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1
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Zhou Y, Ding Y, Xu B, Fei H, Wang Z. Genetically druggable targets for MAPK-activated colorectal cancer by a two-sample mendelian randomization analysis. Sci Rep 2025; 15:12239. [PMID: 40210889 PMCID: PMC11986099 DOI: 10.1038/s41598-024-82567-5] [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: 02/18/2024] [Accepted: 12/06/2024] [Indexed: 04/12/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.
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Affiliation(s)
- Yuxuan Zhou
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Yunlong Ding
- Department of Emergency General Surgery, Weifang People's Hospital, Weifang, Shandong, China
| | - Bangyue Xu
- Jilin Central General Hospital, Changchun, Jilin, China
| | - Hongyang Fei
- Department of Hepatobiliary and Pancreatic Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China.
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2
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Cheung D, Hassan MA, Huynh T, Feng X, Wang H. Shedding light on the role of complement C4 activation in cancer. Hum Immunol 2025; 86:111226. [PMID: 39732132 DOI: 10.1016/j.humimm.2024.111226] [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: 09/19/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 12/30/2024]
Abstract
Complement C4 is a key component in the activation of classical and lectin complement pathways, which are observed in both animal tumor models and cancer patients. While its role in autoimmune disorders has been extensively studied, the functions of complement C4 and its activation in cancer have received inadequate consideration. Recent studies have detected C4 activation in animal tumor models and cancer patients, with its fragment C4d found in cancer tissues and lymph nodes. Elevated C4d levels could be a useful biomarker for detecting various cancers. This review aims to summarize recent developments on the role of complement C4 activation in promoting an immunosuppressive tumor microenvironment, thereby supporting tumor progression and metastasis; C4d as a biomarker; and its potential as a target for cancer immunotherapy. We also conduct a critical evaluation of methods used to measure complement C4 and its activation products, highlighting possible pitfalls and areas for improvement in existing research.
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Affiliation(s)
| | | | | | - Xiaodong Feng
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA
| | - Hongbin Wang
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA.
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3
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Vallejos PA, Fuller RN, Kabagwira J, Kwong ML, Gonda A, McMullen JRW, Le N, Selleck MJ, Miller LD, Perry CC, Senthil M, Wall NR. Exosomal proteins as a source of biomarkers in colon cancer-derived peritoneal carcinomatosis - A pilot study. Proteomics Clin Appl 2023; 17:e2100085. [PMID: 36217952 DOI: 10.1002/prca.202100085] [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: 09/28/2021] [Revised: 09/25/2022] [Accepted: 10/07/2022] [Indexed: 03/15/2023]
Abstract
PURPOSE Peritoneal carcinomatosis (PC), metastasized from colorectal cancer (CRC), remains a highly lethal disease. Outcomes of PC is significantly influenced by the amount of intra-abdominal tumor burden and therefore diagnostic tests that facilitate earlier diagnosis could improve PC treatment and patient outcomes. EXPERIMENTAL DESIGN Using mass-spectrometry-based proteomics, we characterized the protein features of circulating exosomes in the context of CRC PC, CRC with liver metastasis, and primary CRC limited to the colon. We profiled exosomes isolated from patient plasma to identify exosome-associated protein cargoes released by these cancer types. RESULTS Analysis of the resulting data identified metastasis-specific exosome protein signatures. Bioinformatic analyses confirmed enrichment of proteins annotated to vesicle-associated processes and intracellular compartments, as well as representation of cancer hallmark functions and processes. CONCLUSION AND CLINICAL RELEVANCE This research yielded distinct protein profiles for the CRC patient groups and suggests the utility of plasma exosome proteomic analysis for a better understanding of PC development and metastasis.
