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Chuang J, Chen Y, Wang J. Narrative review of neoadjuvant therapy in patients with locally advanced colon cancer. Kaohsiung J Med Sci 2025; 41:e12926. [PMID: 39717937 PMCID: PMC11827549 DOI: 10.1002/kjm2.12926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 11/28/2024] [Accepted: 12/10/2024] [Indexed: 12/25/2024] Open
Abstract
Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with more than 1.9 million new cases reported in 2020, and is associated with major survival challenges, particularly in patients with locally advanced colon cancer (LACC). LACC often involves T4 invasion or extensive nodal involvement and requires a multidisciplinary approach for management. Radical surgery followed by adjuvant chemotherapy remains the primary treatment strategy for LACC. However, achieving complete tumor resection (R0) is challenging because locally advanced colon tumors typically infiltrate adjacent organs or nodes. Advancements in LACC treatment have involved neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiotherapy (NACRT), and neoadjuvant immunotherapy (NAIT). Studies such as FOxTROT and PRODIGE 22 have demonstrated that NACT, particularly with FOLFOX or CAPOX, can lead to major tumor downstaging, improved survival rates, and increased R0 resection rates. Predictive biomarkers, such as mismatch repair (MMR) status and T stage, are crucial in identifying candidates who may benefit from NACT. NACRT has demonstrated promise in enhancing tumor regression, particularly in patients with rectal cancer, underscoring its potential for use with LACC. NAIT, particularly for deficient MMR tumors, has emerged as a novel approach, with studies such as NICHE-2 and NICHE-3 reporting excellent pathologic responses and pathologic complete responses. Integrating these therapies can enhance the surgical and survival outcomes of patients with LACC, highlighting the importance of personalized treatment strategies based on tumor characteristics and response to neoadjuvant interventions. This review discusses the evolving landscape of LACC management, focusing on optimizing treatment approaches for improved patient outcomes.
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Affiliation(s)
- Jen‐Pin Chuang
- Chiayi HospitalMinistry of Health and WelfareChiayiTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineNational Cheng Kung UniversityTainanTaiwan
- Department of SurgeryNational Cheng Kung University HospitalTainanTaiwan
| | - Yen‐Chen Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
| | - Jaw‐Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Center for Cancer ResearchKaohsiung Medical UniversityKaohsiungTaiwan
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Narayana S, Gowda BHJ, Hani U, Shimu SS, Paul K, Das A, Ashique S, Ahmed MG, Tarighat MA, Abdi G. Inorganic nanoparticle-based treatment approaches for colorectal cancer: recent advancements and challenges. J Nanobiotechnology 2024; 22:427. [PMID: 39030546 PMCID: PMC11264527 DOI: 10.1186/s12951-024-02701-3] [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: 05/02/2024] [Accepted: 07/03/2024] [Indexed: 07/21/2024] Open
Abstract
Colorectal cancer, the third most prevalent cancer globally, contributes significantly to mortality rates, with over 1.9 million reported cases and nearly 935,000 fatalities annually. Surgical resection is a primary approach for localized colorectal tumors, with adjunct therapies like chemotherapy, radiotherapy, and targeted/immunotherapy considered depending on the tumor stage. However, despite preferences for targeted and immunotherapy post-surgery, chemotherapy remains commonly chosen due to its lower cost and high cancer-killing efficiency. Yet, chemotherapy faces issues such as tumor resistance and severe side effects. Nanotechnology has emerged in cancer therapy by alleviating the drawbacks of current treatment approaches. In the past few decades, inorganic nanoparticles have shown promise in combating colorectal cancer, offering advantages over conventional chemotherapy. Compared to organic nanoparticles, inorganic nanoparticles exhibit properties like photosensitivity, conductivity, magnetic allure, and thermal proficiency, allowing them to function as both drug carriers and therapeutic agents. Derived primarily from carbon, silica, metals, and metal oxides, they offer superior drug-loading capacity, heightened quantum yield, and participation in advanced photothermal and photodynamic therapies. This review provides a brief overview of the pathophysiology of colorectal cancer and the pivotal role of inorganic nanoparticles in photothermal therapy photodynamic therapy, and drug delivery. Additionally, it discusses numerous inorganic nanoparticles in colorectal cancer therapy based on recent literature.
