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Danek V, Tureckova J, Huebner K, Erlenbach-Wuensch K, Baranova P, Dobes J, Balounova J, Simova M, Novosadova V, Madureira Trufen CE, Prochazkova M, Talacko P, Harant K, Barinka C, Beck IM, Schneider-Stock R, Sedlacek R, Prochazka J. CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling. Cancer Lett 2025; 621:217663. [PMID: 40120800 DOI: 10.1016/j.canlet.2025.217663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/06/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
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Affiliation(s)
- Veronika Danek
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Jolana Tureckova
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Kerstin Huebner
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
| | | | - Petra Baranova
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
| | - Jan Dobes
- Department of Cell Biology, Faculty of Science, Charles University, 128 00, Prague, Czech Republic
| | - Jana Balounova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Michaela Simova
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Vendula Novosadova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Carlos Eduardo Madureira Trufen
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Michaela Prochazkova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Pavel Talacko
- BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
| | - Karel Harant
- BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
| | - Cyril Barinka
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
| | - Inken M Beck
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Animal Research Centre, Ulm University, Ulm, Germany
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany; Institute of Pathology, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Radislav Sedlacek
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Jan Prochazka
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic.
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Matejcic M, Teer JK, Hoehn HJ, Diaz DB, Shankar K, Gong J, Nguyen NT, Loroña NC, Coppola D, Fulmer CG, Saglam O, Jiang K, Cress WD, Muñoz-Antonia T, Flores I, Gordián ER, Oliveras Torres JA, Felder SI, Sanchez J, Fleming JB, Siegel EM, Freedman JA, Dutil J, Stern MC, Fridley BL, Figueiredo JC, Schmit SL. Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles. Cancer Res 2025; 85:1928-1944. [PMID: 40126181 DOI: 10.1158/0008-5472.can-24-0747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/21/2024] [Accepted: 02/25/2025] [Indexed: 03/25/2025]
Abstract
Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.
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Affiliation(s)
- Marco Matejcic
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Hannah J Hoehn
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Diana B Diaz
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kritika Shankar
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jun Gong
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nathalie T Nguyen
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nicole C Loroña
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Clifton G Fulmer
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ozlen Saglam
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kun Jiang
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - W Douglas Cress
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Teresita Muñoz-Antonia
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Idhaliz Flores
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Edna R Gordián
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - José A Oliveras Torres
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Seth I Felder
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Julian Sanchez
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Erin M Siegel
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jennifer A Freedman
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Duke Cancer Institute, Durham, North Carolina
| | - Julie Dutil
- Division of Clinical and Translational Cancer Research, Comprehensive Cancer Center of the University of Puerto Rico, San Juan, Puerto Rico
| | - Mariana C Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephanie L Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio
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Zhang X, Zhang P, Dong H, Li L, Lu L, Lv H, Yu X, Yu H. Homologous Recombination Deficiency Is Associated with Shorter Survival in Colorectal Cancer Patients. J Gastrointest Cancer 2025; 56:105. [PMID: 40261491 DOI: 10.1007/s12029-025-01231-x] [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: 04/12/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) patients benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all patients. The remaining patients still lack effective therapeutic biomarkers to predict their prognosis. METHODS We performed whole-exome sequencing (WES) to analyze 84 CRC specimens, classifying them into different groups based on their microsatellite status (MS), tumor mutation burden (TMB), homologous recombination deficiency (HRD) score, and clinicopathological features, which might be associated with clinical outcomes. Survival analysis and multivariable Cox regression modeling were employed to identify prognostic indicators. Comparative genomic profiling evaluated somatic mutations, copy number variations (CNVs), and pathway activation patterns across clinical subgroups. RESULTS The characteristics of the cohort (N = 84) revealed a median age of 52 years, with a male predominance (61.9%) and a majority of patients presenting with stage IV disease (77%). The HRD-high (HRD-H) subgroup accounted for 16.7%, while 19.0% of cases were microsatellite instability-high (MSI-H) and 22.6% were TMB-high (TMB-H). Multivariable analysis identified HRD-H as an independent predictor of overall survival (OS: HR = 0.19, 95% CI 0.12-0.94, p = 0.002). Comparative genomics demonstrated distinct mutation landscapes between HRD-H and HRD-low subgroups. In microsatellite-stable (MSS) patients, HRD-H status correlated with enriched SMAD4 mutations (p < 0.01) and differential activation of TGF-β/MYC signaling pathways compared to HRD-H-MSI counterparts. CONCLUSION HRD status serves as a novel independent prognostic biomarker in CRC. Our multi-parametric genomic framework delineates stratification-specific molecular signatures, advocating for HRD-integrated molecular diagnostics to optimize CRC management.
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Affiliation(s)
- Xuan Zhang
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Pan Zhang
- Department of Clinical Laboratory, Gongli Hospital of Shanghai Pudong New Area, 219 Miao Pu Road, Shanghai, 200135, China
| | - Hua Dong
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Lin Li
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Lingling Lu
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Hongyuan Lv
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China
| | - Xin Yu
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China.
| | - Hong Yu
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China.
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Al-Shajrawi OM, Tarawneh IA, Tengku Din TADAADAA, Afolabi HA. The role of microalgal extracts and their combination with tamoxifen in the modulation of breast cancer immunotherapy (Review). Mol Clin Oncol 2025; 22:6. [PMID: 39559458 PMCID: PMC11570877 DOI: 10.3892/mco.2024.2801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/01/2024] [Indexed: 11/20/2024] Open
Abstract
Cancer is one of the deadliest health menaces humans have ever witnessed. It is a leading cause of human mortality. Today, it remains a main leading cause of death globally primarily due to lifestyle changes and population ageing. A total of ~12.7 million cancer cases and 7.6 million cancer deaths were reported in 2008. In developing countries, cancer accounted for 56% of cases and 64% of deaths. Tamoxifen is the most reputable and recommended specific oestrogen receptor modulator drug used for the treatment of breast cancer. In the past decade, algae have demonstrated remarkable potency for advanced life applications. They can remain a focus of interest in the coming decades because they are one of the most diverse organisms in the entire ecosystem with immense bio nutritional benefits. Algae and their extracts play a pivotal role in the pharmaceutical industry as bioactive compounds and new drugs and nutraceutical industry as probiotics and antioxidants. However, a broad range of the health benefits of these organisms remains to be explored. The present review highlights the applications and co-application of microalgal crude extracts with tamoxifen for breast cancer immunotherapy. Given that recent studies have suggested that tamoxifen is an essential and primary treatment for breast cancer, the present review focused on the identification of a new treatment approach involving the co-application of tamoxifen and microalgal extracts to provide promising anticancer activity with few side effects on normal cells. The present review includes a general background and blueprint for the use of microalgal extracts as potential and affordable treatments or adjuncts for breast cancer management.
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Affiliation(s)
- Omar Mahmoud Al-Shajrawi
- Department of Chemical Pathology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan 16150, Malaysia
| | - Ibraheam A.M. Tarawneh
- School of Graduate Studies, Management and Science University, Shah Alam, Selangor 40100, Malaysia
| | | | - Hafeez Abiola Afolabi
- Department of Pathology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan 16150, Malaysia
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Suzauddula M, Kobayashi K, Park S, Sun XS, Wang W. Bioengineered Anthocyanin-Enriched Tomatoes: A Novel Approach to Colorectal Cancer Prevention. Foods 2024; 13:2991. [PMID: 39335919 PMCID: PMC11430996 DOI: 10.3390/foods13182991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health challenge, with barriers to effective prevention and treatment including tumor recurrence, chemoresistance, and limited overall survival rates. Anthocyanins, known for their strong anti-cancer properties, have shown promise in preventing and suppressing various cancers, including CRC. However, natural sources of anthocyanins often fail to provide sufficient quantities needed for therapeutic effects. Bioengineered crops, particularly anthocyanin-enriched tomatoes, offer a viable solution to enhance anthocyanin content. Given its large-scale production and consumption, tomatoes present an ideal target for bioengineering efforts aimed at increasing dietary anthocyanin intake. This review provides an overview of anthocyanins and their health benefits, elucidating the mechanisms by which anthocyanins modulate the transcription factors involved in CRC development. It also examines case studies demonstrating the successful bioengineering of tomatoes to boost anthocyanin levels. Furthermore, the review discusses the effects of anthocyanin extracts from bioengineered tomatoes on CRC prevention, highlighting their role in altering metabolic pathways and reducing tumor-related inflammation. Finally, this review addresses the challenges associated with bioengineering tomatoes and proposes future research directions to optimize anthocyanin enrichment in tomatoes.
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Affiliation(s)
- Md Suzauddula
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Kaori Kobayashi
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Sunghun Park
- Department of Horticulture and Nature Resources, Kansas State University, Manhattan, KS 66506, USA;
| | - Xiuzhi Susan Sun
- Department of Grain Science and Industry, Kansas State University, Manhattan, KS 66506, USA;
| | - Weiqun Wang
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
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Dong W, Lu J, Li Y, Zeng J, Du X, Yu A, Zhao X, Chi F, Xi Z, Cao S. SIRT1: a novel regulator in colorectal cancer. Biomed Pharmacother 2024; 178:117176. [PMID: 39059350 DOI: 10.1016/j.biopha.2024.117176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/08/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
The class-III histone deacetylase SIRT1 is the most extensively investigated sirtuin deacetylase. It is resistant to the broad deacetylase inhibitor trichostatin A and depends on oxidized nicotinamide adenine nucleotide (NAD+). SIRT1 plays a crucial role in the tumorigenesis of numerous types of cancers, including colorectal cancer (CRC). Accumulating evidence indicates that SIRT1 is a therapeutic target for CRC; however, the function and underlying mechanism of SIRT1 in CRC still need to be elucidated. Herein, we provide a detailed and updated review to illustrate that SIRT1 regulates many processes that go awry in CRC cells, such as apoptosis, autophagy, proliferation, migration, invasion, metastasis, oxidative stress, resistance to chemo-radio therapy, immune evasion, and metabolic reprogramming. Moreover, we closely link our review to the clinical practice of CRC treatment, summarizing the mechanisms and prospects of SIRT1 inhibitors in CRC therapy. SIRT1 inhibitors as monotherapy in CRC or in combination with chemotherapy, radiotherapy, and immune therapies are comprehensively discussed. From epigenetic regulation to its potential therapeutic effect, we hope to offer novel insights and a comprehensive understanding of SIRT1's role in CRC.