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Affiliation(s)
- Paul A Vallejos
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Ryan N Fuller
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Janviere Kabagwira
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Mei Li Kwong
- Department of General Surgery, National Institutes of Health, Bethesda, Maryland, USA
| | - Amber Gonda
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA.,Department of Surgery, Division of Surgical Oncology, University of California at Irvine, Orange, California, USA
| | - James R W McMullen
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Natasha Le
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Matthew J Selleck
- Department of Surgery, Mountain View Hospital, Las Vegas, Nevada, USA
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Christopher C Perry
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Maheswari Senthil
- Department of Surgery, Division of Surgical Oncology, University of California at Irvine, Orange, California, USA
| | - Nathan R Wall
- Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda University Medical Center, Loma Linda, California, USA
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4
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Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis. Nat Commun 2022; 13:2757. [PMID: 35589723 PMCID: PMC9119985 DOI: 10.1038/s41467-022-30391-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Currently, imaging, fecal immunochemical tests (FITs) and serum carcinoembryonic antigen (CEA) tests are not adequate for the early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively identify and validate more accurate noninvasive biomarkers in urine, we implement a staged discovery-verification-validation pipeline in 657 urine and 993 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The generated diagnostic signature combined with the FIT test reveals a significantly increased sensitivity (+21.2% in the training set, +43.7% in the validation set) compared to FIT alone. Moreover, the generated metastatic signature for risk stratification correctly predicts over 50% of CEA-negative metastatic patients. The tissue validation shows that elevated urinary protein biomarkers reflect their alterations in tissue. Here, we show promising urinary protein signatures and provide potential interventional targets to reliably detect CRC, although further multi-center external validation is needed to generalize the findings. More sensitive and specific non-invasive biomarkers are desired for early detection of cancer. Here, the authors show a protein signature in the urine that increases sensitivity for colorectal cancer detection when combined with fecal immunochemical tests and corrects diagnosis in some fecal immunochemical tests-negative patients.
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Beklen H, Yildirim E, Kori M, Turanli B, Arga KY. Systems-level biomarkers identification and drug repositioning in colorectal cancer. World J Gastrointest Oncol 2021. [DOI: 10.4251/wjgo.v13.i7.463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Beklen H, Yildirim E, Kori M, Turanli B, Arga KY. Systems-level biomarkers identification and drug repositioning in colorectal cancer. World J Gastrointest Oncol 2021; 13:638-661. [PMID: 34322194 PMCID: PMC8299930 DOI: 10.4251/wjgo.v13.i7.638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most commonly diagnosed fatal cancer in both women and men worldwide. CRC ranked second in mortality and third in incidence in 2020. It is difficult to diagnose CRC at an early stage as there are no clinical symptoms. Despite advances in molecular biology, only a limited number of biomarkers have been translated into routine clinical practice to predict risk, prognosis and response to treatment. In the last decades, systems biology approaches at the omics level have gained importance. Over the years, several biomarkers for CRC have been discovered in terms of disease diagnosis and prognosis. On the other hand, a few drugs are being developed and used in clinics for the treatment of CRC. However, the development of new drugs is very costly and time-consuming as the research and development takes about 10 years and more than $1 billion. Therefore, drug repositioning (DR) could save time and money by establishing new indications for existing drugs. In this review, we aim to provide an overview of biomarkers for the diagnosis and prognosis of CRC from the systems biology perspective and insights into DR approaches for the prevention or treatment of CRC.
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Affiliation(s)
- Hande Beklen
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Esra Yildirim
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Medi Kori
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Beste Turanli
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
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Yakar M, Etiz D. Artificial intelligence in rectal cancer. Artif Intell Gastroenterol 2021; 2:10-26. [DOI: 10.35712/aig.v2.i2.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/03/2021] [Accepted: 03/16/2021] [Indexed: 02/06/2023] Open
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Huang XM, Zhang NR, Lin XT, Zhu CY, Zou YF, Wu XJ, He XS, He XW, Wan YL, Lan P. Antitumor immunity of low-dose cyclophosphamide: changes in T cells and cytokines TGF-beta and IL-10 in mice with colon-cancer liver metastasis. Gastroenterol Rep (Oxf) 2020; 8:56-65. [PMID: 32104586 PMCID: PMC7034239 DOI: 10.1093/gastro/goz060] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 10/02/2019] [Accepted: 10/10/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The tumor immune microenvironment is one of the most important prognostic factors in liver metastasis from colorectal cancer. Low-dose cyclophosphamide (CTX) is widely believed to be involved in the modulation of the immune system. However, the underlying mechanism of low-dose CTX remains unknown. This study aimed to investigate the antitumor immunity of low-dose CTX in the treatment of colon-cancer liver metastasis. METHODS Thirty mice were randomly divided into five groups. After liver metastasis was established in colon-cancer models, mice in the treatment groups were injected with low-dose CTX (20 mg/kg) at different time points. Liver and spleen tissues were examined for T-cell markers via flow cytometry. Interleukin (IL)-10 and transforming growth factor (TGF)-β1 expression levels in liver tissues were analysed by immunohistochemistry. Serum interferon (IFN)-γ and IL-10 levels were detected by enzyme-linked immunosorbent assay. An additional 20 mice were randomly allocated into two groups and the survival times were recorded. RESULTS The expression levels of CD4+ T cells, CD8+ T cells, and IFN-γ were down-regulated, whereas those of IL-10 and TGF-β1 were up-regulated in liver metastasis from colon cancer in mice. Furthermore, the local and systemic microenvironments of the liver were altered, which led to reduced antitumor immune responses and subsequently liver metastasis. However, treatment with low-dose CTX reversed these effects. The survival times of mice treated with low-dose CTX were significantly longer than those of the other groups. CONCLUSIONS Low-dose CTX exerts its antitumor activity by changing the systemic and local immune microenvironments and enhancing immune regulation in mice. CTX could be used as a drug to prevent and treat liver metastasis from colon cancer.