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Affiliation(s)
- Soumya Narayana
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, Karnataka, India
| | - B H Jaswanth Gowda
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, Karnataka, India
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, 61421, Saudi Arabia
| | - Sharmin Sultana Shimu
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Karthika Paul
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570015, Karnataka, India.
| | - Avinaba Das
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, Karnataka, India
| | - Sumel Ashique
- Department of Pharmaceutical Sciences, Bengal College of Pharmaceutical Sciences & Research, Durgapur, 713212, West Bengal, India
- School of Pharmaceutical Sciences , Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Mohammed Gulzar Ahmed
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, Karnataka, India
| | - Maryam Abbasi Tarighat
- Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, 75169, Iran
| | - Gholamreza Abdi
- Department of Biotechnology, Persian Gulf Research Institute, Persian Gulf University, Bushehr, 75169, Iran.
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Majumdar A, Lad J, Tumanova K, Serra S, Quereshy F, Khorasani M, Vitkin A. Machine learning based local recurrence prediction in colorectal cancer using polarized light imaging. JOURNAL OF BIOMEDICAL OPTICS 2024; 29:052915. [PMID: 38077502 PMCID: PMC10704263 DOI: 10.1117/1.jbo.29.5.052915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/03/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023]
Abstract
Significance Current treatment for stage III colorectal cancer (CRC) patients involves surgery that may not be sufficient in many cases, requiring additional adjuvant systemic therapy. Identification of this latter cohort that is likely to recur following surgery is key to better personalized therapy selection, but there is a lack of proper quantitative assessment tools for potential clinical adoption. Aim The purpose of this study is to employ Mueller matrix (MM) polarized light microscopy in combination with supervised machine learning (ML) to quantitatively analyze the prognostic value of peri-tumoral collagen in CRC in relation to 5-year local recurrence (LR). Approach A simple MM microscope setup was used to image surgical resection samples acquired from stage III CRC patients. Various potential biomarkers of LR were derived from MM elements via decomposition and transformation operations. These were used as features by different supervised ML models to distinguish samples from patients that locally recurred 5 years later from those that did not. Results Using the top five most prognostic polarimetric biomarkers ranked by their relevant feature importances, the best-performing XGBoost model achieved a patient-level accuracy of 86%. When the patient pool was further stratified, 96% accuracy was achieved within a tumor-stage-III sub-cohort. Conclusions ML-aided polarimetric analysis of collagenous stroma may provide prognostic value toward improving the clinical management of CRC patients.
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Affiliation(s)
- Anamitra Majumdar
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
| | - Jigar Lad
- McMaster University, Department of Physics and Astronomy, Hamilton, Ontario, Canada
| | - Kseniia Tumanova
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
| | - Stefano Serra
- University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada
| | - Fayez Quereshy
- University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada
| | - Mohammadali Khorasani
- University of British Columbia, Department of Surgery, Victoria, British Columbia, Canada
| | - Alex Vitkin
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
- University of Toronto, Department of Radiation Oncology, Toronto, Ontario, Canada
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Alves S, Santos-Pereira C, Oliveira CSF, Preto A, Chaves SR, Côrte-Real M. Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration. Biomolecules 2024; 14:473. [PMID: 38672489 PMCID: PMC11048611 DOI: 10.3390/biom14040473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors.
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Affiliation(s)
| | | | | | | | - Susana R. Chaves
- CBMA—Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, 4710-057 Braga, Portugal; (S.A.); (C.S.-P.); (C.S.F.O.); (A.P.)
| | - Manuela Côrte-Real
- CBMA—Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, 4710-057 Braga, Portugal; (S.A.); (C.S.-P.); (C.S.F.O.); (A.P.)