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Affiliation(s)
- Weiwei Dong
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Jinjing Lu
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - You Li
- Nursing Department, Liaoning Jinqiu Hospital, Shenyang, Liaoning Province 110016, China
| | - Juan Zeng
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xiaoyun Du
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Ao Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xuechan Zhao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Feng Chi
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Zhuo Xi
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Shuo Cao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
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Thangpong R, Nuwongsri P, Ittiwut C, Ittiwut R, Phokaew C, Techavichit P, Suphapeetiporn K. Whole exome sequencing in relapsed or refractory childhood cancer: case series. ASIAN BIOMED 2024; 18:186-191. [PMID: 39309469 PMCID: PMC11414774 DOI: 10.2478/abm-2024-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background The prognosis for relapsed or refractory childhood cancer is approximately 20%. Genetic alterations are one of the significant contributing factors to the prognosis of patients. Objective To investigate the molecular profile of relapsed or refractory childhood cancers in Thai cases. Methods The study design is a descriptive study of patients <18 years old, suspected or diagnosed of relapsed or refractory childhood cancer who underwent whole exome sequencing (WES). Results WES was successfully performed in both the tumor and the blood or saliva samples obtained from 4 unrelated patients. Six different variants were identified in the NCOR2, COL6A3, TP53, and SMAD4 genes. These alterations were found to be associated with tumor aggressiveness. Conclusion This study is the first one to demonstrate genetic alterations by using WES in relapsed or refractory childhood cancer in Thai cases.
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Affiliation(s)
- Rungroj Thangpong
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
| | - Pattarin Nuwongsri
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok10330, Thailand
| | - Chupong Ittiwut
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok10330, Thailand
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
| | - Rungnapa Ittiwut
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok10330, Thailand
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
| | - Chureerat Phokaew
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
| | - Piti Techavichit
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
| | - Kanya Suphapeetiporn
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok10330, Thailand
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
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Márquez-González RM, Saucedo-Sariñana AM, de Jesús Tovar-Jacome C, Barros-Núñez P, Gallegos-Arreola MP, Orozco-Gutiérrez MH, Mariscal-Ramírez I, Pineda-Razo TD, Alcaraz-Wong AA, Marín-Contreras ME, Rosales-Reynoso MA. NME1 and DCC variants are associated with susceptibility and tumor characteristics in Mexican patients with colorectal cancer. J Egypt Natl Canc Inst 2024; 36:10. [PMID: 38556604 DOI: 10.1186/s43046-024-00213-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/06/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1) and netrin 1 receptor (DCC) genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1 (rs34214448 G > T and rs2302254 C > T) and DCC (rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. METHODS Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Associations were assessed using odds ratios (OR), and the p values were adjusted with Bonferroni test. RESULTS Individuals carrying the G/T and T/T genotypes for the NME1 rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76-4.09, P = 0.001 and OR = 2.47, 95% CI: 1.37-4.47, P = 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81-4.54, P = 0.001 and OR = 2.99, 95% CI: 1.54-5.79, P = 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P = 0.001), and tumor location in the rectum (P = 0.001). Furthermore, the DCC rs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28-3.11, P = 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P = 0.001). CONCLUSIONS These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development.
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Affiliation(s)
- Rosa María Márquez-González
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Colonia Independencia Guadalajara, Sierra Mojada # 800, Jalisco, CP, 44340, México
| | - Anilú Margarita Saucedo-Sariñana
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Colonia Independencia Guadalajara, Sierra Mojada # 800, Jalisco, CP, 44340, México
| | - César de Jesús Tovar-Jacome
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Colonia Independencia Guadalajara, Sierra Mojada # 800, Jalisco, CP, 44340, México
| | - Patricio Barros-Núñez
- Doctorado en Genética Humana, Centro Universitario de Ciencias de La Salud. Universidad de Guadalajara, Jalisco, México
| | - Martha Patricia Gallegos-Arreola
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Mario Humberto Orozco-Gutiérrez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Colonia Independencia Guadalajara, Sierra Mojada # 800, Jalisco, CP, 44340, México
| | - Ignacio Mariscal-Ramírez
- Servicio de Oncología Médica, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Tomas Daniel Pineda-Razo
- Servicio de Oncología Médica, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Aldo Antonio Alcaraz-Wong
- Servicio de Anatomía Patológica, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - María Eugenia Marín-Contreras
- Servicio de Gastroenterología, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Mónica Alejandra Rosales-Reynoso
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Colonia Independencia Guadalajara, Sierra Mojada # 800, Jalisco, CP, 44340, México.
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9
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Matejcic M, Teer JK, Hoehn HJ, Diaz DB, Shankar K, Gong J, Nguyen NT, Lorona N, Coppola D, Fulmer C, Saglam O, Jiang K, Cress D, Muñoz-Antonia T, Flores I, Gordian E, Oliveras Torres JA, Felder SI, Sanchez JA, Fleming J, Siegel EM, Freedman JA, Dutil J, Stern MC, Fridley BL, Figueiredo JC, Schmit SL. Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.11.24303880. [PMID: 38558992 PMCID: PMC10980113 DOI: 10.1101/2024.03.11.24303880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.
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10
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Zhang FY, Wu L, Zhang TN, Chen HH. KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2. Commun Biol 2024; 7:262. [PMID: 38438714 PMCID: PMC10912199 DOI: 10.1038/s42003-024-05880-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 02/01/2024] [Indexed: 03/06/2024] Open
Abstract
Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells.
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Affiliation(s)
- Fang-Yuan Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lin Wu
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tie-Ning Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Huan-Huan Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
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11
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Duabil AJN, Cooper CR, Aldujaily E, Halford SER, Hirschberg S, Katugampola SD, Jones GDD. Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differing tumour protein 53 gene status. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1210-1226. [PMID: 38214010 PMCID: PMC10776598 DOI: 10.37349/etat.2023.00193] [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: 06/10/2023] [Accepted: 10/16/2023] [Indexed: 01/13/2024] Open
Abstract
Aim In response to DNA damage the serine/threonine-specific protein kinase checkpoint kinase 1 (CHK1) is activated allowing cells to enter S phase (S) and G2 phase (G2) cell-cycle arrest. CHK1 inhibitors are expected to prevent cells from entering such arrest, thereby enhancing DNA damage-induced cytotoxicity. In contrast, normal cells with intact ataxia-telangiectasia mutated (ATM), CHK2 and tumour suppressor protein 53 (P53) signalling are still able to enter cell-cycle arrest using the functioning G1/S checkpoint, thereby being rescued from enhanced cytotoxicity. The main objective of this work is to investigate the in vitro effects of the novel CHK1 inhibitor SRA737 on pairs of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines, all with genetic aberrations rendering them susceptible to replication stress but of differing tumour protein 53 (TP53) gene status, focusing on DNA damage induction and the subsequent effects on cell proliferation and viability. Methods NSCLC cell lines H23 [TP53 mutant (MUT)] and A549 [TP53 wild-type (WT)] and CRC cell lines HT29 (TP53 MUT) and HCT116 (TP53 WT) were incubated with differing micromolar concentrations of SRA737 for 24 h and then analysed using alkaline comet and phosphorylated H2A.X variant histone (γH2AX)-foci assays to assess mostly DNA single strand break and double strand break damage, respectively. Cell-counting/trypan blue staining was also performed to assess cell proliferation/viability. Results Clear concentration-dependent increases in comet formation and γH2AX-foci/cell were noted for the TP53 MUT cells with no or lower increases being noted in the corresponding TP53 WT cells. Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. Conclusions This study's data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress.
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Affiliation(s)
- Ali JN Duabil
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- Department of Surgery, Faculty of Medicine, University of Kufa, Najaf, Iraq
| | - Christian R Cooper
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- MRC Oxford Institute for Radiation Oncology, University of Oxford, OX3 7DQ Oxon, UK
| | - Esraa Aldujaily
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- Department of Pathology & Forensic Medicine, Faculty of Medicine, University of Kufa, Najaf, Iraq
| | - Sarah ER Halford
- Cancer Research UK Centre for Drug Development, London E20 1JQ, UK
| | | | | | - George DD Jones
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
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12
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Brandt VP, Holland H, Wallenborn M, Koschny R, Frydrychowicz C, Richter M, Holland L, Nestler U, Sander C. SNP array genomic analysis of matched pairs of brain and liver metastases in primary colorectal cancer. J Cancer Res Clin Oncol 2023; 149:18173-18183. [PMID: 38010391 PMCID: PMC10725338 DOI: 10.1007/s00432-023-05505-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/31/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Brain metastasis formation is a rare and late event in colorectal cancer (CRC) patients and associated with poor survival. In contrast to other metastatic sites, the knowledge on chromosomal aberrations in brain metastases is very limited. METHODS Therefore, we carried out single nucleotide polymorphism (SNP) array analyses on matched primary CRC and brain metastases of four patients as well as on liver metastases of three patients. RESULTS Brain metastases showed more chromosomal aberrations than primary tumors or liver metastases. Commonly occurring aberrations were gain of 8q11.1-q24.3 (primary CRC), gain of 13q12.13-q12.3 (liver metastases), and gain of 20q11.1-q13.33 (brain metastases). Furthermore, we found one copy-neutral loss of heterozygosity (cn-LOH) region on chromosome 3 in primary CRC, three cn-LOH regions in liver metastases and 23 cn-LOH regions in brain metastases, comprising 26 previously undescribed sites. CONCLUSION The more frequent occurrence of cn-LOHs and subsequently affected genes in brain metastases shed light on the pathophysiology of brain metastasis formation. Further pairwise genetic analyses between primary tumors and their metastases will help to define the role of affected genes in cn-LOH regions.
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Affiliation(s)
- Vivian-Pascal Brandt
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany.