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Affiliation(s)
- Xiao-Ming Huang
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Nan-Rong Zhang
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Anesthesiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xu-Tao Lin
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Gastrointestinal Endoscopy, Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Cai-Yan Zhu
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Pharmacy, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yi-Feng Zou
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Jian Wu
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Sheng He
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Wen He
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yun-Le Wan
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ping Lan
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Alves Martins BA, de Bulhões GF, Cavalcanti IN, Martins MM, de Oliveira PG, Martins AMA. Biomarkers in Colorectal Cancer: The Role of Translational Proteomics Research. Front Oncol 2019; 9:1284. [PMID: 31828035 PMCID: PMC6890575 DOI: 10.3389/fonc.2019.01284] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 11/05/2019] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer is one of the most common cancers in the world, and it is one of the leading causes of cancer-related death. Despite recent progress in the development of screening programs and in the management of patients with colorectal cancer, there are still many gaps to fill, ranging from the prevention and early diagnosis to the determination of prognosis factors and treatment of metastatic disease, to establish a personalized approach. The genetic profile approach has been increasingly used in the decision-making process, especially in the choice of targeted therapies and in the prediction of drug response, but there are still few validated biomarkers of colorectal cancer for clinical practice. The discovery of non-invasive, sensitive, and specific biomarkers is an urgent need, and translational proteomics play a key role in this process, as they enable better comprehension of colorectal carcinogenesis, identification of potential markers, and subsequent validation. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through proteomics studies according to biomarker function and clinical application.
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Affiliation(s)
| | - Gabriel Fonseca de Bulhões
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
| | - Igor Norat Cavalcanti
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
| | | | | | - Aline Maria Araújo Martins
- Medical Sciences Postgraduate Program, School of Medicine, University of Brasilia, Brasília, Brazil
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
- Metabolomics and Bioanalysis Center, San Pablo CEU University, Madrid, Spain
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Liang M, Cai Z, Zhang H, Huang C, Meng Y, Zhao L, Li D, Ma X, Zhao X. Machine Learning-based Analysis of Rectal Cancer MRI Radiomics for Prediction of Metachronous Liver Metastasis. Acad Radiol 2019; 26:1495-1504. [PMID: 30711405 DOI: 10.1016/j.acra.2018.12.019] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/17/2018] [Accepted: 12/21/2018] [Indexed: 12/12/2022]
Abstract
RATIONALE AND OBJECTIVES To use machine learning-based magnetic resonance imaging radiomics to predict metachronous liver metastases (MLM) in patients with rectal cancer. MATERIALS AND METHODS This study retrospectively analyzed 108 patients with rectal cancer (54 in MLM group and 54 in nonmetastases group). Feature selection were performed in the radiomic feature sets extracted from images of T2-weighted image (T2WI) and venous phase (VP) sequence respectively, and the combining feature set with 2058 radiomic features incorporating two sequences with the least absolute shrinkage and selection operator method. Five-fold cross-validation and two machine learning algorithms (support vector machine [SVM]; logistic regression [LR]) were utilized for predictive model constructing. The diagnostic performance of the models was evaluated by receiver operating characteristic curves with indicators of accuracy, sensitivity, specificity and area under the curve, and compared by DeLong test. RESULTS Five, 8, and 22 optimal features were selected from 1029 T2WI, 1029 VP, and 2058 combining features, respectively. Four-group models were constructed using the five T2WI features (ModelT2), the 8 VP features (ModelVP), the combined 13 optimal features (Modelcombined), and the 22 optimal features selected from 2058 features (Modeloptimal). In ModelVP, the LR was superior to the SVM algorithm (P = 0.0303). The Modeloptimal using LR algorithm showed the best prediction performance (P = 0.0019-0.0081) with accuracy, sensitivity, specificity, and area under the curve of 0.80, 0.83, 0.76, and 0.87, respectively. CONCLUSION Radiomics models based on baseline rectal magnetic resonance imaging has high potential for MLM prediction, especially the Modeloptimal using LR algorithm. Moreover, except for ModelVP, the LR was not superior to the SVM algorithm for model construction.
