Australia.,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.,The Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| |
Collapse
|
|
16
|
Goodarzi G, Mozaffari H, Raeisi T, Mehravar F, Razi B, Ghazi ML, Garousi N, Alizadeh S, Janmohammadi P. Metabolic phenotypes and risk of colorectal cancer: a systematic review and meta-analysis of cohort studies. BMC Cancer 2022; 22:89. [PMID: 35062912 PMCID: PMC8781040 DOI: 10.1186/s12885-021-09149-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/24/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The association of obesity with colorectal cancer (CRC) may vary depending on metabolic status. OBJECTIVE This meta-analysis aimed to investigate the combined impacts of obesity and metabolic status on CRC risk. METHODS The Scopus, PubMed, and web of sciences databases were systematically searched up to Jun 2021 to find all eligible publications examining CRC risk in individuals with metabolically unhealthy normal-weight (MUHNW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUHO) phenotypes. RESULTS A total of 7 cohort studies with a total of 759,066 participants were included in this meta-analysis. Compared with healthy normal-weight people, MUHNW, MHO, and MUHO individuals indicated an increased risk for CRC with a pooled odds ratio of 1.19 (95% CI = 1.09-1.31) in MUHNW, 1.14 (95% CI = 1.06-1.22) in MHO, and 1.24 (95% CI = 1.19-1.29) in MUHO subjects. When analyses were stratified based on gender, associations remained significant for males. However, the elevated risk of CRC associated with MHO and MUHO was not significant in female participants. CONCLUSIONS The individuals with metabolic abnormality, although at a normal weight, have an increased risk for CRC. Moreover, obesity is associated with CRC irrespective of metabolic status.
Collapse
Affiliation(s)
- Golnoosh Goodarzi
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hadis Mozaffari
- Faculty of Land and Food Systems, University of British Columbia, Vancouver, Canada
| | - Tahereh Raeisi
- Department of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Mehravar
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Bahman Razi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Lafzi Ghazi
- Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Nazila Garousi
- Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahab Alizadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Tehran Province, Iran
| | - Parisa Janmohammadi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Tehran Province, Iran.
| |
Collapse
|
|
17
|
Schreiner P, Velasquez MP, Gottschalk S, Zhang J, Fan Y. Unifying heterogeneous expression data to predict targets for CAR-T cell therapy. Oncoimmunology 2021; 10:2000109. [PMID: 34858726 PMCID: PMC8632331 DOI: 10.1080/2162402x.2021.2000109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/08/2021] [Accepted: 10/26/2021] [Indexed: 10/29/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy combines antigen-specific properties of monoclonal antibodies with the lytic capacity of T cells. An effective and safe CAR-T cell therapy strategy relies on identifying an antigen that has high expression and is tumor specific. This strategy has been successfully used to treat patients with CD19+ B-cell acute lymphoblastic leukemia (B-ALL). Finding a suitable target antigen for other cancers such as acute myeloid leukemia (AML) has proven challenging, as the majority of currently targeted AML antigens are also expressed on hematopoietic progenitor cells (HPCs) or mature myeloid cells. Herein, we developed a computational method to perform a data transformation to enable the comparison of publicly available gene expression data across different datasets or assay platforms. The resulting transformed expression values (TEVs) were used in our antigen prediction algorithm to assess suitable tumor-associated antigens (TAAs) that could be targeted with CAR-T cells. We validated this method by identifying B-ALL antigens with known clinical effectiveness, such as CD19 and CD22. Our algorithm predicted TAAs being currently explored preclinically and in clinical CAR-T AML therapy trials, as well as novel TAAs in pediatric megakaryoblastic AML. Thus, this analytical approach presents a promising new strategy to mine diverse datasets for identifying TAAs suitable for immunotherapy.
Collapse
Affiliation(s)
- Patrick Schreiner
- The Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Mireya Paulina Velasquez
- Department of Bone Marrow Transplantation and Cell Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cell Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jinghui Zhang
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Yiping Fan
- The Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| |
Collapse
|
|
18
|
Proske A, Bossen J, von Frieling J, Roeder T. Low-protein diet applied as part of combination therapy or stand-alone normalizes lifespan and tumor proliferation in a model of intestinal cancer. Aging (Albany NY) 2021; 13:24017-24036. [PMID: 34766923 PMCID: PMC8610115 DOI: 10.18632/aging.203692] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/26/2021] [Indexed: 12/27/2022]
Abstract
Tumors of the intestinal tract are among the most common tumor diseases in humans, but, like many other tumor entities, show an unsatisfactory prognosis with a need for effective therapies. To test whether nutritional interventions and a combination with a targeted therapy can effectively cure these cancers, we used the fruit fly Drosophila as a model. In this system, we induced tumors by EGFR overexpression in intestinal stem cells. Limiting the amount of protein in the diet restored life span to that of control animals. In combination with a specific EGFR inhibitor, all major tumor-associated phenotypes could be rescued. This form of treatment was also successful in a real treatment scenario, which means when they started after the full tumor phenotype was expressed. In conclusion, reduced protein administration can be a very promising form of adjuvant cancer therapy.
Collapse
Affiliation(s)
- Alina Proske
- Department of Molecular Physiology, Zoological Institute, Kiel University, Kiel, Germany
| | - Judith Bossen
- Department of Molecular Physiology, Zoological Institute, Kiel University, Kiel, Germany.,Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany
| | - Jakob von Frieling
- Department of Molecular Physiology, Zoological Institute, Kiel University, Kiel, Germany
| | - Thomas Roeder
- Department of Molecular Physiology, Zoological Institute, Kiel University, Kiel, Germany.,Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany
| |
Collapse
|
|
19
|
Identifying key regulators of the intestinal stem cell niche. Biochem Soc Trans 2021; 49:2163-2176. [PMID: 34665221 PMCID: PMC8589435 DOI: 10.1042/bst20210223] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022]
Abstract
The intestinal tract is lined by a single layer of epithelium that is one of the fastest regenerating tissues in the body and which therefore requires a very active and exquisitely controlled stem cell population. Rapid renewal of the epithelium is necessary to provide a continuous physical barrier from the intestinal luminal microenvironment that contains abundant microorganisms, whilst also ensuring an efficient surface for the absorption of dietary components. Specialised epithelial cell populations are important for the maintenance of intestinal homeostasis and are derived from adult intestinal stem cells (ISCs). Actively cycling ISCs divide by a neutral drift mechanism yielding either ISCs or transit-amplifying epithelial cells, the latter of which differentiate to become either absorptive lineages or to produce secretory factors that contribute further to intestinal barrier maintenance or signal to other cellular compartments. The mechanisms controlling ISC abundance, longevity and activity are regulated by several different cell populations and signalling pathways in the intestinal lamina propria which together form the ISC niche. However, the complexity of the ISC niche and communication mechanisms between its different components are only now starting to be unravelled with the assistance of intestinal organoid/enteroid/colonoid and single-cell imaging and sequencing technologies. This review explores the interaction between well-established and emerging ISC niche components, their impact on the intestinal epithelium in health and in the context of intestinal injury and highlights future directions and implications for this rapidly developing field.