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany.
| | - Heidrun Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Marco Wallenborn
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ronald Koschny
- Interdisciplinary Endoscopy Center (IEZ), Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Clara Frydrychowicz
- Paul Flechsig Institute of Neuropathology, University Medicine Leipzig, Leipzig, Saxony, Germany
| | - Mandy Richter
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Lydia Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ulf Nestler
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
| | - Caroline Sander
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
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13
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Singh S, Gouri V, Samant M. TGF-β in correlation with tumor progression, immunosuppression and targeted therapy in colorectal cancer. Med Oncol 2023; 40:335. [PMID: 37855975 DOI: 10.1007/s12032-023-02204-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/25/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer (CRC) is a complex malignancy responsible for the second-highest cancer deaths worldwide. TGF-β maintains normal cellular homeostasis by inhibiting the cell cycle and inducing apoptosis, but its elevated level is correlated with colorectal cancer progression, as TGF-β is a master regulator of the epithelial-to-mesenchymal transition, a critical step of metastasis. Tumors, including CRC, use elevated TGF-β levels to avoid immune surveillance by modulating immune cell differentiation, proliferation, and effector function. Presently, the treatment of advanced CRC is mainly based on chemotherapy, with multiple adverse effects. Thus, there is a need to develop alternate tactics because CRC continue to be mostly resistant to the present therapeutic regimen. TGF-β blockade has emerged as a promising therapeutic target in cancer therapy. Blocking TGF-β with phytochemicals and other molecules, such as antisense oligonucleotides, monoclonal antibodies, and bifunctional traps, alone or in combination, may be a safer and more effective way to treat CRC. Furthermore, combination immunotherapy comprising TGF-β blockers and immune checkpoint inhibitors is gaining popularity because both molecules work synergistically to suppress the immune system. Here, we summarize the current understanding of TGF-β as a therapeutic target for managing CRC and its context-dependent tumor-promoting or tumor-suppressing nature.
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Affiliation(s)
- Sumeet Singh
- Cell and Molecular Biology Laboratory, Department of Zoology, Soban Singh Jeena University, Almora, Uttarakhand, India
| | - Vinita Gouri
- Cell and Molecular Biology Laboratory, Department of Zoology, Soban Singh Jeena University, Almora, Uttarakhand, India
- Department of Zoology, Kumaun University, Nainital, Uttarakhand, India
| | - Mukesh Samant
- Cell and Molecular Biology Laboratory, Department of Zoology, Soban Singh Jeena University, Almora, Uttarakhand, India.
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Nolano A, Rossi GB, D'Angelo V, Liccardo R, Rosa MD, Izzo P, Duraturo F. Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion. Int J Mol Sci 2023; 24:ijms24065970. [PMID: 36983044 PMCID: PMC10051096 DOI: 10.3390/ijms24065970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/19/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer.
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Affiliation(s)
- Antonio Nolano
- Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy
| | - Giovanni Battista Rossi
- Endoscopy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semola, 80131 Naples, Italy
| | - Valentina D'Angelo
- Endoscopy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semola, 80131 Naples, Italy
| | - Raffaella Liccardo
- Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy
| | - Marina De Rosa
- Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy
| | - Paola Izzo
- Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy
| | - Francesca Duraturo
- Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy
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15
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Mason SE, Manoli E, Alexander JL, Poynter L, Ford L, Paizs P, Adebesin A, McKenzie JS, Rosini F, Goldin R, Darzi A, Takats Z, Kinross JM. Lipidomic Profiling of Colorectal Lesions for Real-Time Tissue Recognition and Risk-Stratification Using Rapid Evaporative Ionization Mass Spectrometry. Ann Surg 2023; 277:e569-e577. [PMID: 34387206 DOI: 10.1097/sla.0000000000005164] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Rapid evaporative ionization mass spectrometry (REIMS) is a metabolomic technique analyzing tissue metabolites, which can be applied intraoperatively in real-time. The objective of this study was to profile the lipid composition of colorectal tissues using REIMS, assessing its accuracy for real-time tissue recognition and risk-stratification. SUMMARY BACKGROUND DATA Metabolic dysregulation is a hallmark feature of carcinogenesis; however, it remains unknown if this can be leveraged for real-time clinical applications in colorectal disease. METHODS Patients undergoing colorectal resection were included, with carcinoma, adenoma and paired-normal mucosa sampled. Ex vivo analysis with REIMS was conducted using monopolar diathermy, with the aerosol aspirated into a Xevo G2S QToF mass spectrometer. Negatively charged ions over 600 to 1000 m/z were used for univariate and multivariate functions including linear discriminant analysis. RESULTS A total of 161 patients were included, generating 1013 spectra. Unique lipidomic profiles exist for each tissue type, with REIMS differentiating samples of carcinoma, adenoma, and normal mucosa with 93.1% accuracy and 96.1% negative predictive value for carcinoma. Neoplasia (carcinoma or adenoma) could be predicted with 96.0% accuracy and 91.8% negative predictive value. Adenomas can be risk-stratified by grade of dysplasia with 93.5% accuracy, but not histological subtype. The structure of 61 lipid metabolites was identified, revealing that during colorectal carcinogenesis there is progressive increase in relative abundance of phosphatidylglycerols, sphingomyelins, and mono-unsaturated fatty acid-containing phospholipids. CONCLUSIONS The colorectal lipidome can be sampled by REIMS and leveraged for accurate real-time tissue recognition, in addition to riskstratification of colorectal adenomas. Unique lipidomic features associated with carcinogenesis are described.
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Affiliation(s)
- Sam E Mason
- Department of Surgery and Cancer, Imperial College, London
| | | | - James L Alexander
- Department of Metabolism, Digestion and Reproduction, Imperial College, London; and
| | - Liam Poynter
- Department of Surgery and Cancer, Imperial College, London
| | - Lauren Ford
- Department of Surgery and Cancer, Imperial College, London
| | - Petra Paizs
- Department of Metabolism, Digestion and Reproduction, Imperial College, London; and
| | - Afeez Adebesin
- Department of Surgery and Cancer, Imperial College, London
| | - James S McKenzie
- Department of Metabolism, Digestion and Reproduction, Imperial College, London; and
| | | | - Rob Goldin
- Department of Metabolism, Digestion and Reproduction, Imperial College, London; and
| | - Ara Darzi
- Department of Surgery and Cancer, Imperial College, London
| | - Zoltan Takats
- Department of Metabolism, Digestion and Reproduction, Imperial College, London; and
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16
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Merhi M, Ahmad F, Taib N, Inchakalody V, Uddin S, Shablak A, Dermime S. The complex network of transcription factors, immune checkpoint inhibitors and stemness features in colorectal cancer: A recent update. Semin Cancer Biol 2023; 89:1-17. [PMID: 36621515 DOI: 10.1016/j.semcancer.2023.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/19/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.
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Affiliation(s)
- Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Fareed Ahmad
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Nassiba Taib
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Inchakalody
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Alaaeldin Shablak
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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17
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Huang W, Su D, Liao X, Yang T, Lu Y, Zhang Z. Prognostic costimulatory molecule-related signature risk model correlates with immunotherapy response in colon cancer. Sci Rep 2023; 13:789. [PMID: 36646765 PMCID: PMC9842650 DOI: 10.1038/s41598-023-27826-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 01/09/2023] [Indexed: 01/17/2023] Open
Abstract
Costimulatory molecules can promote the activation and proliferation of T cells and play an essential role in immunotherapy. However, their role in the prognosis of colon adenocarcinoma remains elusive. In this study, the expression data of costimulatory molecules and clinicopathological information of 429 patients with colon adenocarcinoma were obtained from The Cancer Genome Atlas database. The patients were divided into training and verification cohorts. Correlation, Cox regression, and Lasso regression analyses were performed to identify costimulatory molecules related to prognosis. After mentioning the construction of the risk mode, a nomogram integrating the clinical characteristics and risk scores of patients was constructed to predict prognosis. Eventually, three prognostic costimulatory molecules were identified and used for constructing a risk model. High expression of these three molecules indicated a poor prognosis. The predictive accuracy of the risk model was verified in the GSE17536 dataset. Subsequently, multivariate regression analysis showed that the signature based on the three costimulatory molecules was an independent risk factor in the training cohort (HR = 2.12; 95% CI = 1.26, 3.56). Based on the risk model and clinicopathological data, the AUC values for predicting the 1-, 3-, and 5-year survival probability of patients with colon adenocarcinoma were 0.77, 0.77, and 0.71, respectively. To the best of our knowledge, this study is the first to report a risk signature constructed based on the costimulatory molecules TNFRSF10c, TNFRSF13c, and TNFRSF11a. This risk signature can serve as a prognostic biomarker for colon adenocarcinoma and is related to the immunotherapeutic response of patients.
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Affiliation(s)
- Wanze Huang
- Department of Breast and Thyroid, Xiangya Boai Rehabilitation Hospital, 168 Wanjiali North Road, Changsha, 410100, China
| | - Duntao Su
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, China
| | - Xin Liao
- Department of Cardiac Macrovascular Surgery, Yueyang Central Hospital, 39 Dongmaoling Road, Yueyang, 410000, China
| | - Tongtong Yang
- Hunan Sany Industrial Vocational and Technical College, Changsha, China
| | - Yan Lu
- Department of Breast and Thyroid, Xiangya Boai Rehabilitation Hospital, 168 Wanjiali North Road, Changsha, 410100, China
| | - Zhejia Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, China.
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Wang Z, Chen J, Sun F, Zhao X, Dong Y, Yu S, Li J, Liang H. LncRNA CRLM1 inhibits apoptosis and promotes metastasis through transcriptional regulation cooperated with hnRNPK in colorectal cancer. Cell Biosci 2022; 12:120. [PMID: 35907898 PMCID: PMC9338583 DOI: 10.1186/s13578-022-00849-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/10/2022] [Indexed: 12/24/2022] Open
Abstract
Background Colorectal liver metastases (CRLM) continue to have a low survival rate. The number of CRLM regulators and clinical indicators remains limited. Long non-coding RNAs (lncRNAs) are a new master regulator of cell invasion and metastasis. However, the function and regulation mechanism of lncRNAs in colorectal cancer (CRC) metastasis are yet unknown. Methods To screen and identify CRLM-related lncRNAs, public transcriptome data were used. Gain and loss of function experiments were carried out to investigate the biological activities of lncRNA CRLM1 in vitro and in vivo. RNA sequencing (RNA-seq), chromatin isolation by RNA purification (ChIRP), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), western blotting, and rescue experiments were performed to explore the molecular mechanism of CRLM1. Moreover, identified the proteins, DNAs, and RNAs that interact with CRLM1. Results The investigation of lncRNA expression dynamics in CRLM, primary CRC, and normal tissues in this work resulted in identifying a series of lncRNAs associated with metastasis, including CRLM1. CRLM1 inhibited apoptosis of CRC cells and promoted liver metastasis in Balb/C nude mice. CRLM1 was weakly associated with the chromatin regions of genes involved in cell adhesion and DNA damage, and this association was bidirectionally correlated with CRLM1-regulated pro-metastatic gene expression. CRLM1 physically interacts with the hnRNPK protein and promotes its nuclear localization. CRLM1 effectively enhances hnRNPK promoter occupancy and co-regulates the expression of a panel of metastatic genes. Conclusions The finding of the clinically significant lncRNA CRLM1 in promoting metastasis and regulating gene expression suggests a potential biomarker and target for CRLM therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00849-9.