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Affiliation(s)
- Meng Liang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Zhengting Cai
- Huiying Medical Technology Co., Ltd., HaiDian District, Beijing City, 100192, People's Republic of China
| | - Hongmei Zhang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Chencui Huang
- Huiying Medical Technology Co., Ltd., HaiDian District, Beijing City, 100192, People's Republic of China
| | - Yankai Meng
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China; Department of Radiology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, People's Republic of China
| | - Li Zhao
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Dengfeng Li
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Xiaohong Ma
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
| | - Xinming Zhao
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
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Reyes A, Marti J, Marfà S, Jiménez W, Reichenbach V, Pelegrina A, Fondevila C, Garcia Valdecasas JC, Fuster J. Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases. Future Oncol 2017; 13:875-882. [PMID: 28088872 DOI: 10.2217/fon-2016-0461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
AIM To obtain proteomic profiles in patients with colorectal liver metastases (CRLM) and identify the relationship between profiles and the prognosis of CRLM patients. MATERIALS & METHODS Prognosis prediction (favorable or unfavorable according to Fong's score) by a classification and regression tree algorithm of surface-enhanced laser desorption/ionization TOF-MS proteomic profiles from cryopreserved CRLM (patients) and normal liver tissue (controls). RESULTS The protein peak 7371 m/z showed the clearest differences between CRLM and control groups (94.1% sensitivity, 100% specificity, p < 0.001). The algorithm that best differentiated favorable and unfavorable groups combined 2970 and 2871 m/z protein peaks (100% sensitivity, 90% specificity). CONCLUSION Proteomic profiling in liver samples using classification and regression tree algorithms is a promising technique to differentiate healthy subjects from CRLM patients and to classify the severity of CRLM patients.
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Affiliation(s)
- Adalgiza Reyes
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Josep Marti
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Santiago Marfà
- Biochemistry & Molecular Genetics Service, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Wladimiro Jiménez
- Biochemistry & Molecular Genetics Service, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain.,Physiological Sciences Department I, University of Barcelona, Casanova, 143, 08036, Barcelona, Spain
| | - Vedrana Reichenbach
- Biochemistry & Molecular Genetics Service, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Amalia Pelegrina
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Constantino Fondevila
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Juan Carlos Garcia Valdecasas
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
| | - Josep Fuster
- Liver Surgery & Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic, IDIBAPS, CIBERehd, Villarroel, 170, 08036, Barcelona, Spain
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12
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Marfà S, Marti J, Reyes A, Casals G, Fernández-Varo G, Carvajal S, García-Valdecasas JC, Fuster J, Jiménez W. Metastatic Tissue Proteomic Profiling Predicts 5-Year Outcomes in Patients with Colorectal Liver Metastases. Transl Oncol 2016; 9:445-452. [PMID: 27751349 PMCID: PMC5067925 DOI: 10.1016/j.tranon.2016.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 08/03/2016] [Accepted: 08/08/2016] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers in the developed countries, and nearly 70% of patients with CRC develop colorectal liver metastases (CRLMs). During the last decades, several scores have been proposed to predict recurrence after CRLM resection. However, these risk scoring systems do not accurately reflect the prognosis of these patients. Therefore, this investigation was designed to identify a proteomic profile in human hepatic tumor samples to classify patients with CRLM as “mild” or “severe” based on the 5-year survival. The study was performed on 85 CRLM tumor samples. Firstly, to evaluate any distinct tumor proteomic signatures between mild and severe CRLM patients, a training group of 57 CRLM tumor samples was characterized by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, and a classification and regression tree (CART) analysis was subsequently performed. Finally, 28 CRLM tumor samples were used to confirm and validate the results obtained. Based on all the protein peaks detected in the training group, the CART analysis was generated, and four peaks were considered to be the most relevant to construct a diagnostic algorithm. Indeed, the multivariate model yielded a sensitivity of 85.7% and a specificity of 86.1%, respectively. In addition, the receiver operating characteristic (ROC) curve showed an excellent diagnostic accuracy to discriminate mild from severe CRLM patients (area under the ROC: 0.903). Finally, the validation process yielded a sensitivity and specificity of 68.8% and 83.3%, respectively. We identified a proteomic profile potentially useful to determine the prognosis of CRLM patients based on the 5-year survival.