Collapse
|
|
20
|
Berbecka M, Forma A, Baj J, Furtak-Niczyporuk M, Maciejewski R, Sitarz R. A Systematic Review of the Cyclooxygenase-2 (COX-2) Expression in Rectal Cancer Patients Treated with Preoperative Radiotherapy or Radiochemotherapy. J Clin Med 2021; 10:4443. [PMID: 34640461 PMCID: PMC8509380 DOI: 10.3390/jcm10194443] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/14/2021] [Accepted: 09/24/2021] [Indexed: 02/05/2023] Open
Abstract
The main objective of this systematic review is to investigate the expression level of the cyclooxygenase-2 (COX-2) in rectal cancer treated with either preoperative radiotherapy or radiochemotherapy. In addition, we have summarized the effects of preoperative treatment of rectal cancer with regards to the expression levels of COX-2. A systematic literature review was performed in The Cochrane Library, PubMed, Web of Science, and Scopus databases on 1 January 2021 with the usage of the following search string-(cyclooxygenase-2) OR (COX-2) AND (rectal cancer) AND (preoperative radiochemotherapy) OR (preoperative radiotherapy). Among the 176 included in the analysis, only 13 studies were included for data extraction with a total number of 2095 patients. The results of the analysis are based on the articles concerning the expression of COX-2 in rectal cancer among patients treated with preoperative radiotherapy or radiochemotherapy. A COX-2 expression is an early event involved in rectal cancer development. In cases of negative COX-2 expression, radiotherapy and radiochemotherapy might contribute to the reduction of a local recurrence. Therefore, COX-2 may be considered as a biologic factor while selecting patients for more effective, less time-consuming and less expensive preoperative treatment. However, the utility of the administration of COX-2 inhibitors to patients with COX-2 overexpression, in an attempt to improve the patients' response rate to the neoadjuvant treatment, needs an assessment in further clinical trials.
Collapse
Affiliation(s)
- Monika Berbecka
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.B.); (J.B.); (R.M.)
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.B.); (J.B.); (R.M.)
| | | | - Ryszard Maciejewski
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.B.); (J.B.); (R.M.)
| | - Robert Sitarz
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.B.); (J.B.); (R.M.)
- Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
| |
Collapse
|
|
21
|
Ginghină O, Hudiță A, Zaharia C, Tsatsakis A, Mezhuev Y, Costache M, Gălățeanu B. Current Landscape in Organic Nanosized Materials Advances for Improved Management of Colorectal Cancer Patients. MATERIALS (BASEL, SWITZERLAND) 2021; 14:2440. [PMID: 34066710 PMCID: PMC8125868 DOI: 10.3390/ma14092440] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022]
Abstract
Globally, colorectal cancer (CRC) ranks as one of the most prevalent types of cancers at the moment, being the second cause of cancer-related deaths. The CRC chemotherapy backbone is represented by 5-fluorouracil, oxaliplatin, irinotecan, and their combinations, but their administration presents several serious disadvantages, such as poor bioavailability, lack of tumor specificity, and susceptibility to multidrug resistance. To address these limitations, nanomedicine has arisen as a powerful tool to improve current chemotherapy since nanosized carriers hold great promise in improving the stability and solubility of the drug payload and enhancing the active concentration of the drug that reaches the tumor tissue, increasing, therefore, the safety and efficacy of the treatment. In this context, the present review offers an overview of the most recent advances in the development of nanosized drug-delivery systems as smart therapeutic tools in CRC management and highlights the emerging need for improving the existing in vitro cancer models to reduce animal testing and increase the success of nanomedicine in clinical trials.
Collapse
Affiliation(s)
- Octav Ginghină
- Department of Surgery, “Sf. Ioan” Emergency Clinical Hospital, 13 Vitan Barzesti Street, 042122 Bucharest, Romania;
- Department II, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 17-21 Calea Plevnei Street, 010232 Bucharest, Romania
| | - Ariana Hudiță
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| | - Cătălin Zaharia
- Advanced Polymer Materials Group, Department of Bioresources and Polymer Science, University Politehnica of Bucharest, 1-7 Gh. Polizu Street, 011061 Bucharest, Romania;
| | - Aristidis Tsatsakis
- Department of Toxicology and Forensic Sciences, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - Yaroslav Mezhuev
- Center of Biomaterials, D Mendeleev University of Chemical Technology of Russia, Miusskaya Sq. 9, 125047 Moscow, Russia;
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| | - Bianca Gălățeanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei Street, 050095 Bucharest, Romania; (M.C.); (B.G.)
| |
Collapse
|
|
22
|
Fuentes NR, Mlih M, Wang X, Webster G, Cortes-Acosta S, Salinas ML, Corbin IR, Karpac J, Chapkin RS. Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation. J Lipid Res 2021; 62:100026. [PMID: 33515553 PMCID: PMC7933808 DOI: 10.1016/j.jlr.2021.100026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 01/11/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) signaling drives the formation of many types of cancer, including colon cancer. Docosahexaenoic acid (DHA, 22∶6Δ4,7,10,13,16,19), a chemoprotective long-chain n-3 polyunsaturated fatty acid suppresses EGFR signaling. However, the mechanism underlying this phenotype remains unclear. Therefore, we used super-resolution microscopy techniques to investigate the mechanistic link between EGFR function and DHA-induced alterations to plasma membrane nanodomains. Using isogenic in vitro (YAMC and IMCE mouse colonic cell lines) and in vivo (Drosophila, wild type and Fat-1 mice) models, cellular DHA enrichment via therapeutic nanoparticle delivery, endogenous synthesis, or dietary supplementation reduced EGFR-mediated cell proliferation and downstream Ras/ERK signaling. Phospholipid incorporation of DHA reduced membrane rigidity and the size of EGFR nanoclusters. Similarly, pharmacological reduction of plasma membrane phosphatidic acid (PA), phosphatidylinositol-4,5-bisphosphate (PIP2) or cholesterol was associated with a decrease in EGFR nanocluster size. Furthermore, in DHA-treated cells only the addition of cholesterol, unlike PA or PIP2, restored EGFR nanoscale clustering. These findings reveal that DHA reduces EGFR signaling in part by reshaping EGFR proteolipid nanodomains, supporting the feasibility of using membrane therapy, i.e., dietary/drug-related strategies to target plasma membrane organization, to reduce EGFR signaling and cancer risk.
Collapse
Affiliation(s)
- Natividad R Fuentes
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA; Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, TX, USA
| | - Mohamed Mlih
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, Bryan, TX, USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Gabriella Webster
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Sergio Cortes-Acosta
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Michael L Salinas
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Ian R Corbin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jason Karpac
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, Bryan, TX, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA; Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, TX, USA; Center for Translational Environmental Health Research, Texas A&M University, College Station, TX, USA.
| |
Collapse
|
|
23
|
Yarla NS, Madka V, Pathuri G, Rao CV. Molecular Targets in Precision Chemoprevention of Colorectal Cancer: An Update from Pre-Clinical to Clinical Trials. Int J Mol Sci 2020; 21:ijms21249609. [PMID: 33348563 PMCID: PMC7765969 DOI: 10.3390/ijms21249609] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/07/2020] [Accepted: 12/13/2020] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients.
Collapse
Affiliation(s)
- Nagendra S. Yarla
- Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (N.S.Y.); (V.M.); (G.P.)
| | - Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (N.S.Y.); (V.M.); (G.P.)
| | - Gopal Pathuri
- Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (N.S.Y.); (V.M.); (G.P.)
| | - Chinthalapally V. Rao
- Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (N.S.Y.); (V.M.); (G.P.)