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19
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Peng X, Zhang T, Jia X, Wang T, Lin H, Li G, Li R, Zhang A. Impact of a haplotype (composed of the APC, KRAS, and TP53 genes) on colorectal adenocarcinoma differentiation and patient prognosis. Cancer Genet 2022; 268-269:115-123. [PMID: 36288643 DOI: 10.1016/j.cancergen.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/02/2022] [Accepted: 10/12/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Many types of gene mutation are associated with the drug resistance of cancer cells. XELOX is a new and efficient surgical adjuvant chemotherapy for colorectal adenocarcinoma. However, drug-resistant related genetic mutations associated with this treatment remain unknown. METHODS Next-generation sequencing (NGS) was performed on 36 colorectal cancer patients to identify mutations among patients with residual tumors following preoperative chemotherapy. Enrichment and prognosis of these mutations were evaluated in a TCGA cohort. The pathology of cases with poor prognosis-related mutations was also determined. RESULTS A sequence of SNPs associated with the APC, KRAS, and TP53 genes in 13 of 19 subjects with residual tumors after preoperative chemotherapy was identified. Using survival analysis data from 317 cases in the TCGA database, a prognosis-related haplotype composed of SNPs from APC, KRAS, and TP53 was assembled. Colorectal cancer patients with these mutations had a lower 5-year tumor-specific survival rate than those without (p < 0.05). Most patients with these mutations were at a higher clinical stage (III-IV) of disease. Enrolled subjects with the identified haplotype tended to have poor cancer cell differentiation. CONCLUSIONS The prognosis-related haplotype can be used as a marker of drug resistance and prognosis in colorectal cancer patients after preoperative chemotherapy.
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Affiliation(s)
- Xinyu Peng
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
| | - Tao Zhang
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
| | - Xiongjie Jia
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
| | - Tong Wang
- General Surgery Department, Laiyuan County Hospital, No. 299, Zhongxin Road, Laiyuan County, Baoding City, Hebei Province, PR China 074399
| | - Hengxue Lin
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
| | - Gang Li
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
| | - Riheng Li
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000.
| | - Aimin Zhang
- Department of Gastrointestinal Surgery,Affiliated Hospital of Hebei University, No.212 Yuhua East Road, Baoding City, Hebei Province, PR China 071000
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20
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Lepore Signorile M, Grossi V, Fasano C, Forte G, Disciglio V, Sanese P, De Marco K, La Rocca F, Armentano R, Valentini AM, Giannelli G, Simone C. c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer. Cancers (Basel) 2022; 14:4840. [PMID: 36230763 PMCID: PMC9562641 DOI: 10.3390/cancers14194840] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022] Open
Abstract
c-MYC is one of the most important factors involved in colorectal cancer (CRC) initiation and progression; indeed, it is found to be upregulated in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC is maintained upregulated through β-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization. Our data demonstrate that p38α, a kinase involved in CRC metabolism and survival, contributes to c-Myc protein stability. Moreover, we show that p38α, like ERK, stabilizes c-MYC protein levels by preventing its ubiquitination. Of note, we found that p38α phosphorylates c-MYC and interacts with it both in vitro and in cellulo. Extensive molecular analyses in the cellular and in vivo models revealed that the p38α kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38α as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance.
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Affiliation(s)
- Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Francesca La Rocca
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy
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21
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Ma L, Liu T, Lu Y, Dong Y, Zhao X, Man S. A natural halogenated fluoride adenosine analog 5'-fluorodeoxy adenosine induced anticolon cancer activity in vivo and in vitro. ENVIRONMENTAL TOXICOLOGY 2022; 37:2493-2502. [PMID: 35866996 DOI: 10.1002/tox.23612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/15/2022] [Accepted: 06/25/2022] [Indexed: 06/15/2023]
Abstract
Adenosine (ADO) and its analogs have been introduced into the anticancer clinical trials, especial for the ADO derivatives with fluoride. The biosynthesis of fluorinase produces a fluorine-containing ADO analog 5'-fluorodeoxy adenosine (5'-FDA). The toxicity and application of 5'-FDA has not been evaluated, which limits the application of ADO analogs. In order to study its potential mechanism, we carried out the following experiments. In our research, 5'-FDA displayed good antitumor activity in colon cancer cells and two colon cancer models. As a result, 5'-FDA concentration-dependently inhibited the proliferation, migration, and invasion in colon cancer cells through its proapoptosis and cell cycle arrest pathway. Furthermore, 5'-FDA inhibited the growth of colon cancer and its pulmonary metastasis in CT26 inbred mice without affecting their body weight. It was found that 5'-FDA remarkably increased the protein levels of Caspase 3 and cleaved-Caspase 9 and decreased Cyclin A2 and CDK2 via the regulation of p53 signaling pathway, and increased the protein levels of Caspase 8 and cleaved-Caspase 8 which participated in apoptosis pathway. All in all, 5'-FDA displayed excellent therapeutic effects on colon cancer and its pulmonary metastasis. We believed that our study provided a theoretical basis for further preclinical research of 5'-FDA in the treatment of cancer.
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Affiliation(s)
- Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Taohua Liu
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Yingying Lu
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Yanan Dong
- Tianjin Jizhou District People's Hospital, Tianjin, China
| | - Xia Zhao
- College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
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22
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Shen X, Jain A, Aladelokun O, Yan H, Gilbride A, Ferrucci LM, Lu L, Khan SA, Johnson CH. Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review. Front Mol Biosci 2022; 9:958666. [PMID: 36090030 PMCID: PMC9453556 DOI: 10.3389/fmolb.2022.958666] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/21/2022] [Indexed: 02/05/2023] Open
Abstract
Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.
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Affiliation(s)
- Xinyi Shen
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Abhishek Jain
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Oladimeji Aladelokun
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Hong Yan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Austin Gilbride
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Leah M. Ferrucci
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Sajid A. Khan
- Division of Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Caroline H. Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
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23
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Role of the WNT/β-catenin/ZKSCAN3 Pathway in Regulating Chromosomal Instability in Colon Cancer Cell lines and Tissues. Int J Mol Sci 2022; 23:ijms23169302. [PMID: 36012568 PMCID: PMC9409321 DOI: 10.3390/ijms23169302] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) acts as an oncogenic transcription factor in human malignant tumors, including colon and prostate cancer. However, most of the ZKSCAN3-induced carcinogenic mechanisms remain unknown. In this study, we identified ZKSCAN3 as a downstream effector of the oncogenic Wnt/β-catenin signaling pathway, using RNA sequencing and ChIP analyses. Activation of the Wnt pathway by recombinant Wnt gene family proteins or the GSK inhibitor, CHIR 99021 upregulated ZKSCAN3 expression in a β-catenin-dependent manner. Furthermore, ZKSCAN3 upregulation suppressed the expression of the mitotic spindle checkpoint protein, Mitotic Arrest Deficient 2 Like 2 (MAD2L2) by inhibiting its promoter activity and eventually inducing chromosomal instability in colon cancer cells. Conversely, deletion or knockdown of ZKSCAN3 increased MAD2L2 expression and delayed cell cycle progression. In addition, ZKSCAN3 upregulation by oncogenic WNT/β-catenin signaling is an early event of the adenoma–carcinoma sequence in colon cancer development. Specifically, immunohistochemical studies (IHC) were performed using normal (NM), hyperplastic polyps (HPP), adenomas (AD), and adenocarcinomas (AC). Their IHC scores were considerably different (61.4 in NM; 88.4 in HPP; 189.6 in AD; 246.9 in AC). In conclusion, ZKSCAN3 could be responsible for WNT/β-catenin-induced chromosomal instability in colon cancer cells through the suppression of MAD2L2 expression.
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24
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Huang HC, Shiu BH, Nassef Y, Huang CC, Chou YE, Ting WC, Chang LC, Lin JC, Hsiao LK, Yang SF, Su SC. Impact of carbonic anhydrase 9 gene polymorphism on the progression of colorectal cancer. J Cancer 2022; 13:2775-2780. [PMID: 35812185 PMCID: PMC9254877 DOI: 10.7150/jca.73898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/02/2022] [Indexed: 11/20/2022] Open
Abstract
Colorectal cancer (CRC) is a commonly occurring tumor type worldwide, and its development is governed by a connection between genetic variations and acquired factors. Carbonic anhydrase 9 (CA9) is a cell-surface pH modulator that has been demonstrated to contribute to key steps of cancer progression. Here, we attempted to interrogate the effect of CA9 gene polymorphisms on the development of CRC in 470 cases and 470 gender- and age-matched non-cancer controls. We found that none of three CA9 single-nucleotide polymorphisms (SNPs) tested, including rs2071676, rs3829078, and rs1048638, was significantly associated with the occurrence of CRC. Yet, while evaluating the clinicopathological variables, cases carrying at least one reference allele (G allele) of rs2071676 tended to develop poorly differentiated tumors less frequently than those who are homozygous for the alternative allele (A allele) of rs2071676 (GA+GG vs AA; OR, 0.483; 95% CI, 0.242-0.963; p=0.036). Further stratification revealed that as compared to homozygous carriers of the alternative allele (AA), cases of colon cancer bearing at least one reference allele of rs2071676 (GA+GG) less frequently developed poorly differentiated tumors (OR, 0.449; 95% CI, 0.221-0.911; p=0.024) and lymphovascular invasion (OR, 0.570; 95% CI, 0.361-0.900; p=0.015). Such genetic effect was exclusively observed in colon cancer but not in rectal cancer. Our results indicate an anatomical site-specific impact of CA9 gene polymorphisms on modulating the progression of colorectal malignancies.