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Affiliation(s)
- Santiago Marfà
- Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Josep Marti
- HepatoBilioPancreatic Surgery and Transplant Unit Department of Surgery, ICMDM, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Adalgiza Reyes
- HepatoBilioPancreatic Surgery and Transplant Unit Department of Surgery, ICMDM, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Gregori Casals
- Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Guillermo Fernández-Varo
- Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain
| | - Silvia Carvajal
- Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - J C García-Valdecasas
- HepatoBilioPancreatic Surgery and Transplant Unit Department of Surgery, ICMDM, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Josep Fuster
- HepatoBilioPancreatic Surgery and Transplant Unit Department of Surgery, ICMDM, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain.
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Fahmidehkar MA, Shafiee SM, Eftekhar E, Mahbudi L, Seghatoleslam A. Induction of cell proliferation, clonogenicity and cell accumulation in S phase as a consequence of human UBE2Q1 overexpression. Oncol Lett 2016; 12:2169-2174. [PMID: 27602158 DOI: 10.3892/ol.2016.4860] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 06/17/2016] [Indexed: 02/07/2023] Open
Abstract
Ubiquitination is an important cellular mechanism with a pivotal role in the degradation of abnormal or short-lived proteins and the regulation of cell cycle and cell growth. The ubiquitin-proteasome pathway is altered in multiple types of human malignancies, including colorectal cancer (CRC). The alteration in the expression of the novel human gene ubiquitin-conjugating enzyme E2 Q1 (UBE2Q1), as a putative member of the E2 ubiquitin-conjugating enzyme family, has been reported in several malignancies, including carcinoma of the breast, hepatocellular and colorectal cancer, and pediatric acute lymphoblastic leukemia. In the present study, the effect of UBE2Q1 overexpression on cell growth, clonogenicity, motility and cell cycle was investigated in a CRC cell line. The UBE2Q1 gene was cloned in the pCMV6-AN-GFP expression vector. A series of stable transfectants of SW1116 cells overexpressing UBE2Q1 protein were established and confirmed by fluorescence microscopy and western blotting. Using these cells, MTT assay was performed to evaluate cell growth and proliferation, while crystal violet staining was used for clonogenicity assay. Cell cycle analysis was also performed to survey the ratio of cells accumulated in different phases of the cell cycle upon transfection. The motility of these cells was also studied using wound healing assay. UBE2Q1 transfectants exhibited a faster growth in cell culture, increased colony formation capacity and enhanced motility compared with control non-transfected cells and cells transfected with empty vector (mock-transfected cells). UBE2Q1 overexpression also resulted in a significant decrease in the number of cells accumulated in the G0/G1 phase of the cell cycle. The present findings suggest that UBE2Q1 may function as an oncogene that induces proliferation of cancer cells, and could be a novel diagnostic tool and a potential therapeutic target for CRC.
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Affiliation(s)
- Mohammad Ali Fahmidehkar
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
| | - Sayed Mohammad Shafiee
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
| | - Ebrahim Eftekhar
- Food and Cosmetic Health Research Center, Hormozgan University of Medical Sciences, Bandar Abbas 79158-73665, Iran
| | - Laleh Mahbudi
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
| | - Atefeh Seghatoleslam
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran; Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz 71439-14693, Iran
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Álvarez-Chaver P, Otero-Estévez O, Páez de la Cadena M, Rodríguez-Berrocal FJ, Martínez-Zorzano VS. Proteomics for discovery of candidate colorectal cancer biomarkers. World J Gastroenterol 2014; 20:3804-3824. [PMID: 24744574 PMCID: PMC3983438 DOI: 10.3748/wjg.v20.i14.3804] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/24/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Europe and other Western countries, mainly due to the lack of well-validated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early stages. Although it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes, much less is known at the proteome level. Therefore, in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of colorectal carcinogenesis. An important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single study. This review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods, quantitative mass spectrometry-based techniques or protein microarrays. Additionally, we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue, serum and faeces, besides cell lines and murine models, discussing their advantages and disadvantages, and summarize the most frequently identified candidate CRC markers.
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