- VA Medical Center, Oklahoma City, OK 73104, USA
- Correspondence: ; Tel.: +1-405-271-3224; Fax: +1-405-271-3225
| |
Collapse
|
|
24
|
Dai D, Wang Y, Zhu L, Jin H, Wang X. Prognostic value of KRAS mutation status in colorectal cancer patients: a population-based competing risk analysis. PeerJ 2020; 8:e9149. [PMID: 32547859 PMCID: PMC7271887 DOI: 10.7717/peerj.9149] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022] Open
Abstract
Background To use competing analyses to estimate the prognostic value of KRAS mutation status in colorectal cancer (CRC) patients and to build nomogram for CRC patients who had KRAS testing. Method The cohort was selected from the Surveillance, Epidemiology, and End Results database. Cumulative incidence function model and multivariate Fine-Gray regression for proportional hazards modeling of the subdistribution hazard (SH) model were used to estimate the prognosis. An SH model based nomogram was built after a variable selection process. The validation of the nomogram was conducted by discrimination and calibration with 1,000 bootstraps. Results We included 8,983 CRC patients who had KRAS testing. SH model found that KRAS mutant patients had worse CSS than KRAS wild type patients in overall cohort (HR = 1.10 (95% CI [1.04–1.17]), p < 0.05), and in subgroups that comprised stage III CRC (HR = 1.28 (95% CI [1.09–1.49]), p < 0.05) and stage IV CRC (HR = 1.14 (95% CI [1.06–1.23]), p < 0.05), left side colon cancer (HR = 1.28 (95% CI [1.15–1.42]), p < 0.05) and rectal cancer (HR = 1.23 (95% CI [1.07–1.43]), p < 0.05). We built the SH model based nomogram, which showed good accuracy by internal validation of discrimination and calibration. Calibration curves represented good agreement between the nomogram predicted CRC caused death and actual observed CRC caused death. The time dependent area under the curve of receiver operating characteristic curves (AUC) was over 0.75 for the nomogram. Conclusion This is the first population based competing risk study on the association between KRAS mutation status and the CRC prognosis. The mutation of KRAS indicated a poor prognosis of CRC patients. The current competing risk nomogram would help physicians to predict cancer specific death of CRC patients who had KRAS testing.
Collapse
Affiliation(s)
- Dongjun Dai
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yanmei Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liyuan Zhu
- Laboratory of Cancer Biology, Key Lab of Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongchuan Jin
- Laboratory of Cancer Biology, Key Lab of Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xian Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
25
|
Kim EK, Song MJ, Jung Y, Lee WS, Jang HH. Proteomic Analysis of Primary Colon Cancer and Synchronous Solitary Liver Metastasis. Cancer Genomics Proteomics 2020; 16:583-592. [PMID: 31659112 DOI: 10.21873/cgp.20161] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/12/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM Colon cancer is prone to distant metastases to other sites and the risk of recurrence is relatively high. Therefore, the identification of liver metastasis-related factors is important for the diagnosis or treatment of colon cancer. The aim of this study was to identify the metastasis-related factors that are differentially expressed in synchronous solitary liver metastasis compared to primary colon cancer. MATERIALS AND METHODS Tissues of primary colon cancer and associated with liver metastases of five patients were used for mass spectrometry. Identified proteins were validated by western blotting. The in silico analysis was performed using the STRING database and GeneMANIA. RESULTS We identified 58 differentially expressed proteins (DEPs), including 51 under-expressed and 7 over-expressed proteins among a total of 164 identified proteins. Major hubs of protein-protein networks were ACTC1, PRDX6, TPI1, and ALDH1A1. DEPs were located in the extracellular region and cytoplasm and were involved in the regulation of enzymatic activity. The metabolic process was significantly enriched in biological processes and an involvement in the KEGG pathway. CONCLUSION These DEPs can potentially be used as biomarkers for the diagnosis of liver metastasis and they may provide a new strategy for developing anti-metastatic liver drugs in colon cancer patients.
Collapse
Affiliation(s)
- Eun-Kyung Kim
- Department of Biochemistry, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Min-Jeong Song
- Department of Biochemistry, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Yunjae Jung
- Department of Microbiology, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Won-Suk Lee
- Department of Surgery, Gil Medical Center, Gachon University, Incheon, Republic of Korea
| | - Ho Hee Jang
- Department of Biochemistry, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| |
Collapse
|
|
26
|
Kennedy SA, Jarboui MA, Srihari S, Raso C, Bryan K, Dernayka L, Charitou T, Bernal-Llinares M, Herrera-Montavez C, Krstic A, Matallanas D, Kotlyar M, Jurisica I, Curak J, Wong V, Stagljar I, LeBihan T, Imrie L, Pillai P, Lynn MA, Fasterius E, Al-Khalili Szigyarto C, Breen J, Kiel C, Serrano L, Rauch N, Rukhlenko O, Kholodenko BN, Iglesias-Martinez LF, Ryan CJ, Pilkington R, Cammareri P, Sansom O, Shave S, Auer M, Horn N, Klose F, Ueffing M, Boldt K, Lynn DJ, Kolch W. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS G13D. Nat Commun 2020; 11:499. [PMID: 31980649 PMCID: PMC6981206 DOI: 10.1038/s41467-019-14224-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023] Open
Abstract
Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
Collapse
Affiliation(s)
- Susan A Kennedy
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Mohamed-Ali Jarboui
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
- Werner Siemens Imaging Center, University of Tübingen, Tübingen, Germany
| | - Sriganesh Srihari
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
- QIMR-Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Cinzia Raso
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Kenneth Bryan
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Layal Dernayka
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Theodosia Charitou
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Manuel Bernal-Llinares
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | | | | | - David Matallanas
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Max Kotlyar
- Krembil Research Institute, University Health Network, Toronto, Canada
| | - Igor Jurisica
- Krembil Research Institute, University Health Network, Toronto, Canada
- Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Canada
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Jasna Curak
- Donnelly Centre, University of Toronto, Toronto, Canada
- Department of Biochemistry, University of Toronto, Toronto, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Victoria Wong
- Donnelly Centre, University of Toronto, Toronto, Canada
- Department of Biochemistry, University of Toronto, Toronto, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Igor Stagljar
- Donnelly Centre, University of Toronto, Toronto, Canada
- Department of Biochemistry, University of Toronto, Toronto, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Canada
- Mediterranean Institute for Life Sciences, Split, Croatia
| | - Thierry LeBihan
- Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK
| | - Lisa Imrie
- Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK
| | - Priyanka Pillai
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Miriam A Lynn
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Erik Fasterius
- School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Cristina Al-Khalili Szigyarto
- School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - James Breen
- School of Biological Sciences, University of Adelaide Bioinformatics Hub, Adelaide, SA, Australia
- Computational & Systems Biology Program, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Christina Kiel
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Conway Institute, University College Dublin, Dublin, Ireland
| | - Luis Serrano
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Nora Rauch
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | | | - Boris N Kholodenko
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- Conway Institute, University College Dublin, Dublin, Ireland
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
| | | | - Colm J Ryan
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- School of Computer Science, University College Dublin, Dublin, Ireland
| | - Ruth Pilkington
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | | | - Owen Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Studies, Glasgow University, Glasgow, UK
| | - Steven Shave
- School of Biological Sciences and School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Manfred Auer
- School of Biological Sciences and School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Nicola Horn
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Franziska Klose
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Marius Ueffing
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Karsten Boldt
- Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
| | - David J Lynn
- EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
- College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia.
| | - Walter Kolch
- Systems Biology Ireland, University College Dublin, Dublin, Ireland.
- Conway Institute, University College Dublin, Dublin, Ireland.
- School of Medicine, University College Dublin, Dublin, Ireland.
| |
Collapse
|
|
27
|
Foroughi S, Tie J, Gibbs P, Burgess AW. Epidermal growth factor receptor ligands: targets for optimizing treatment of metastatic colorectal cancer. Growth Factors 2019; 37:209-225. [PMID: 31878812 DOI: 10.1080/08977194.2019.1703702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The discovery of epidermal growth factor (EGF) and its receptor (EGFR) revealed the connection between EGF-like ligands, signaling from the EGFR family members and cancer. Over the next fifty years, analysis of EGFR expression and mutation led to the use of monoclonal antibodies to target EGFR in the treatment of metastatic colorectal cancer (mCRC) and this treatment has improved outcomes for patients. The use of the RAS oncogene mutational status has helped to refine patient selection for EGFR antibody therapy, but an effective molecular predictor of likely responders is lacking. This review analyzes the potential utility of measuring the expression, levels and activation of EGF-like ligands and associated processes as prognostic or predictive markers for the identification of patient risk and more effective mCRC therapies.