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Affiliation(s)
- Hsien-Cheng Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Emergency Medicine, Kuang Tien General Hospital, Taichung, Taiwan
| | - Bei-Hao Shiu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yasser Nassef
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chi-Chou Huang
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ying-Erh Chou
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Wen-Chien Ting
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Lun-Ching Chang
- Department of Mathematical Sciences, Florida Atlantic University, Florida, USA
| | - Jian-Cheng Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | | | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.,Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan
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25
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Sjöstedt S, Vieira FG, Karnov K, Agander TK, Willemoe GL, Rohrberg KS, Nielsen FC, von Buchwald C. Differences in gene expression despite identical histomorphology in sinonasal intestinal-type adenocarcinoma and metastases from colorectal adenocarcinoma. APMIS 2022; 130:551-559. [PMID: 35662259 DOI: 10.1111/apm.13252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
Sinonasal intestinal-type adenocarcinoma (sITAC) is histomorphologically indistinguishable from colorectal adenocarcinoma (CRC) leading to diagnostic challenges. Metastases from CRCs to the sinonasal tract have been reported. The aim of the study was to identify a biomarker making it possible to distinguish between sITAC and metastases of colorectal origin. Formalin-fixated paraffin-embedded (FFPE) tissue from 20 consecutive patients with sITAC treated at Rigshospitalet, Denmark from 2005 to 2017, 20 patients with CRC, and second patients with both sinonasal and colorectal carcinomas were included, and RNA-sequencing was performed on all samples. Moreover, a series of 26 samples from metastasizing CRC were included (in-house data). 3139 differentially expressed genes were identified, of these several were deemed as possible biomarkers, including CSDE1, for which immunohistochemical staining was performed. sITAC and CRC differ in genomic expression. CSDE1, previously found upregulated in CRC, was significantly differentially expressed. Using immunohistochemical staining, no sITACs displayed strong and diffuse staining for CSDE1, which represents a potential marker to use in distinguishing sITAC from a metastasis of colorectal origin. This knowledge could improve the diagnostic process and hopefully the outcome in patients with this rare tumor.
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Affiliation(s)
- Sannia Sjöstedt
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Kirstine Karnov
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Gro Linno Willemoe
- Department of Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Finn Cilius Nielsen
- Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Copenhagen University Hospital, Copenhagen, Denmark
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26
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Nakamura F, Sato Y, Okamoto K, Fujino Y, Mitsui Y, Kagemoto K, Kawaguchi T, Miyamoto H, Muguruma N, Sonoda T, Tsuneyama K, Takayama T. Colorectal carcinoma occurring via the adenoma-carcinoma pathway in patients with serrated polyposis syndrome. J Gastroenterol 2022; 57:286-299. [PMID: 35194694 DOI: 10.1007/s00535-022-01858-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 02/02/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS. METHODS We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues. RESULTS Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75-23) HPs, 4.0 (2.0-6.0) SSLs, 0 (0-0) TSA, and 1 (0-3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma-carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma-carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC. CONCLUSIONS Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma-carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.
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Affiliation(s)
- Fumika Nakamura
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasuteru Fujino
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kaizo Kagemoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tomoko Sonoda
- Department of Public Health, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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Roberto M, Arrivi G, Pilozzi E, Montori A, Balducci G, Mercantini P, Laghi A, Ierinò D, Panebianco M, Marinelli D, Tomao S, Marchetti P, Mazzuca F. The Potential Role of Genomic Signature in Stage II Relapsed Colorectal Cancer (CRC) Patients: A Mono-Institutional Study. Cancer Manag Res 2022; 14:1353-1369. [PMID: 35418781 PMCID: PMC9000544 DOI: 10.2147/cmar.s342612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose The absolute benefit of adjuvant chemotherapy in stage II CRC is only 3–4%. The identification of biomarkers through molecular profiling could identify patients who will more benefit from adjuvant chemotherapy. Patients and Methods This retrospective analysis examined tissue blocks from 17 patients affected by relapsed stage II CRC, whose comprehensive genomic profiling of tumors was conducted through next-generation sequencing (NGS) via Roche-FoundationOne®. Results Mutations were found in APC (76.5%), TP53 (58.8%) and KRAS (52.9%). Only KRAS wild-type samples showed FBXW7. APC frameshift mutations and MLH1 splice variant were conversely significant correlated (7% v 93%, P = 0.014). The median number of gene mutations reported was 6 (range 2–14). The TP53 mutation was associated most frequently with lung metastasis (P = 0.07) and high tumor budding (P = 0.03). Despite no statistical significance, lung recurrence, LVI/Pni, MSI and more than 6 genetic mutations were correlated to worse DFS and OS. Patients carried co-mutations of TP53-FBXW7 reported the worse DFS (4 v 14 months) and OS (4 v 65 months) compared to the other patients. Conclusion According to the present analysis, the setting of relapsed CRC emerges as one of the fields of greatest utility for NGS, looking at personalized cancer care.
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Affiliation(s)
- Michela Roberto
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy
| | - Giulia Arrivi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Rome, Italy
- Correspondence: Giulia Arrivi, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Via di Grottarossa 1035-1039, Rome, 00189, Italy, Tel +39 3387231524, Fax +39 0633776629, Email
| | - Emanuela Pilozzi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Anatomia Patologica Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Andrea Montori
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Anatomia Patologica Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Genoveffa Balducci
- Department of Medical-Surgical Sciences and Translation Medicine, Sapienza University of Rome, Gastro-intestinal Surgery Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Paolo Mercantini
- Department of Medical-Surgical Sciences and Translation Medicine, Sapienza University of Rome, Gastro-intestinal Surgery Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Andrea Laghi
- Department of Medical-Surgical Sciences and Translation Medicine, Sapienza University of Rome, Radiology Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Debora Ierinò
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Martina Panebianco
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Daniele Marinelli
- Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy
| | - Paolo Marchetti
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Rome, Italy
| | - Federica Mazzuca
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea University Hospital, Rome, Italy
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Bagaria J, Kim KO, Bagyinszky E, An SSA, Baek JH. Discriminating Potential Genetic Markers for Complete Response and Non-Complete Response Patients to Neoadjuvant Chemotherapy with Locally Advanced Rectal Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19074008. [PMID: 35409691 PMCID: PMC8997875 DOI: 10.3390/ijerph19074008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 02/07/2023]
Abstract
Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is considered standard therapy for locally advanced rectal cancer. Unfortunately, most patients with rectal cancer are resistant to radiotherapy. This might be a genetic cause. The role of certain rectal cancer-causing genes has not been completely elucidated. This study aims to investigate the genes responsible for locally advanced rectal cancer patients not reacting to radiotherapy. Methods: Whole exome sequencing of the DNA samples was performed on the samples. Bioinformatic analysis on the subjects was established. Individual genetic information was screened to identify differently expressed genes that more frequently appeared in non-complete response (NCR) compared to complete response (CR) patients after nCRT. All variations were verified by Sanger sequencing. Results: Genotyping information and pathway analyses of the samples indicated genes such as FLCN, CALML5, and ANTXR1 to be commonly mutated in CR group, whereas genes such as GALNTL14, CNKSR1, ACD, and CUL3 were more commonly mutated in the NCR group. Chi-square test revealed some significant variants (<0.05) such as rs3744124 (FLCN), rs28365986 (ANTXR1), rs10904516 (CALML5), rs3738952 (CUL3), rs13394 and rs2293013 (PIH1D1), rs2274531 (GPA33), rs4963048 (BRSK2), rs17883366 (IL3RA), rs2297575 (PSMD5), rs2288101 (GALNT14), and rs11954652 (DCTN4). Conclusion: Identifying an array of genes that separate NCRs from CRs would lead to finding genetic biomarkers for early detection of rectal cancer patients that are resistant to nCRT. A further investigation to validate the significance of genetic biomarkers to segregate NCRs from CRs should be performed with a larger CRC dataset. Protein expression levels, as well as transcriptomic analysis, would also help us understand the mechanism of how these genes could play a role in preventing radiation therapy to patients. This would be essential to prevent redundant radiation therapy.
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Affiliation(s)
- Jaya Bagaria
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
| | - Kyung-Ok Kim
- Gachon Medical Research Institute, Gil Medical Center, Gachon University, Incheon 21565, Korea;
| | - Eva Bagyinszky
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
| | - Seong Soo A. An
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
- Correspondence: (S.S.A.A.); (J.-H.B.); Tel.: +82-10-4344-9633 (S.S.A.A.); +82-10-5248-6656 (J.-H.B.)
| | - Jeong-Heum Baek
- Division of Colon and Rectal Surgery, Department of Surgery, Gil Medical Center, College of Medicine, Gachon University, Incheon 21565, Korea
- Correspondence: (S.S.A.A.); (J.-H.B.); Tel.: +82-10-4344-9633 (S.S.A.A.); +82-10-5248-6656 (J.-H.B.)
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Youssef ASED, Abdel-Fattah MA, Lotfy MM, Nassar A, Abouelhoda M, Touny AO, Hassan ZK, Mohey Eldin M, Bahnassy AA, Khaled H, Zekri ARN. Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience. Curr Issues Mol Biol 2022; 44:1332-1352. [PMID: 35723313 PMCID: PMC8947625 DOI: 10.3390/cimb44030090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 12/11/2022] Open
Abstract
This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.
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Affiliation(s)
- Amira Salah El-Din Youssef
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Mai M. Lotfy
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Auhood Nassar
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Ahmed O. Touny
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Zeinab K. Hassan
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Mohammed Mohey Eldin
- Tropical Medicine Department, El Kasr Al-Aini, Cairo University, Cairo 11562, Egypt;
| | - Abeer A. Bahnassy
- Molecular Pathology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Hussein Khaled
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Abdel Rahman N. Zekri
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
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Yuan K, Zeng T, Chen L. Interpreting Functional Impact of Genetic Variations by Network QTL for Genotype–Phenotype Association Study. Front Cell Dev Biol 2022; 9:720321. [PMID: 35155440 PMCID: PMC8826544 DOI: 10.3389/fcell.2021.720321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 12/13/2021] [Indexed: 12/18/2022] Open
Abstract
An enormous challenge in the post-genome era is to annotate and resolve the consequences of genetic variation on diverse phenotypes. The genome-wide association study (GWAS) is a well-known method to identify potential genetic loci for complex traits from huge genetic variations, following which it is crucial to identify expression quantitative trait loci (eQTL). However, the conventional eQTL methods usually disregard the systematical role of single-nucleotide polymorphisms (SNPs) or genes, thereby overlooking many network-associated phenotypic determinates. Such a problem motivates us to recognize the network-based quantitative trait loci (QTL), i.e., network QTL (nQTL), which is to detect the cascade association as genotype → network → phenotype rather than conventional genotype → expression → phenotype in eQTL. Specifically, we develop the nQTL framework on the theory and approach of single-sample networks, which can identify not only network traits (e.g., the gene subnetwork associated with genotype) for analyzing complex biological processes but also network signatures (e.g., the interactive gene biomarker candidates screened from network traits) for characterizing targeted phenotype and corresponding subtypes. Our results show that the nQTL framework can efficiently capture associations between SNPs and network traits (i.e., edge traits) in various simulated data scenarios, compared with traditional eQTL methods. Furthermore, we have carried out nQTL analysis on diverse biological and biomedical datasets. Our analysis is effective in detecting network traits for various biological problems and can discover many network signatures for discriminating phenotypes, which can help interpret the influence of nQTL on disease subtyping, disease prognosis, drug response, and pathogen factor association. Particularly, in contrast to the conventional approaches, the nQTL framework could also identify many network traits from human bulk expression data, validated by matched single-cell RNA-seq data in an independent or unsupervised manner. All these results strongly support that nQTL and its detection framework can simultaneously explore the global genotype–network–phenotype associations and the underlying network traits or network signatures with functional impact and importance.