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Igder S, Zamani M, Fakher S, Siri M, Ashktorab H, Azarpira N, Mokarram P. Circulating Nucleic Acids in Colorectal Cancer: Diagnostic and Prognostic Value. DISEASE MARKERS 2024; 2024:9943412. [PMID: 38380073 PMCID: PMC10878755 DOI: 10.1155/2024/9943412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 01/07/2024] [Accepted: 01/25/2024] [Indexed: 02/22/2024]
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer in the world and the fourth leading cause of cancer-related mortality. DNA (cfDNA/ctDNA) and RNA (cfRNA/ctRNA) in the blood are promising noninvasive biomarkers for molecular profiling, screening, diagnosis, treatment management, and prognosis of CRC. Technological advancements that enable precise detection of both genetic and epigenetic abnormalities, even in minute quantities in circulation, can overcome some of these challenges. This review focuses on testing for circulating nucleic acids in the circulation as a noninvasive method for CRC detection, monitoring, detection of minimal residual disease, and patient management. In addition, the benefits and drawbacks of various diagnostic techniques and associated bioinformatics tools have been detailed.
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Affiliation(s)
- Somayeh Igder
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shima Fakher
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hassan Ashktorab
- Department of Medicine, Gastroenterology Division and Cancer Center, Howard University College of Medicine, Washington, DC, USA
| | - Negar Azarpira
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran
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李 静, 殷 丽, 张 敏, 夏 勇, 左 芦, 刘 牧, 胡 建. [Construction of a fecal protein Luminex liquid chip detection system for early diagnosis of colorectal tumors]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:1874-1880. [PMID: 38081604 PMCID: PMC10713475 DOI: 10.12122/j.issn.1673-4254.2023.11.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Indexed: 12/18/2023]
Abstract
OBJECTIVE To construct a stool-based human protein diagnostic system using the Luminex liquid chip system for early diagnosis of colorectal tumors. METHODS From January, 2021 to January, 2023, 70 patients with colorectal cancer (CRC), 42 patients with colorectal adenoma (CRA), and 38 healthy individuals were recruited from our hospital for detecting fecal protein levels of matrix metalloproteinase-9 (MMP-9), retinol-binding protein 4 (RBP4), chitinase-3-like protein 1 (CHI3L1), and complement component 3a (C3a) using Luminex liquid chip technology and serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) using chemiluminescence assay. Receiver-operating characteristic (ROC) curve analysis was used for assessing the diagnostic efficacy of the combination of MMP-9, RBP4, CHI3L1 and C3a and the combination of CEA and CA19-9 for colorectal tumors. RESULTS The fecal contents of MMP-9, RBP4, CHI3L1, and C3a were significantly higher in CRC patients than in healthy individuals (P < 0.05). Fecal MMP-9 and CHI3L1 levels were significantly higher in CRC than in CRA patients (P < 0.05), but RBP4 and C3a levels did not differ significantly (P>0.05). CRC patients had significantly higher serum CEA and CA19-9 levels than healthy individuals and CRA patients (P < 0.05), but the differences were not significant between the latter two groups (P>0.05). ROC analysis showed that the sensitivity and specificity of the combination of MMP-9, RBP4, CHI3L1, and C3a was 91.4% and 100.0%, for diagnosing CRC, 81.0% and 89.5% for diagnosing CRA, and 83.9% and 97.4% for a combined diagnosis of CRC and CRA, respectively. Z-test analysis indicated that fecal MMP-9, RBP4, CHI3L1, and C3a contents had a greater diagnostic efficacy than serum tumor markers CEA and CA19-9 for a combined diagnosis of colorectal tumors (P < 0.05). CONCLUSION The Luminex liquid chip detection system for detecting decal RBP4, MMP-9, CHI3L1, and C3a provides an effective means for early diagnosis of colorectal tumors with a greater diagnostic efficacy than serum CEA and CA19-9 levels.