Collapse
Affiliation(s)
- Siavash Foroughi
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Jeanne Tie
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
| | - Peter Gibbs
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
| | - Antony Wilks Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
| |
Collapse
|
|
28
|
Xing Y, Jing H, Zhang Y, Suo J, Qian M. MicroRNA-141-3p affected proliferation, chemosensitivity, migration and invasion of colorectal cancer cells by targeting EGFR. Int J Biochem Cell Biol 2019; 118:105643. [PMID: 31704502 DOI: 10.1016/j.biocel.2019.105643] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/17/2019] [Accepted: 11/05/2019] [Indexed: 01/27/2023]
Abstract
Colorectal cancer (CRC) is one of the most often diagnosed cancers globally. MicroRNAs are small RNA molecules that play essential roles in tumorigenesis and progression of CRC. Here we evaluated the effects of miR-141-3p on growth, cetuximab sensitivity, migration and invasion of CRC cells. We found that miR-141-3p negatively regulated the proliferation, migration and invasion in CRC cells. In addition, miR-141-3p enhanced the cetuximab sensitivity of CRC cells by EGFR suppression. Moreover, miR-141-3p improved cetuximab-induced apoptosis in CRC cells. Furthermore, miR-141-3p altered the expression of E-cadherin, N-cadherin, snail and Vimentin, indicating miR-141-3p might play a role on epithelial to mesenchymal transition (EMT). Luciferase reporter assay showed that EGFR was the direct binding site of miR-141-3p and the expression levels of p-EGFR, Raf-1, pAKT and p-ERK1/2 were regulated by miR-141-3p. After down-regulation of EGFR by siRNA in CRC cells, the effects of miR-141-3p on proliferation, migration and invasion were reversed. miR-141-3p played important roles in CRC growth and response to cetuximab treatment, and might function as a potential biomarker to predict cetuximab response.
Collapse
Affiliation(s)
- Yanpeng Xing
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Hongyu Jing
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130021, China
| | - Ye Zhang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, 130021, China
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Ming Qian
- Department of Prosthodontics, School of Stomatology, Jilin University, Changchun, 130021, China.
| |
Collapse
|
|
29
|
miR-145-5p restrained cell growth, invasion, migration and tumorigenesis via modulating RHBDD1 in colorectal cancer via the EGFR-associated signaling pathway. Int J Biochem Cell Biol 2019; 117:105641. [PMID: 31693935 DOI: 10.1016/j.biocel.2019.105641] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 11/21/2022]
Abstract
miR-145-5p has been reported to be downregulated and described functioning as a tumor suppressive gene in colorectal cancer (CRC), yet its detailed regulatory function and mechanism in malignant progression of the disease have not been thoroughly understood. In our study, miR-145-5p and rhomboid domain containing 1 (RHBDD1) in CRC tissues and cells were examined by qRT-PCR and western blot. MTT, colony formation, wound healing, Transwell invasion, and flow cytometry assays were performed to evaluate the malignant phenotypes of CRC cells. Xenograft tumor, qRT-PCR, and western blot assays were applied to validate the roles and mechanism of miR-145-5p in CRC in vivo. The interaction between miR-145-5p and RHBDD1 was investigated by luciferase reporter assay and western blot. The changes of the EGFR/Raf/MEK/ERK pathway were detected by western blot. We found miR-145-5p was lowly expressed and low miR-145-5p predicted poor prognosis in CRC, while RHBDD1 was greatly enhanced in CRC cells and tissues. RHBDD1 silencing resulted in inhibiting cell proliferative, invasive, and migratory potentials as well as elevating apoptotic ones in CRC cells. miR-145-5p was inversely related with RHBDD1 expression in CRC tissues. miR-145-5p was found to directly bind to RHBDD1 and restrained its expression in CRC cells. miR-145-5p overexpression repressed CRC cell proliferation, invasion, migration and induced apoptosis, and these effects were reversed by RHBDD1 upregulation. Moreover, in CRC xenograft tumor, its growth was impeded by miR-145-5p via suppressing RHBDD1. Furthermore, miR-145-5p inhibited the expression of EGFR, p-MEK1/2 and p-ERK1/2, in vitro and in vivo by targeting RHBDD1. In conclusion, our study revealed that miR-145-5p overexpression inhibited tumorigenesis in CRC by downregulating RHBDD1 via suppressing the EGFR-associated signaling pathway (EGFR/Raf/MEK/ERK cascades).
Collapse
|
|
30
|
Targeted cancer therapies: Oral health care implications. J Am Dent Assoc 2019; 149:100-111. [PMID: 29389333 DOI: 10.1016/j.adaj.2017.08.046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 08/23/2017] [Accepted: 08/28/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Targeted treatments have been incorporated into oncology protocols, often with more traditional therapies, and are not totally free of adverse reactions, some of which affect the orofacial region. METHODS The authors searched PubMed, the Cochrane Library, and the US Food and Drug Administration Approved Drug Products database to identify reported adverse effects of targeted agents in the orofacial region as well as other implications in oral health care. Their principal focus was the relatively newer category of molecularly targeted drugs which are called small molecules (SMs). RESULTS The authors identified several categories of SMs and biological agents (for example, monoclonal antibodies) with adverse effects in the orofacial region. The oral and perioral regions are also fields for which there are therapeutic applications for targeted therapies, particularly to treat malignant neoplasms such as head and neck cancers. CONCLUSIONS SMs are the most rapidly growing group of targeted cancer treatments. Patients receiving SMs and other targeted antineoplastic agents may require oral medicine advice and special-care dentistry. PRACTICAL IMPLICATIONS In this narrative review, the authors focus mainly on the orofacial adverse effects of targeted cancer therapies and outline many of the agents that are in use so the dentally focused reader can familiarize themselves with these adverse effects and agents.
Collapse
|
|
31
|
Jin P, Jiang J, Xie N, Zhou L, Huang Z, Zhang L, Qin S, Fu S, Peng L, Gao W, Li B, Lei Y, Nice EC, Li C, Shao J, Xie K. MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling. Cell Death Dis 2019; 10:615. [PMID: 31409796 PMCID: PMC6692318 DOI: 10.1038/s41419-019-1844-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 07/21/2019] [Accepted: 07/24/2019] [Indexed: 02/05/2023]
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.
Collapse
Affiliation(s)
- Ping Jin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Lu Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Shuyue Fu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Liyuan Peng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Wei Gao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Bowen Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Yunlong Lei
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Changlong Li
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jichun Shao
- Department of Urology, Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, Sichuan, China.
| | - Ke Xie
- Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, P. R. China.
| |
Collapse
|
|
32
|
Chen CL, Chen CK, Ho CL, Chi WM, Yeh CH, Hu SP, Friebe P, Palmer S, Huang CS. Clinical Evaluation of IntelliPlex™ KRAS G12/13 Mutation Kit for Detection of KRAS Mutations in Codon 12 and 13: A Novel Multiplex Approach. Mol Diagn Ther 2019; 23:645-656. [DOI: 10.1007/s40291-019-00418-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
33
|
Elmetwally SA, Saied KF, Eissa IH, Elkaeed EB. Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg Chem 2019; 88:102944. [PMID: 31051400 DOI: 10.1016/j.bioorg.2019.102944] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 03/20/2019] [Accepted: 04/20/2019] [Indexed: 01/05/2023]
Abstract
Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT; and the most active compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC50 values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC50 ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G2/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFRWT and EGFRT790M.