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Affiliation(s)
- Kai Yuan
- Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Tao Zeng
- Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- Guangzhou Laboratory, Guangzhou, China
- *Correspondence: Tao Zeng, ; Luonan Chen,
| | - Luonan Chen
- Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
- *Correspondence: Tao Zeng, ; Luonan Chen,
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31
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Kim IH, Eom T, Park JY, Kim HJ, Nam TJ. Dichloromethane fractions of Calystegia soldanella induce S‑phase arrest and apoptosis in HT‑29 human colorectal cancer cells. Mol Med Rep 2021; 25:60. [PMID: 34935054 PMCID: PMC8767546 DOI: 10.3892/mmr.2021.12576] [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: 09/08/2021] [Accepted: 11/11/2021] [Indexed: 11/22/2022] Open
Abstract
Calystegia soldanella is a halophyte and a perennial herb that grows on coastal sand dunes worldwide. Extracts from this plant have been previously revealed to have a variety of bioactive properties in humans. However, their effects on colorectal cancer cells remain poorly understood. In the present study, the potential biological activity of C. soldanella extracts in the colorectal cancer cell line HT-29 was examined. First, five solvent fractions [n-hexane, dichloromethane (DCM), ethyl acetate, n-butanol and water] were obtained from the crude extracts of C. soldanella through an organic solvent extraction method. In particular, the DCM fraction was demonstrated to exert marked dose- and time-dependent inhibitory effects according to results from the cell viability assay. Data obtained from the apoptosis assay suggested that the inhibition of HT-29 cell viability induced by DCM treatment was attributed to increased apoptosis. The apoptotic rate was markedly increased in a dose-dependent manner, which was associated with the protein expression levels of apoptosis-related proteins, including increased Fas, Bad and Bax, and decreased pro-caspase-8, Bcl-2, Bcl-xL, pro-caspase-9, pro-caspase-7 and pro-caspase-3. A mitochondrial membrane potential assay demonstrated that more cells became depolarized and the extent of cytochrome c release was markedly increased in a dose-dependent manner in HT-29 cells treated with DCM. In addition, cell cycle analysis confirmed S-phase arrest following DCM fraction treatment, which was associated with decreased protein expression levels of cell cycle-related proteins, such as cyclin A, CDK2, cell division cycle 25 A and cyclin dependent kinase inhibitor 1. Based on these results, the present study suggested that the DCM fraction of the C. soldanella extract can inhibit HT-29 cell viability whilst inducing apoptosis through mitochondrial membrane potential regulation and S-phase arrest. These results also suggested that the DCM fraction has potential anticancer activity in HT-29 colorectal cells. Further research on the composition of the DCM fraction is warranted.
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Affiliation(s)
- In-Hye Kim
- Future Fisheries Food Research Center, Institute of Fisheries Sciences, Pukyong National University, Busan 46041, Republic of Korea
| | - Taekil Eom
- Future Fisheries Food Research Center, Institute of Fisheries Sciences, Pukyong National University, Busan 46041, Republic of Korea
| | - Joon-Young Park
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Republic of Korea
| | - Hyung-Joo Kim
- Future Fisheries Food Research Center, Institute of Fisheries Sciences, Pukyong National University, Busan 46041, Republic of Korea
| | - Taek-Jeong Nam
- Future Fisheries Food Research Center, Institute of Fisheries Sciences, Pukyong National University, Busan 46041, Republic of Korea
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32
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Zhao S, Zhou L, Dicker DT, Lev A, Zhang S, Ross E, El-Deiry WS. Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90. Sci Rep 2021; 11:20871. [PMID: 34686682 PMCID: PMC8536770 DOI: 10.1038/s41598-021-00150-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 09/27/2021] [Indexed: 12/23/2022] Open
Abstract
A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O2 oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) and heat shock protein 90 (HSP90). We show that CDK1 may contribute to HSP90-mediated HIF1α stabilization. CDK1 knockdown enhances the decrease of HIF1α by HSP90 inhibition. Dual inhibition of CDK1 and HSP90 significantly increases apoptosis and synergistically inhibits cancer cell viability. Similarly, targeting CDK4/6 using FDA-approved inhibitors in combination with HSP90 inhibition shows a class effect on HIF1α inhibition and cancer cell viability suppression not only in colorectal but also in various other cancer types, including Rb-deficient cancer cells. Dual inhibition of CDK4/6 and HSP90 suppresses tumor growth in vivo. In summary, combined targeting of CDK(s) (CDK1 or CDK4/6) and HSP90 remarkably inhibits the expression level of HIF1α and shows promising anti-cancer efficacy with therapeutic potential.
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Affiliation(s)
- Shuai Zhao
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA.,Pathobiology Graduate Program, Brown University, Providence, RI, USA.,Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.,Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA
| | - Lanlan Zhou
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA.,Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.,Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA.,Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - David T Dicker
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA.,Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.,Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA
| | - Avital Lev
- Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA.,Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.,Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA.,Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Eric Ross
- Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA. .,Pathobiology Graduate Program, Brown University, Providence, RI, USA. .,Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA. .,Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA. .,Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI, USA. .,Fox Chase Cancer Center, Philadelphia, PA, USA. .,Hematology/Oncology Division, Lifespan Cancer Institute, Providence, RI, USA.
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The Effect of Different Ester Chain Modifications of Two Guaianolides for Inhibition of Colorectal Cancer Cell Growth. Molecules 2021; 26:molecules26185481. [PMID: 34576952 PMCID: PMC8469367 DOI: 10.3390/molecules26185481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/10/2021] [Accepted: 08/17/2021] [Indexed: 12/24/2022] Open
Abstract
Several sesquiterpene lactones (STLs) have been tested as lead drugs in cancer clinical trials. Salograviolide-A (Sal-A) and salograviolide-B (Sal-B) are two STLs that have been isolated from Centaurea ainetensis, an indigenous medicinal plant of the Middle Eastern region. The parent compounds Sal-A and Sal-B were modified and successfully prepared into eight novel guaianolide-type STLs (compounds 1-8) bearing ester groups of different geometries. Sal-A, Sal-B, and compounds 1-8 were tested against a human colorectal cancer cell line model with differing p53 status; HCT116 with wild-type p53 and HCT116 p53-/- null for p53, and the normal-like human colon mucosa cells with wild-type p53, NCM460. IC50 values indicated that derivatization of Sal-A and Sal-B resulted in potentiation of HCT116 cell growth inhibition by 97% and 66%, respectively. The effects of the different molecules on cancer cell growth were independent of p53 status. Interestingly, the derivatization of Sal-A and Sal-B molecules enhanced their anti-growth properties versus 5-Fluorouracil (5-FU), which is the drug of choice in colorectal cancer. Structure-activity analysis revealed that the enhanced molecule potencies were mainly attributed to the position and number of the hydroxy groups, the lipophilicity, and the superiority of ester groups over hydroxy substituents in terms of their branching and chain lengths. The favorable cytotoxicity and selectivity of the potent molecules, to cancer cells versus their normal counterparts, pointed them out as promising leads for anti-cancer drug design.
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34
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Zhang W, Sun R, Zhang Y, Hu R, Li Q, Wu W, Cao X, Zhou J, Pei J, Yuan P. Cabazitaxel suppresses colorectal cancer cell growth via enhancing the p53 antitumor pathway. FEBS Open Bio 2021; 11:3032-3050. [PMID: 34496154 PMCID: PMC8564099 DOI: 10.1002/2211-5463.13290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/15/2021] [Accepted: 09/07/2021] [Indexed: 11/25/2022] Open
Abstract
There were approximately 1.93 million new cases and 940 000 deaths from colorectal cancer in 2020. The first‐line chemotherapeutic drugs for colorectal cancer are mainly based on 5‐fluorouracil, although the use of these drugs is limited by the development of drug resistance. Consequently, there is a need for novel chemotherapeutic drugs for the efficient treatment of colorectal cancer patients. In the present study, we screened 160 drugs approved by the Food and Drug Administration and identified that cabazitaxel (CBT), a microtube inhibitor, can suppress colony formation and cell migration of colorectal cancer cells in vitro. CBT also induces G2/M phase arrest and apoptosis of colorectal cancer cells. Most importantly, it inhibits the growth of colorectal cancer cell xenograft tumors in vivo. Transcriptome analysis by RNA‐sequencing revealed that Tub family genes are abnormally expressed in CBT‐treated colorectal cancer cells. The expression of several p53 downstream genes that are associated with cell cycle arrest, apoptosis, and inhibition of angiogenesis and metastasis is induced by CBT in colorectal cancer cells. Overall, our results suggests that CBT suppresses colorectal cancer by upregulating the p53 pathway, and thus CBT may have potential as an alternative chemotherapeutic drug for colorectal cancer.