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Affiliation(s)
- 静 李
- 蚌埠医学院第一附属医院检验科，安徽 蚌埠 233000Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
- 蚌埠医学院第一附属医院炎症相关性疾病基础与转化研究安徽省重点实验室，安徽 蚌埠 233000Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 丽霞 殷
- 蚌埠医学院第一附属医院检验科，安徽 蚌埠 233000Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 敏 张
- 蚌埠医学院第一附属医院检验科，安徽 蚌埠 233000Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 勇生 夏
- 蚌埠医学院第一附属医院胃肠外科，安徽 蚌埠 233000Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 芦根 左
- 蚌埠医学院第一附属医院胃肠外科，安徽 蚌埠 233000Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
- 蚌埠医学院第一附属医院炎症相关性疾病基础与转化研究安徽省重点实验室，安徽 蚌埠 233000Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 牧林 刘
- 蚌埠医学院第一附属医院胃肠外科，安徽 蚌埠 233000Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - 建国 胡
- 蚌埠医学院第一附属医院检验科，安徽 蚌埠 233000Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
- 蚌埠医学院第一附属医院炎症相关性疾病基础与转化研究安徽省重点实验室，安徽 蚌埠 233000Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
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Tumanova K, Serra S, Majumdar A, Lad J, Quereshy F, Khorasani M, Vitkin A. Mueller matrix polarization parameters correlate with local recurrence in patients with stage III colorectal cancer. Sci Rep 2023; 13:13424. [PMID: 37591987 PMCID: PMC10435541 DOI: 10.1038/s41598-023-40480-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/10/2023] [Indexed: 08/19/2023] Open
Abstract
The peri-tumoural stroma has been explored as a useful source of prognostic information in colorectal cancer. Using Mueller matrix (MM) polarized light microscopy for quantification of unstained histology slides, the current study assesses the prognostic potential of polarimetric characteristics of peri-tumoural collagenous stroma architecture in 38 human stage III colorectal cancer (CRC) patient samples. Specifically, Mueller matrix transformation and polar decomposition parameters were tested for association with 5-year patient local recurrence outcomes. The results show that some of these polarimetric parameters were significantly different (p value < 0.05) for the recurrence versus the no-recurrence patient cohorts (Mann-Whitney U test). MM parameters may thus be prognostically valuable towards improving clinical management/treatment stratification in CRC patients.
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Affiliation(s)
- Kseniia Tumanova
- Department of Medical Biophysics, University of Toronto, Toronto, Canada.
| | - Stefano Serra
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Anamitra Majumdar
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Jigar Lad
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Fayez Quereshy
- Department of Surgery, University of Toronto, Toronto, Canada
| | | | - Alex Vitkin
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Division of Biophysics and Bioimaging, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
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Nguyen DD, Kim E, Le NT, Ding X, Jaiswal RK, Kostlan RJ, Nguyen TNT, Shiva O, Le MT, Chai W. Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair. SCIENCE ADVANCES 2023; 9:eadd8023. [PMID: 37163605 PMCID: PMC10171824 DOI: 10.1126/sciadv.add8023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 04/05/2023] [Indexed: 05/12/2023]
Abstract
Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.
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Affiliation(s)
- Dinh Duc Nguyen
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Eugene Kim
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Nhat Thong Le
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Rishi Kumar Jaiswal
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Raymond Joseph Kostlan
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Thi Ngoc Thanh Nguyen
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Olga Shiva
- Office of Research, Washington State University-Spokane, Spokane, WA, USA
| | - Minh Thong Le
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam
| | - Weihang Chai
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
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Chuang JP, Tsai HL, Chen PJ, Chang TK, Su WC, Yeh YS, Huang CW, Wang JY. Comprehensive Review of Biomarkers for the Treatment of Locally Advanced Colon Cancer. Cells 2022; 11:3744. [PMID: 36497002 PMCID: PMC9740797 DOI: 10.3390/cells11233744] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/25/2022] Open
Abstract
Despite the implementation of global screening programs, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths worldwide. More than 10% of patients with colon cancer are diagnosed as having locally advanced disease with a relatively poor five-year survival rate. Locally advanced colon cancer (LACC) presents surgical challenges to R0 resection. The advantages and disadvantages of preoperative radiotherapy for LACC remain undetermined. Although several reliable novel biomarkers have been proposed for the prediction and prognosis of CRC, few studies have focused solely on the treatment of LACC. This comprehensive review highlights the role of predictive biomarkers for treatment and postoperative oncological outcomes for patients with LACC. Moreover, this review discusses emerging needs and approaches for the discovery of biomarkers that can facilitate the development of new therapeutic targets and surveillance of patients with LACC.