Collapse
Affiliation(s)
- Souad A Elmetwally
- Department of Basic Science, Higher Technological Institute, 10(th) of Ramadan City 228, Egypt.
| | - Khaled F Saied
- Department of Basic Science, Oral and Dental Medicine, Nahda University, East Beni-Suef, 62511 Beni-Suef, Egypt.
| | - Ibrahim H Eissa
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11884 Cairo, Egypt.
| | - Eslam B Elkaeed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11884 Cairo, Egypt.
| |
Collapse
|
|
34
|
Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:156. [PMID: 30975211 PMCID: PMC6460662 DOI: 10.1186/s13046-019-1094-2] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 02/07/2019] [Indexed: 02/08/2023]
Abstract
Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Herein, we introduce targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD-1 L).
Collapse
Affiliation(s)
- N A Seebacher
- Faculty of Medicine, The University of Sydney, Camperdown, New South Wales, 2006, Australia
| | - A E Stacy
- Faculty of Medicine, The University of Notre Dame, Darlinghurst, New South Wales, 2010, Australia
| | - G M Porter
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Kensington, New South Wales, 2031, Australia
| | - A M Merlot
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Kensington, New South Wales, 2031, Australia. .,School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Kensington, New South Wales, 2031, Australia. .,UNSW Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Kensington, New South Wales, 2031, Australia.
| |
Collapse
|
|
35
|
Fan X, Liu M, Tang H, Leng D, Hu S, Lu R, Wan W, Yuan S. MicroRNA-7 Exerts Antiangiogenic Effect on Colorectal Cancer via ERK Signaling. J Surg Res 2019; 240:48-59. [PMID: 30909065 DOI: 10.1016/j.jss.2019.02.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/27/2018] [Accepted: 02/21/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent studies have suggested that microRNA-7 (miR-7) family members may play important roles in human cancer by regulating cell proliferation, apoptosis, migration, and invasion. Therefore, the present study aimed to investigate the clinical significance and biological function of miR-7 in colorectal cancer (CRC). METHODS Initially, cancer and adjacent tissues were collected from 76 patients with CRC. Then, microvascular density was detected using the Weidner counting method. The functional role of miR-7 in CRC was determined using ectopic expression, knockdown, and reporter assay experiments. The vasculogenic mimicry density was determined. Expression of miR-7, epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), vascular endothelial growth factor, and thrombospondin-1 was determined. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays, scratch tests, and Transwell assays were conducted to examine cell proliferation, migration, and invasion, respectively. Finally, flow cytometry was applied to evaluate cell apoptosis. RESULTS CRC tissues showed increased microvascular density and EGFR expression, activated ERK signaling, and miR-7 downregulation. EGFR was a target gene of miR-7. miR-7 overexpression and EGFR silencing decreased vasculogenic mimicry density, cell migration, and cell invasion, but increased cell apoptosis. In addition, miR-7 overexpression and EGFR silencing upregulated thrombospondin-1 and downregulated EGFR, ERK1/2, and vascular endothelial growth factor. Furthermore, we observed that the effect of miR-7 inhibition was abolished after EGFR silencing. CONCLUSIONS Overexpressed miR-7 suppresses angiogenesis of CRC cells through ERK signaling by downregulating EGFR. It may identify new targets for CRC treatment.
Collapse
Affiliation(s)
- Xuepeng Fan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Mei Liu
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Hao Tang
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Dewen Leng
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Shuli Hu
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Rong Lu
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Weibo Wan
- Department of Intensive Care Unit, Wuhan NO.1 Hospital, Wuhan, China
| | - Shiying Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
36
|
Xie X, Zhang Y, Li F, Lv T, Li Z, Chen H, Jia L, Gao Y. Challenges and Opportunities from Basic Cancer Biology for Nanomedicine for Targeted Drug Delivery. Curr Cancer Drug Targets 2019; 19:257-276. [DOI: 10.2174/1568009618666180628160211] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 12/11/2022]
Abstract
Background:Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment.Objective:Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers.Methods:We collected related information and data from articles.Results:In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment.Conclusion:The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.
Collapse
Affiliation(s)
- Xiaodong Xie
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yingying Zhang
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Fengqiao Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Tingting Lv
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Ziying Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Haijun Chen
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Lee Jia
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yu Gao
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| |
Collapse
|
|
37
|
Osumi H, Shinozaki E, Takeda Y, Wakatsuki T, Ichimura T, Saiura A, Yamaguchi K, Takahashi S, Noda T, Zembutsu H. Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer. Cancer Med 2018; 8:408-417. [PMID: 30575318 PMCID: PMC6346227 DOI: 10.1002/cam4.1913] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 12/16/2022] Open
Abstract
Because circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance, the development of cell‐free DNA (cfDNA) panel covering hundreds of mutation hot spots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon‐based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next‐generation sequencing (NGS) was carried out to evaluate the feasibility of this assay and was compared with their clinical parameters and RAS status in matched tissue samples. Somatic mutations of the 14 genes in plasma cfDNA were detected in 88 patients (87.1%) with mCRC. Mutations in TP53, KRAS, and APC genes were detected in 70 (69.3%), 39 (38.6%), and 24 (23.7%) patients, respectively. Mutant allele frequencies in plasma were significantly associated with metastasis (liver, P = 0.00004, lymph node, P = 0.008, number of metastatic organs, P = 0.0006), tumor markers (CEA, P = 0.000007, CA19‐9, P = 0.006, LDH, P = 0.00001), and tumor diameter (maximum, P = 0.00002, sum of diameter, P = 0.00009). The overall concordance rate of RAS status between ctDNA and matched tissue was 77.2% (78/101). Our data confirmed that mutant allele in cfDNA can be sensitively detected by amplicon‐based NGS system. These results suggest that ctDNA could be a novel diagnostic biomarker to monitor changes in mutational status and tumor burden in patients with mCRC.
Collapse
Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshinori Takeda
- Department of Hepato-Biliary-Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Ichimura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akio Saiura
- Department of Hepato-Biliary-Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shunji Takahashi
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuo Noda
- Cancer Precision Medicine Center, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hitoshi Zembutsu
- Cancer Precision Medicine Center, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| |
Collapse
|
|
38
|
Kim NH, Jung YS, Park JH, Park DI, Sohn CI. Influence of Obesity and Metabolic Abnormalities on the Risk of Developing Colorectal Neoplasia. Dig Dis Sci 2018; 63:3126-3133. [PMID: 30094620 DOI: 10.1007/s10620-018-5239-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 08/01/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obesity and metabolic syndrome are risk factors for colorectal neoplasia (CRN). However, the association between metabolically healthy obese (MHO) or metabolically unhealthy non-obese (MUNO) status and the risk of CRN remains unclear. AIMS We aimed to elucidate the association between MHO or MUNO status and the risk of CRN. METHODS A total of 139,023 asymptomatic subjects who underwent a primary screening colonoscopy were categorized into 4 groups according to obesity and metabolic status: metabolically healthy non-obese (MHNO), MHO, MUNO, and metabolically unhealthy obese (MUO). RESULTS Mean participant age was 41.0 years, and the proportion of men was 65.3%. Among men, the risk of overall CRN increased in MHO (adjusted odds ratio [AOR] 1.22, 95% confidence intervals [CI] 1.12-1.33), MUNO (AOR 1.25, 95% CI 1.18-1.31), and MUO groups (AOR 1.47, 95% CI 1.40-1.54) compared with the MHNO group, whereas the risk of advanced CRN (ACRN) increased in MUNO (AOR 1.16, 95% CI 1.002-1.33) and MUO groups (AOR 1.49, 95% CI 1.31-1.70), but not in the MHO group (AOR 0.92, 95% CI 0.70-1.21). Moreover, among non-obese men, the risk of overall CRN and ACRN linearly increased with an increasing number of metabolic abnormalities. However, among women, only the MUO group had an increased risk of overall CRN (AOR 1.34, 95% CI 1.21-1.47) and no other significant associations were observed. CONCLUSIONS Poor metabolic health, regardless of obesity, is an independent risk factor for CRN in men. Our results suggest that men with metabolic abnormalities should be considered as a high-risk group for colorectal cancer, even if they are not obese.