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Affiliation(s)
- Wen Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Ruiqian Sun
- Guangdong Country Garden School, Foshan City, China
| | - Yongjun Zhang
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Rong Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Qian Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Weili Wu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Xinyu Cao
- Institute of Clinical Medical Sciences,， Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jiajian Zhou
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Jianfeng Pei
- Center for Quantitative Biology,， Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Ping Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
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35
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Synthetic Evaluation of MicroRNA-1-3p Expression in Head and Neck Squamous Cell Carcinoma Based on Microarray Chips and MicroRNA Sequencing. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6529255. [PMID: 34485523 PMCID: PMC8410410 DOI: 10.1155/2021/6529255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/09/2021] [Indexed: 11/20/2022]
Abstract
Background MicroRNA-1-3p (miR-1-3p) exerts significant regulation in various tumor cells, but its molecular mechanisms in head and neck squamous cell carcinoma (HNSCC) are still ill defined. This study is aimed at detecting the expression of miR-1-3p in HNSCC and at determining its significant regulatory pathways. Methods Data were obtained from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Oncomine, ArrayExpress, Sequence Read Archive (SRA) databases, and additional literature. Expression values of miR-1-3p in HNSCC were analyzed comprehensively. The R language software was employed to screen differentially expressed genes, and bioinformatics assessment was performed. One sequence dataset (HNSCC: n = 484; noncancer: n = 44) and 18 chip datasets (HNSCC: n = 656; noncancer: n = 199) were obtained. Results The expression of miR-1-3p in HNSCC was visibly decreased in compare with noncancerous tissues. There were distinct differences in tumor state (P = 0.0417), pathological stage (P = 0.0058), and T stage (P = 0.0044). Comprehensive analysis of sequence and chip data also indicated that miR-1-3p was lowly expressed in HNSCC. The diagnostic performance of miR-1-3p in HNSCC is reflected in the sensitivity and specificity of the collection, etc. Bioinformatics analysis showed the possible biological process, cellular component, molecular function, and KEGG pathways of miR-1-3p in HNSCC. And ITGB4 was a possible target of miR-1-3p. Conclusions miR-1-3p's low expression may facilitate tumorigenesis and evolution in HNSCC through signaling pathways. ITGB4 may be a key gene in targeting pathways but still needs verification through in vitro experiments.
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Sabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-β in Gastrointestinal Tumors. Cancers (Basel) 2021; 13:cancers13163960. [PMID: 34439114 PMCID: PMC8391793 DOI: 10.3390/cancers13163960] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The transforming growth factor β signaling pathway elicits a broad range of physiological re-sponses, and its misregulation has been related to cancer. The secreted cytokine TGFβ exerts a tumor-suppressive effect that counteracts malignant transformation. However, once tumor has developed, TGFβ can support tumor progression regulating epithelial to mesenchymal transition, invasion and metastasis, stimulating fibrosis, angiogenesis and immune suppression. Here we review the dichotomous role of TGF-β in the progression of gastrointestinal tumors, as well as its intricate crosstalk with other signaling pathways. We also discuss about the therapeutic strate-gies that are currently explored in clinical trials to counteract TGF-β functions. Abstract Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.
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Affiliation(s)
- Fabio Sabbadini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Monica Bertolini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena De Matteis
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, University of Bologna, 40126 Bologna, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
- Correspondence:
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Ziranu P, Lai E, Schirripa M, Puzzoni M, Persano M, Pretta A, Munari G, Liscia N, Pusceddu V, Loupakis F, Demurtas L, Libertini M, Mariani S, Migliari M, Dubois M, Giampieri R, Sotgiu G, Dei Tos AP, Lonardi S, Zaniboni A, Fassan M, Scartozzi M. The Role of p53 Expression in Patients with RAS/BRAF Wild-Type Metastatic Colorectal Cancer Receiving Irinotecan and Cetuximab as Later Line Treatment. Target Oncol 2021; 16:517-527. [PMID: 33970400 PMCID: PMC8266772 DOI: 10.1007/s11523-021-00816-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2021] [Indexed: 11/05/2022]
Abstract
BACKGROUND Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. OBJECTIVE In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. PATIENTS AND METHODS p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan-Meier method, while the log-rank test was used for survival comparison. RESULTS Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. CONCLUSIONS In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients.
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Affiliation(s)
- Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Marta Schirripa
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Giada Munari
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Fotios Loupakis
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | | | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy
| | - Riccardo Giampieri
- Medical Oncology Unit, University Hospital and Università Politecnica delle Marche, Ancona, Italy
| | - Giovanni Sotgiu
- Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Angelo Paolo Dei Tos
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, S.S. 554 Bivio per Sestu Km 4, 500, 09042, Monserrato, Cagliari, Italy.
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Inoue A, Robinson FS, Minelli R, Tomihara H, Rizi BS, Rose JL, Kodama T, Srinivasan S, Harris AL, Zuniga AM, Mullinax RA, Ma X, Seth S, Daniele JR, Peoples MD, Loponte S, Akdemir KC, Khor TO, Feng N, Roszik J, Sobieski MM, Brunell D, Stephan C, Giuliani V, Deem AK, Shingu T, Deribe YL, Menter DG, Heffernan TP, Viale A, Bristow CA, Kopetz S, Draetta GF, Genovese G, Carugo A. Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer. Gastroenterology 2021; 161:196-210. [PMID: 33745946 PMCID: PMC8238881 DOI: 10.1053/j.gastro.2021.03.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 02/24/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
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Affiliation(s)
- Akira Inoue
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan.
| | - Frederick S Robinson
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rosalba Minelli
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hideo Tomihara
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bahar Salimian Rizi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Johnathon L Rose
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Sanjana Srinivasan
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela L Harris
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andy M Zuniga
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Mullinax
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaoyan Ma
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sahil Seth
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joseph R Daniele
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael D Peoples
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sara Loponte
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kadir C Akdemir
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tin Oo Khor
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jason Roszik
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mary M Sobieski
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - David Brunell
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Clifford Stephan
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Virginia Giuliani
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela K Deem
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takashi Shingu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yonathan Lissanu Deribe
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Timothy P Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher A Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giulio F Draetta
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giannicola Genovese
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Alessandro Carugo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lepore Signorile M, Disciglio V, Di Carlo G, Pisani A, Simone C, Ingravallo G. From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome. Int J Mol Sci 2021; 22:ijms22136767. [PMID: 34201893 PMCID: PMC8268977 DOI: 10.3390/ijms22136767] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/30/2022] Open
Abstract
Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype.
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Affiliation(s)
- Martina Lepore Signorile
- Medical Genetics, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (M.L.S.); (V.D.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (M.L.S.); (V.D.)
| | - Gabriella Di Carlo
- Department of Emergency and Organ Transplantation, Section of Pathology, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Antonio Pisani
- Gastroenterology and Digestive Endoscopy Unit, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Cristiano Simone
- Medical Genetics, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (M.L.S.); (V.D.)
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy
- Correspondence: (C.S.); (G.I.)
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathology, University of Bari Aldo Moro, 70124 Bari, Italy;
- Correspondence: (C.S.); (G.I.)
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Evaluation of photodynamic effect of Indocyanine green (ICG) on the colon and glioblastoma cancer cell lines pretreated by cold atmospheric plasma. Photodiagnosis Photodyn Ther 2021; 35:102408. [PMID: 34171459 DOI: 10.1016/j.pdpdt.2021.102408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/03/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cold Atmospheric Plasma (CAP) has been proposed as a new approach based on its anticancer potential. However, its biological effects in combination with other physical modalities may also enhance efficiency and expand the applicability of the CAP method Photodynamic Therapy (PDT) may be improved by the use of indocyanine green (ICG) photosensitizer with absorption wavelength in the near infrared region to allow for deeper treatment depth.. In this study, the effectiveness of cold atmospheric helium plasma (He-CAP) as a pretreatment on the efficiency of ICG mediated PDT was investigated. METHODS AND MATERIAL First, toxicity of different concentrations of ICG on HT-29 and U-87MG cell lines was examined for 24 h. IC10 and IC30 of ICG were determined and then cells were treated with this ICG concentrations with different plasma radiation doses and light exposures for 48 h. Finally, MTT assay was performed for all treatment groups. The experiments were repeated at least 4 times at each group for two cell lines, separately. In order to compare the results, several indicators such as treatment efficiency, synergistic ratio, and the amount of optical exposure required for 50% cell death (ED50) were also defined. Finally, SPSS 20 software is used for statistical analysis of data. RESULTS Pretreatment with CAP could significantly reduce cell survival in both cell lines (P<0.05). Also concentrations, irradiation time with CAP, and appropriate light exposure in both cell lines increased therapeutic efficiency compared to either treatment alone (P<0.05). While increasing the efficiency of photodynamic therapy varied between the two cell lines, the improvement in the PDT process was demonstrated by pretreatment with CAP. CONCLUSION Synergistic effect in the cell death with PDT were observed following He-CAP treatment and the results indicated that pretreatment with He-CAP improves the efficiency of photodynamic therapy.
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Shiu BH, Hsieh MH, Ting WC, Chou MC, Chang LC, Huang CC, Su SC, Yang SF. Impact of FGFR4 Gene Polymorphism on the Progression of Colorectal Cancer. Diagnostics (Basel) 2021; 11:diagnostics11060978. [PMID: 34071523 PMCID: PMC8227855 DOI: 10.3390/diagnostics11060978] [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: 03/30/2021] [Revised: 05/19/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG; AOR, 0.236; p = 0.046) or rs351855 (GA and AA; AOR, 0.191; p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.
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Affiliation(s)
- Bei-Hao Shiu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Ming-Hong Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Wen-Chien Ting
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Lun-Ching Chang
- Department of Mathematical Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA;
| | - Chi-Chou Huang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Correspondence: (C.-C.H.); (S.-C.S.); (S.-F.Y.)
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung 204, Taiwan
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou 333, Taiwan
- Correspondence: (C.-C.H.); (S.-C.S.); (S.-F.Y.)
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-H.S.); (M.-H.H.); (W.-C.T.); (M.-C.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Correspondence: (C.-C.H.); (S.-C.S.); (S.-F.Y.)
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42
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Li XL, Zhou J, Xia CJ, Min H, Lu ZK, Chen ZR. PRIMA‑1 met induces autophagy in colorectal cancer cells through upregulation of the mTOR/AMPK‑ULK1‑Vps34 signaling cascade. Oncol Rep 2021; 45:86. [PMID: 33846805 PMCID: PMC8025076 DOI: 10.3892/or.2021.8037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/05/2021] [Indexed: 12/26/2022] Open
Abstract
p53‑reactivation and induction of massive apoptosis‑1, APR‑017 methylated (PRIMA‑1met; APR246) targets mutant p53 to restore its wild‑type structure and function. It was previously demonstrated that PRIMA‑1met effectively inhibited the growth of colorectal cancer (CRC) cells in a p53‑independent manner, and distinctly induced apoptosis by upregulating Noxa in p53‑mutant cell lines. The present study including experiments of western blotting, acridine orange staining and transmission electron microscopy revealed that PRIMA‑1met induced autophagy in CRC cells independently of p53 status. Importantly, PRIMA‑1met not only promoted autophagic vesicle (AV) formation and AV‑lysosome fusion, but also increased lysosomal degradation. Furthermore, Cell Counting Kit‑8 assay, colony formation assay and small interfering RNA transfection were performed to investigate the underling mechanisms. The study indicated that activation of the mTOR/AMPK‑ULK1‑Vps34 autophagic signaling cascade was key for PRIMA‑1met‑induced autophagy. Additionally, autophagy served a crucial role in the inhibitory effect of PRIMA‑1met in cells harboring wild‑type p53, which was closely associated with the increased expression of Noxa. Taken together, the results determined the effect of PRIMA‑1met on autophagy, and further revealed mechanistic insights into different CRC cell lines. It was concluded that PRIMA‑1met‑based therapy may be an effective strategy for CRC treatment.