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Affiliation(s)
- Jen-Pin Chuang
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, Tainan 70101, Taiwan
| | - Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tsung-Kun Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yung-Sung Yeh
- Department of Emergency Medicine, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jaw-Yuan Wang
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Hermawan A, Putri H. Computational analysis of G-protein-coupled receptor kinase family members as potential targets for colorectal cancer therapy. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00349-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
G-protein-coupled receptor (GPCR) kinases (GRKs) interact with ligand-activated GPCR, causing intracellular phosphorylation and interfering with the intracellular signal transduction associated with the development of cancer. Colorectal cancer (CRC) is a fast-growing disease, and its molecular mechanism involves various regulatory proteins, including kinases. However, the GRK mechanism in CRC has not been explored.
Methods
We used an integrated computational approach to investigate the potential of GRK family members as targeted proteins in CRC. The GRK expression levels in tumor and normal tissues, colon adenocarcinoma samples, and metastatic colon adenocarcinoma were analyzed using ONCOMINE, GEPIA, and UALCAN, as well as TNM plots. Genetic changes in the GRK family genes were investigated using cBioportal. The prognostic value related to the gene expression of the GRK family was examined using GEPIA and UALCAN. Co-expression analysis of the GRK family was conducted using COXPRESdb. Association analysis of the Gene Ontology, KEGG pathway enrichment, and drug-gene analyses were performed using the over-representation analysis (ORA) in WebGestalt.
Results
GRK2, GRK3, and GRK5 mRNA levels increased significantly in patients with CRC and metastatic CRC. Genetic changes were detected in patients with CRC, including GRK7 (1.1%), GRK2 (1.7%), GRK4 (2.3%), GRK5 (2.5%), GRK6 (2.5%), GRK3 (2.9%), and GRK1 (4%). CRC patients with low mRNA of GRK7 levels had better disease-free and overall survival than those with high GRK7 levels. Hierarchical clustering analysis revealed significant positive correlations between GRK5 and GRK2 and between GRK2 and GRK6. KEGG pathway enrichment analysis showed that the gene network (GN) regulated several cellular pathways, such as the morphine addiction signaling and chemokine signaling pathways in cancer. The drug-gene association analysis indicated that the GN was associated with several drugs, including reboxetine, pindolol, beta-blocking agents, and protein kinase inhibitors.
Conclusion
No research has been conducted on the relation of GRK1 and GRK7 to cancer, particularly CRC. In this work, genes GRK2, GRK3, GRK5, and GRK6 were found to be oncogenes in CRC. Although inhibitors against GRK2, GRK5, and GRK6 have previously been developed, further research, particularly preclinical and clinical studies, is needed before these agents may be used to treat CRC.
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11
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Chang YK, Tseng HH, Leung CM, Lu KC, Tsai KW. Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma Receiving or Not Receiving Neoadjuvant Chemoradiotherapy. Int J Mol Sci 2022; 23:ijms231810353. [PMID: 36142267 PMCID: PMC9499649 DOI: 10.3390/ijms231810353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.
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Affiliation(s)
- You-Kang Chang
- Department of Radiation Oncology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan
- College of Medicine, Tzu Chi University, Hualien City 97004, Taiwan
| | - Hui-Hwa Tseng
- Department of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan
| | - Chung-Man Leung
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung 81341, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
- Correspondence: ; Tel.: +886-2-266289779 (ext. 5796); Fax: +886-2-66281258
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12
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Tivey A, Church M, Rothwell D, Dive C, Cook N. Circulating tumour DNA - looking beyond the blood. Nat Rev Clin Oncol 2022; 19:600-612. [PMID: 35915225 PMCID: PMC9341152 DOI: 10.1038/s41571-022-00660-y] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2022] [Indexed: 02/06/2023]
Abstract
Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.