Collapse
Affiliation(s)
- Nam Hee Kim
- Preventive Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Suk Jung
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul, 03181, Korea.
| | - Jung Ho Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul, 03181, Korea
| | - Dong Il Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul, 03181, Korea
| | - Chong Il Sohn
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul, 03181, Korea
| |
Collapse
|
|
39
|
Sahin C, Mamillapalli R, Yi KW, Taylor HS. microRNA Let-7b: A Novel treatment for endometriosis. J Cell Mol Med 2018; 22:5346-5353. [PMID: 30063121 PMCID: PMC6201226 DOI: 10.1111/jcmm.13807] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 06/26/2018] [Accepted: 06/29/2018] [Indexed: 12/13/2022] Open
Abstract
Endometriosis is an oestrogen-dependent, chronic inflammatory disease that affects 10% of reproductive-aged women. Current treatment options depend on female sex steroid hormone modulation; however, all have side effects and are not useful in women who want to conceive. microRNAs treatments have provided promising results for some chronic diseases and cancers. We have previously shown the microRNA Let-7b is repressed in endometriosis and that loss of Let-7 contributes to the pathophysiology of the disease. Here, we propose using microRNA Let-7b for the treatment of endometriosis in a murine model. Endometriosis was treated using microRNA Let-7b or a scrambled control microRNA. Let-7b treatment resulted in reduced endometriosis lesion size. Decreased gene expression was noted in several genes known to promote endometriosis growth including ER-α, ER-ß, Cyp19a, KRAS 4A, KRAS 4B and IL-6. These results indicate that microRNA Let-7b has a pleiotropic role in endometriosis pathophysiology affecting oestrogen signalling, inflammation and growth factor receptors. Local treatment of endometriosis with Let-7b is a promising therapy for endometriosis that simultaneously affects multiple pathways driving endometriosis without systemic hormonal side effects.
Collapse
Affiliation(s)
- Cagdas Sahin
- Department of Obstetrics, Gynecology and Reproductive SciencesYale School of MedicineNew HavenConnecticut
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive SciencesYale School of MedicineNew HavenConnecticut
| | - Kyong W. Yi
- Department of Obstetrics, Gynecology and Reproductive SciencesYale School of MedicineNew HavenConnecticut
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive SciencesYale School of MedicineNew HavenConnecticut
| |
Collapse
|
|
40
|
Dong W, Liu L, Dou Y, Xu M, Liu T, Wang S, Zhang Y, Deng B, Wang B, Cao H. Deoxycholic acid activates epidermal growth factor receptor and promotes intestinal carcinogenesis by ADAM17-dependent ligand release. J Cell Mol Med 2018; 22:4263-4273. [PMID: 29956475 PMCID: PMC6111862 DOI: 10.1111/jcmm.13709] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 05/04/2018] [Indexed: 12/12/2022] Open
Abstract
High fat diet is implicated in the elevated deoxycholic acid (DCA) in the intestine and correlated with increased colon cancer risk. However, the potential mechanisms of intestinal carcinogenesis by DCA remain unclarified. Here, we investigated the carcinogenic effects and mechanisms of DCA using the intestinal tumour cells and Apcmin/+ mice model. We found that DCA could activate epidermal growth factor receptor (EGFR) and promote the release of EGFR ligand amphiregulin (AREG), but not HB‐EGF or TGF‐α in intestinal tumour cells. Moreover, ADAM‐17 was required in DCA‐induced promotion of shedding of AREG and activation of EGFR/Akt signalling pathway. DCA significantly increased the multiplicity of intestinal tumours and accelerated adenoma‐carcinoma sequence in Apcmin/+ mice. ADAM‐17/EGFR signalling axis was also activated in intestinal tumours of DCA‐treated Apcmin/+ mice, whereas no significant change occurred in tumour adjacent tissues after DCA exposure. Conclusively, DCA activated EGFR and promoted intestinal carcinogenesis by ADAM17‐dependent ligand release.
Collapse
Affiliation(s)
- Wenxiao Dong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Li Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Yan Dou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Mengque Xu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Yujie Zhang
- Department of Pathology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Baoru Deng
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| |
Collapse
|
|
41
|
Pellino G, Gallo G, Pallante P, Capasso R, De Stefano A, Maretto I, Malapelle U, Qiu S, Nikolaou S, Barina A, Clerico G, Reginelli A, Giuliani A, Sciaudone G, Kontovounisios C, Brunese L, Trompetto M, Selvaggi F. Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives. Gastroenterol Res Pract 2018; 2018:2397863. [PMID: 30008744 PMCID: PMC6020538 DOI: 10.1155/2018/2397863] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 04/03/2018] [Accepted: 04/15/2018] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.
Collapse
Affiliation(s)
- Gianluca Pellino
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
- Colorectal Surgery Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, OU of General Surgery, University of Catanzaro, Catanzaro, Italy
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Pierlorenzo Pallante
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, Naples, Italy
| | - Raffaella Capasso
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Alfonso De Stefano
- Department of Abdominal Oncology, Division of Abdominal Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione G. Pascale, ” IRCCS, Naples, Italy
| | - Isacco Maretto
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Umberto Malapelle
- Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Shengyang Qiu
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Stella Nikolaou
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Andrea Barina
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giuseppe Clerico
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Alfonso Reginelli
- Department of Internal and Experimental Medicine, Magrassi-Lanzara, Institute of Radiology, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Antonio Giuliani
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
| | - Guido Sciaudone
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Christos Kontovounisios
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
- Department of Surgery and Cancer, Chelsea and Westminster Hospital Campus, Imperial College London, London, UK
| | - Luca Brunese
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Mario Trompetto
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Francesco Selvaggi
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| |
Collapse
|
|
42
|
Amawi H, Hussein NA, Ashby CR, Alnafisah R, Sanglard LM, Manivannan E, Karthikeyan C, Trivedi P, Eisenmann KM, Robey RW, Tiwari AK. Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis. Front Pharmacol 2018; 9:520. [PMID: 29875662 PMCID: PMC5974752 DOI: 10.3389/fphar.2018.00520] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/30/2018] [Indexed: 12/31/2022] Open
Abstract
The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a−15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro, 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.