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Affiliation(s)
- Xiao-Lan Li
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
| | - Chen-Jing Xia
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Kunshan, Suzhou, Jiangsu 215300, P.R. China
| | - Han Min
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Zhong-Kai Lu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Zhi-Rong Chen
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
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43
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Xuan Y, Zhao S, Xiao X, Xiang L, Zheng HC. Inhibition of chaperone‑mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer. Mol Med Rep 2021; 23:360. [PMID: 33760140 PMCID: PMC7974415 DOI: 10.3892/mmr.2021.11999] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Chaperone-mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines. In engineered 5-FU-resistant CRC cell lines, a significant elevation of lysosome-associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5-FU resistance and to enhance PLD2 expression through the activation of NF-κB pathway. Accordingly, loss or gain of function of LAMP2A in 5-FU-resistant CRC cells rendered them sensitive or resistant to 5-FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5-FU treatment and anti-CMA therapy may be a novel therapeutic option for patients with CRC.
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Affiliation(s)
- Ying Xuan
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Shuang Zhao
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xingjun Xiao
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Liwei Xiang
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Hua-Chuan Zheng
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Naseer M, Hadi S, Syed A, Safdari A, Tahan V. Exosomes: A new frontier under the spotlight for diagnosis and treatment of gastrointestinal diseases. World J Meta-Anal 2021; 9:12-28. [DOI: 10.13105/wjma.v9.i1.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/15/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
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Rajedadram A, Pin KY, Ling SK, Yan SW, Looi ML. Hydroxychavicol, a polyphenol from Piper betle leaf extract, induces cell cycle arrest and apoptosis in TP53-resistant HT-29 colon cancer cells. J Zhejiang Univ Sci B 2021; 22:112-122. [PMID: 33615752 DOI: 10.1631/jzus.b2000446] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
This study aims to elucidate the antiproliferative mechanism of hydroxychavicol (HC). Its effects on cell cycle, apoptosis, and the expression of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) in HT-29 colon cancer cells were investigated. HC was isolated from Piper betle leaf (PBL) and verified by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and gas chromatography-mass spectrometry (GC-MS). The cytotoxic effects of the standard drug 5-fluorouracil (5-FU), PBL water extract, and HC on HT-29 cells were measured after 24, 48, and 72 h of treatment. Cell cycle and apoptosis modulation by 5-FU and HC treatments were investigated up to 30 h. Changes in phosphorylated JNK (pJNK) and P38 (pP38) MAPK expression were observed up to 18 h. The half maximal inhibitory concentration (IC50) values of HC (30 μg/mL) and PBL water extract (380 μg/mL) were achieved at 24 h, whereas the IC50 of 5-FU (50 μmol/L) was obtained at 72 h. Cell cycle arrest at the G0/G1 phase in HC-treated cells was observed from 12 h onwards. Higher apoptotic cell death in HC-treated cells compared to 5-FU-treated cells (P<0.05) was observed. High expression of pJNK and pP38 MAPK was observed at 12 h in HC-treated cells, but not in 5-FU-treated HT-29 cells (P<0.05). It is concluded that HC induces cell cycle arrest and apoptosis of HT-29 cells, with these actions possibly mediated by JNK and P38 MAPK.
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Affiliation(s)
- Aiysvariyah Rajedadram
- School of Biosciences, Taylor's University, Lakeside Campus, 47500 Subang Jaya, Malaysia
| | - Kar Yong Pin
- Forest Research Institute Malaysia, 52109 Kepong, Malaysia
| | - Sui Kiong Ling
- Forest Research Institute Malaysia, 52109 Kepong, Malaysia
| | - See Wan Yan
- School of Biosciences, Taylor's University, Lakeside Campus, 47500 Subang Jaya, Malaysia
| | - Mee Lee Looi
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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46
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Ren Z, Rajani C, Jia W. The Distinctive Serum Metabolomes of Gastric, Esophageal and Colorectal Cancers. Cancers (Basel) 2021; 13:cancers13040720. [PMID: 33578739 PMCID: PMC7916516 DOI: 10.3390/cancers13040720] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/18/2021] [Accepted: 02/07/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Cancer of the stomach, esophagus and colon are often fatal. Ways are being sought to establish patient-friendly screening tests that would allow these cancers to be detected earlier. Examination of the metabolomics results of cancer patient’s serum for certain metabolites unique for a particular cancer was the goal of this review. From studies conducted within the past five years several metabolites were found to be changed in cancer compared to non-cancer patients for each of the three cancers. Further confirmation of what was discovered in this review coupled with establishment of standard protocols may allow for cancer screening on patient blood samples to become routine clinical tests. Abstract Three of the most lethal cancers in the world are the gastrointestinal cancers—gastric (GC), esophageal (EC) and colorectal cancer (CRC)—which are ranked as third, sixth and fourth in cancer deaths globally. Early detection of these cancers is difficult, and a quest is currently on to find non-invasive screening tests to detect these cancers. The reprogramming of energy metabolism is a hallmark of cancer, notably, an increased dependence on aerobic glycolysis which is often referred to as the Warburg effect. This metabolic change results in a unique metabolic profile that distinguishes cancer cells from normal cells. Serum metabolomics analyses allow one to measure the end products of both host and microbiota metabolism present at the time of sample collection. It is a non-invasive procedure requiring only blood collection which encourages greater patient compliance to have more frequent screenings for cancer. In the following review we will examine some of the most current serum metabolomics studies in order to compare their results and test a hypothesis that different tumors, notably, from EC, GC and CRC, have distinguishing serum metabolite profiles.
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Affiliation(s)
- Zhenxing Ren
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China;
| | - Cynthia Rajani
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
- Correspondence: (C.R.); or (W.J.)
| | - Wei Jia
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China;
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Correspondence: (C.R.); or (W.J.)
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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.
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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
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48
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Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications. Oncogene 2020; 40:1555-1569. [PMID: 33323976 DOI: 10.1038/s41388-020-01587-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 11/02/2020] [Accepted: 11/24/2020] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, however, the molecular mechanisms underlying the pathogenesis of CRC remain largely unclear. Recent studies have revealed crucial roles of transcription factors in CRC development. Transcription factors essential for the regulation of gene expression by interacting with transcription corepressor/enhancer complexes and they orchestrate downstream signal transduction. Deregulation of transcription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expression profiles play fundamental roles in multistep process of tumorigenesis, from cellular transformation, disease progression to metastatic disease. Herein, we summarized current and emerging key transcription factors that participate in CRC tumorigenesis, and highlighted their oncogenic or tumor suppressive functions. Moreover, we presented critical transcription factors of CRC, emphasized the major molecular mechanisms underlying their effect on signal cascades associated with tumorigenesis, and summarized of their potential as molecular biomarkers for CRC prognosis therapeutic response, as well as drug targets for CRC treatment. A better understanding of transcription factors involved in the development of CRC will provide new insights into the pathological mechanisms and reveal novel prognostic biomarkers and therapeutic strategies for CRC.
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49
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Xiang R, Fu T. Gastrointestinal adenocarcinoma analysis identifies promoter methylation-based cancer subtypes and signatures. Sci Rep 2020; 10:21234. [PMID: 33277583 PMCID: PMC7719188 DOI: 10.1038/s41598-020-78228-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/23/2020] [Indexed: 12/31/2022] Open
Abstract
Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality. Numerous studies have shown that its occurrence and progression are significantly related to abnormal DNA methylation, especially CpG island methylation. However, little is known about the application of DNA methylation in GAC and CAC. The methylation profiles were accessed from the Cancer Genome Atlas database to identify promoter methylation-based cancer subtypes and signatures for GAC and CAC. Six hypo-methylated clusters for GAC and six hyper-methylated clusters for CAC were separately generated with different OS profiles, tumor progression became worse as the methylation level decreased in GAC or increased in CAC, and hypomethylation in GAC and hypermethylation in CAC were negatively correlated with microsatellite instability. Additionally, the hypo- and hyper-methylated site-based signatures with high accuracy, high efficiency and strong independence can separately predict the OS of GAC and CAC patients. By integrating the methylation-based signatures with prognosis-related clinicopathologic characteristics, two clinicopathologic-epigenetic nomograms were cautiously established with strong predictive performance and high accuracy. Our research indicates that methylation mechanisms differ between GAC and CAC, and provides novel clinical biomarkers for the diagnosis and treatment of GAC and CAC.
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Affiliation(s)
- Renshen Xiang
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
- The Central Laboratory of the First Clinical College of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
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50
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Razzaque MS, Atfi A. TGIF1-Twist1 axis in pancreatic ductal adenocarcinoma. Comput Struct Biotechnol J 2020; 18:2568-2572. [PMID: 33005315 PMCID: PMC7520386 DOI: 10.1016/j.csbj.2020.09.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
TG-interacting factor 1 (TGIF1) exerts inhibitory effects on transforming growth factor-beta (TGF-β) signaling by suppressing Smad signaling pathway at multiple levels. TGIF1 activity is important for normal embryogenesis and organogenesis, yet its dysregulation can culminate in tumorigenesis. For instance, increased expression of TGIF1 correlates with poor prognosis in triple-negative breast cancer patients, and enforced expression of TGIF1 facilitates Wnt-driven mammary tumorigenesis, suggesting that TGIF1 might function as an oncoprotein. Quite surprisingly, TGIF1 has recently been shown to function as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC), possibly owing to its ability to antagonize the pro-malignant transcription factor Twist1. In this article, we will briefly elaborate on the biological and clinical significance of the unique tumor-suppressive function of TGIF1 and its functional interaction with Twist1 in the context of PDAC pathogenesis and progression.
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Affiliation(s)
- Mohammed S Razzaque
- Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
| | - Azeddine Atfi
- Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
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