Collapse
Affiliation(s)
- Haneen Amawi
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Noor A Hussein
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Charles R Ashby
- Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, NY, United States
| | - Rawan Alnafisah
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Leticia M Sanglard
- Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, United States
| | | | | | - Piyush Trivedi
- School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India
| | - Kathryn M Eisenmann
- Department of Cancer Biology, University of Toledo, Toledo, OH, United States
| | - Robert W Robey
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| |
Collapse
|
|
43
|
Zhang X, Liu G, Ding L, Jiang T, Shao S, Gao Y, Lu Y. HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway. J Cell Biochem 2018; 119:2864-2874. [PMID: 29073728 DOI: 10.1002/jcb.26461] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Homeobox A3 (HOXA3), one of HOX transcription factors, regulates gene expression during embryonic development. HOXA3 expression has been reported to be associated with several cancers; however, its role in colon cancer and underlying mechanism are still unclear. The expression of HOXA3 in 232 paired of human colon tumor and adjacent non-tumorous tissues were measured by qPCR. The relationship between HOXA3 expression and clinical outcomes were analyzed by Kaplan-Meier survival curves analysis. Human colon cancer cell lines HT29 and HTC116 were transfected with HOXA3 siRNA, or HOXA3 expressing vector, and then cell proliferation and apoptosis were assessed, respectively. Western blot was performed to detect the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. Moreover, HOXA3-overexpressing and HOXA3-suppressing HT29 cells were subcutaneous injected into nod mice to confirm the regulation of HOXA3 on EGFR/Ras/Raf/MEK/ERK signaling in regulating tumor growth. HOXA3 was upregulated in colon tumor tissues and cell lines, and upregulated expression of HOXA3 was associated with low survival rate. Knockdown of HOXA3 suppressed cell viability and clone formation, while induced cell apoptosis. HOXA3 knockdown could not induce the increase of cell apoptosis on the condition of EGFR overexpression. In vivo xenograft studies, HOXA3-suppressing cells showed less tumorigenic. Moreover, HOXA3 knockdown suppressed the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. To conclude, this study indicated that HOXA3 might act as a promoter of human colon cancer formation by regulating EGFR/Ras/Raf/MEK/ERK signaling pathway. HOXA3 might be a potential therapeutic target for the treatment of colon cancer.
Collapse
Affiliation(s)
- Xianxiang Zhang
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guangwei Liu
- Department of Outpatient, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Ding
- Office of Medical Safety Management, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Jiang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shihong Shao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuan Gao
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yun Lu
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
44
|
Aznar N, Ear J, Dunkel Y, Sun N, Satterfield K, He F, Kalogriopoulos NA, Lopez-Sanchez I, Ghassemian M, Sahoo D, Kufareva I, Ghosh P. Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple. Sci Signal 2018; 11:11/519/eaao4220. [PMID: 29487190 DOI: 10.1126/scisignal.aao4220] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades, and their dysregulation plays an integral role in cancer progression. Three cascades that contribute to oncogenic potential are those mediated by Wnt proteins and the receptor Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and heterotrimeric G proteins and associated GPCRs. Daple is a guanine nucleotide exchange factor (GEF) for the G protein Gαi Daple also binds to FZD and the Wnt/FZD mediator Dishevelled (Dvl), and it enhances β-catenin-independent Wnt signaling in response to Wnt5a-FZD7 signaling. We identified Daple as a substrate of multiple RTKs and non-RTKs and, hence, as a point of convergence for the three cascades. We found that phosphorylation near the Dvl-binding motif in Daple by both RTKs and non-RTKs caused Daple/Dvl complex dissociation and augmented the ability of Daple to bind to and activate Gαi, which potentiated β-catenin-independent Wnt signals and stimulated epithelial-mesenchymal transition (EMT) similarly to Wnt5a/FZD7 signaling. Although Daple acts as a tumor suppressor in the healthy colon, the concurrent increased abundance of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors was associated with poor patient prognosis. Thus, the Daple-dependent activation of Gαi and the Daple-dependent enhancement of β-catenin-independent Wnt signals are not only stimulated by Wnt5a/FZD7 to suppress tumorigenesis but also hijacked by growth factor-activated RTKs to enhance tumor progression. These findings identify a cross-talk paradigm among growth factor RTKs, heterotrimeric G proteins, and the Wnt/FZD pathway in cancer.
Collapse
Affiliation(s)
- Nicolas Aznar
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Jason Ear
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Ying Dunkel
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Nina Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Kendall Satterfield
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Fang He
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | | | | | - Majid Ghassemian
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
| | - Debashis Sahoo
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.,Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Irina Kufareva
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Pradipta Ghosh
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. .,Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| |
Collapse
|
|
45
|
Ferguson HJM, Wragg JW, Ward S, Heath VL, Ismail T, Bicknell R. Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer. Oncotarget 2018; 7:20440-54. [PMID: 26943033 PMCID: PMC4991466 DOI: 10.18632/oncotarget.7812] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/31/2016] [Indexed: 12/27/2022] Open
Abstract
Current vascular-targeted therapies in colorectal cancer (CRC) have shown limited benefit. The lack of novel, specific treatment in CRC has been hampered by a dearth of specific endothelial markers. Microarray comparison of endothelial gene expression in patient-matched CRC and normal colon identified a panel of putative colorectal tumour endothelial markers. Of these the glutamate dependent NMDA receptor GRIN2D emerged as the most interesting target. GRIN2D expression was shown to be specific to colorectal cancer vessels by RTqPCR and IHC analysis. Its expression was additionally shown be predictive of improved survival in CRC. Targeted knockdown studies in vitro demonstrated a role for GRIN2D in endothelial function and angiogenesis. This effect was also shown in vivo as vaccination against the extracellular region of GRIN2D resulted in reduced vascularisation in the subcutaneous sponge angiogenesis assay. The utility of immunologically targeting GRIN2D in CRC was demonstrated by the vaccination approach inhibiting murine CRC tumour growth and vascularisation. GRIN2D represents a promising target for the future treatment of CRC.
Collapse
Affiliation(s)
- Henry J M Ferguson
- Molecular Angiogenesis Group, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.,Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH, UK
| | - Joseph W Wragg
- Molecular Angiogenesis Group, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Stephen Ward
- Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH, UK
| | - Victoria L Heath
- Molecular Angiogenesis Group, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Tariq Ismail
- Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH, UK
| | - Roy Bicknell
- Molecular Angiogenesis Group, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| |
Collapse
|
|
46
|
Sheng J, Yin M, Sun Z, Kang X, Liu D, Jiang K, Xu J, Zhao F, Guo Q, Zheng W. SPC24 promotes osteosarcoma progression by increasing EGFR/MAPK signaling. Oncotarget 2017; 8:105276-105283. [PMID: 29285250 PMCID: PMC5739637 DOI: 10.18632/oncotarget.22167] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/29/2017] [Indexed: 12/18/2022] Open
Abstract
In this study, we investigated the role of the spindle checkpoint protein SPC24 in osteosarcoma progression. SPC24 knockdown in 143B and U2OS osteosarcoma cells decreased cell growth, survival and invasiveness. The SPC24 knockdown cells also exhibited low EGFR, Ras and phospho-ERK levels and high E-cadherin levels, suggesting inhibition of EGFR/Ras/ERK signaling and epithelial-to-mesenchymal transitioning. Xenografted SPC24 knockdown osteosarcoma cells showed reduced tumor growth in nude mice with decreased EGFR and phospho-ERK levels and increased E-cadherin levels. By contrast, human osteosarcoma tissue samples showed high SPC24 and phospho-ERK levels and low E-cadherin levels. These results suggest SPC24 promotes osteosarcoma progression by increasing EGFR/Ras/ERK signaling.
Collapse
Affiliation(s)
- Jun Sheng
- Department of Orthopedics, Chengdu Military General Hospital, Chengdu, Sichuan, China
| | - Mengchen Yin
- Department of Orthopedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengwang Sun
- Department of Orthopedics, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Xia Kang
- Department of Orthopedics, Chengdu Military General Hospital, Chengdu, Sichuan, China
| | - Da Liu
- Department of Orthopedics, Chengdu Military General Hospital, Chengdu, Sichuan, China
| | - Kai Jiang
- Department of Orthopedics, Chengdu Military General Hospital, Chengdu, Sichuan, China
| | - Jia Xu
- Department of Personnel Office, Traditional Chinese Medical Hospital of Zhuji, Zhuji, Zhejiang, China
| | - Feixing Zhao
- Department of Pathology, Zhuji People's Hospital of Zhejiang Province, Zhuji, Zhejiang, China
| | - Qunfeng Guo
- Department of Orthopedics, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Wei Zheng
- Department of Orthopedics, Chengdu Military General Hospital, Chengdu, Sichuan, China
| |
Collapse
|
|
47
|
Ishimura E, Nakagawa T, Moriwaki K, Hirano S, Matsumori Y, Asahi M. Augmented O-GlcNAcylation of AMP-activated kinase promotes the proliferation of LoVo cells, a colon cancer cell line. Cancer Sci 2017; 108:2373-2382. [PMID: 28973823 PMCID: PMC5715261 DOI: 10.1111/cas.13412] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/22/2017] [Accepted: 09/25/2017] [Indexed: 12/23/2022] Open
Abstract
Increasing incidence of various cancers has been reported in diabetic patients. O‐linked N‐acetylglucosamine (O‐GlcNAc) modification of proteins at serine/threonine residues (O‐GlcNAcylation) is an essential post‐translational modification that is upregulated in diabetic patients and has been implicated in tumor growth. However, the mechanisms by which O‐GlcNAcylation promotes tumor growth remain unclear. Given that AMP‐activated kinase (AMPK) has been thought to play important roles in suppressing tumor growth, we evaluated the involvement of AMPK O‐GlcNAcylation on the growth of LoVo cells, a human colon cancer cell line. Results revealed that treatment with Thiamet G (TMG), an inhibitor of O‐GlcNAc hydrolase, increased both anchorage‐dependent and ‐independent growth of the cells. O‐GlcNAc transferase overexpression also increased the growth. These treatments increased AMPK O‐GlcNAcylation in a dose‐dependent manner, which led to reduced AMPK phosphorylation and mTOR activation. Chemical inhibition or activation of AMPK led to increased or decreased growth, respectively, which was consistent with the data with genetic inhibition of AMPK. In addition, TMG‐mediated acceleration of tumor growth was abolished by both chemical and genetic inhibition of AMPK. To examine the effects of AMPK O‐GlcNAcylation in vivo, the LoVo cells were s.c. transplanted onto the backs of BALB/c‐nu/nu mice. Injection of TMG promoted the growth and enhanced O‐GlcNAcylation of the tumors of the mice. Consistent with in vitro data, AMPK O‐GlcNAcylation was increased, which reduced AMPK phosphorylation and resulted in activation of mTOR. Collectively, the higher colon cancer risk of diabetic patients could be due to O‐GlcNAcylation‐mediated AMPK inactivation and subsequent activation of mTOR.
Collapse
Affiliation(s)
- Emi Ishimura
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Japan.,Department of Gastroenterology, Amagasaki Daimotsu Hospital, Amagasahi, Hyogo, 660-0828, Japan
| | - Takatoshi Nakagawa
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Japan
| | - Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Japan
| | - Seiichi Hirano
- Department of Gastroenterology, Takatsuki General Hospital, Takatsuki, Japan
| | | | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Japan
| |
Collapse
|
|
48
|
Ko SH, Baeg MK, Ko SY, Jung HS, Kim P, Choi MG. Obesity and Metabolic Unhealthiness Have Different Effects on Colorectal Neoplasms. J Clin Endocrinol Metab 2017; 102:2762-2769. [PMID: 28510711 DOI: 10.1210/jc.2017-00152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/02/2017] [Indexed: 02/07/2023]
Abstract
CONTEXT Obesity and insulin resistance are risk factors for colorectal neoplasms (CRN), but data regarding metabolic status, obesity, and CRN are lacking. OBJECTIVE To investigate the relationship between metabolic status, obesity, and CRN in Koreans who underwent colonoscopy. DESIGN Retrospective, cross-sectional. PARTICIPANTS Subjects were divided based on metabolic and obesity criteria, as follows: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). MAIN OUTCOME MEASURES Multiple regression was used to identify CRN and advanced CRN risk factors, with the MHNO group as reference. RESULTS A total of 10,235 subjects was included, as follows: 5096 MHNO, 1538 MHO, 1746 MUNO, and 1855 MUO. Of these, 3297 had CRN (32.2%), and 434 (4.2%) had advanced CRN. Number of subjects with CRN in each group were: MHNO 25.8%, MHO 33.9%, MUNO 38.9%, and MUO 42.0% (P for trend < 0.001). Risk of CRN was increased in the MHO [odds ratio (OR) 1.239, 95% confidence interval (CI) 1.082 to 1.418, P = 0.002], the MUNO (OR 1.233, 95% CI 1.086 to 1.400, P = 0.001), and the MUO groups (OR 1.510, 95% CI 1.338 to 1.706, P < 0.001), whereas risk of advanced CRN was increased in the MUNO (OR 1.587, 95% CI 1.222 to 2.062, P = 0.001) and the MUO groups (OR 1.456, 95% CI 1.116 to 1.900, P = 0.006). CONCLUSIONS Obesity increased CRN risk with metabolically unhealthy status adding risk. For advanced CRN, metabolically unhealthy status increased the risk but obesity did not.
Collapse
Affiliation(s)
- Sun-Hye Ko
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea
| | - Myong Ki Baeg
- Department of Internal Medicine, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, South Korea
| | - Seung Yeon Ko
- Department of Surgery, Incheon St. Mary's Hospital, College of Medicine, Catholic University of Korea, Incheon 21431, South Korea
| | - Hee Sun Jung
- Department of Health Promotion, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul 06591, South Korea
| | - Pumsoo Kim
- Department of Internal Medicine, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, South Korea
| | - Myung-Gyu Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul 06591, South Korea
| |
Collapse
|
|
49
|
Hardbower DM, Coburn LA, Asim M, Singh K, Sierra JC, Barry DP, Gobert AP, Piazuelo MB, Washington MK, Wilson KT. EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene 2017; 36:3807-3819. [PMID: 28263971 PMCID: PMC5501754 DOI: 10.1038/onc.2017.23] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 01/12/2017] [Accepted: 01/25/2017] [Indexed: 02/08/2023]
Abstract
Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+ blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
Collapse
Affiliation(s)
- Dana M. Hardbower
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Lori A. Coburn
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System; Nashville, TN, USA
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Kshipra Singh
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Johanna C. Sierra
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Daniel P. Barry
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Alain P. Gobert
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - M. Kay Washington
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Keith T. Wilson
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Department of Cancer Biology; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Vanderbilt Ingram Cancer Center; Vanderbilt University Medical Center; Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System; Nashville, TN, USA
| |
Collapse
|
|
50
|
Peterson TA, Gauran IIM, Park J, Park D, Kann MG. Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples. PLoS Comput Biol 2017; 13:e1005428. [PMID: 28426665 PMCID: PMC5398485 DOI: 10.1371/journal.pcbi.1005428] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 02/28/2017] [Indexed: 12/28/2022] Open
Abstract
The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are 'gene-centric' in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer. In this work, we present oncodomain hotspots, a new 'domain-centric' method for identifying clusters of somatic mutations across entire gene families using protein domain models. Our analysis confirms that our approach creates a framework for leveraging structural and functional information encapsulated by protein domains into the analysis of somatic variants in cancer, enabling the assessment of even rare somatic variants by comparison to similar genes. Our results reveal a vast landscape of somatic variants that act at the level of domain families altering pathways known to be involved with cancer such as protein phosphorylation, signaling, gene regulation, and cell metabolism. Due to oncodomain hotspots' unique ability to assess rare variants, we expect our method to become an important tool for the analysis of sequenced tumor genomes, complementing existing methods.
Collapse
Affiliation(s)
- Thomas A. Peterson
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
- University of California, San Francisco, Institute for Computational Health Science, San Francisco, California, United States of America
| | - Iris Ivy M. Gauran
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - Junyong Park
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - DoHwan Park
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - Maricel G. Kann
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| |
Collapse
|