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Affiliation(s)
- Ann Tivey
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- The Christie NHS Foundation Trust, Manchester, UK
| | - Matt Church
- The Christie NHS Foundation Trust, Manchester, UK
| | - Dominic Rothwell
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Manchester, UK
| | - Caroline Dive
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Manchester, UK
| | - Natalie Cook
- Division of Cancer Sciences, The University of Manchester, Manchester, UK.
- The Christie NHS Foundation Trust, Manchester, UK.
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13
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Polarimetric biomarkers of peri-tumoral stroma can correlate with 5-year survival in patients with left-sided colorectal cancer. Sci Rep 2022; 12:12652. [PMID: 35879367 PMCID: PMC9314438 DOI: 10.1038/s41598-022-16178-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022] Open
Abstract
Using a novel variant of polarized light microscopy for high-contrast imaging and quantification of unstained histology slides, the current study assesses the prognostic potential of peri-tumoral collagenous stroma architecture in 32 human stage III colorectal cancer (CRC) patient samples. We analyze three distinct polarimetrically-derived images and their associated texture features, explore different unsupervised clustering algorithm models to group the data, and compare the resultant groupings with patient survival. The results demonstrate an appreciable total accuracy of ~ 78% with significant separation (p < 0.05) across all approaches for the binary classification of 5-year patient survival outcomes. Surviving patients preferentially belonged to Cluster 1 irrespective of model approach, suggesting similar stromal microstructural characteristics in this sub-population. The results suggest that polarimetrically-derived stromal biomarkers may possess prognostic value that could improve clinical management/treatment stratification in CRC patients.
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Long Noncoding RNA LOC550643 Acts as an Oncogene in the Growth Regulation of Colorectal Cancer Cells. Cells 2022; 11:cells11071065. [PMID: 35406629 PMCID: PMC8997465 DOI: 10.3390/cells11071065] [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: 02/09/2022] [Revised: 03/15/2022] [Accepted: 03/20/2022] [Indexed: 12/24/2022] Open
Abstract
Long noncoding RNAs play a key role in the progression of colorectal cancer (CRC). However, the role and mechanism of LOC550643 in CRC cell growth and metastasis remain largely unknown. In this study, we assessed the clinical impacts of LOC550643 on CRC through the analysis of The Cancer Genome Atlas database, which revealed the significant upregulation of LOC550643 in CRC. Moreover, the high expression of LOC550643 was associated with poor survival in patients with CRC (p = 0.001). Multivariate Cox regression analysis indicated that LOC550643 overexpression was an independent prognostic factor for shorter overall survival in patients with CRC (adjusted hazard ratio, 1.90; 95% confidence interval, 1.21-3.00; p = 0.006). A biological function analysis revealed that LOC550643 knockdown reduced colon cancer cell growth by hindering cell cycle progression. In addition, LOC550643 knockdown significantly induced cell apoptosis through the inhibition of signaling activity in phosphoinositide 3-kinases. Moreover, LOC550643 knockdown contributed to the inhibition of migration and invasion ability in colon cancer cells. Furthermore, miR-29b-2-5p interacted with the LOC550643 sequence. Ectopic miR-29b-2-5p significantly suppressed colon cancer cell growth and motility and induced cell apoptosis. Our findings suggest that, LOC550643-miR-29b-2-5p axis was determined to participate in the growth and metastasis of colon cancer cells; this could serve as a useful molecular biomarker for cancer diagnosis and as a potential therapeutic target for CRC.
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15
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de Assis JV, Coutinho LA, Oyeyemi IT, Oyeyemi OT, Grenfell RFEQ. Diagnostic and therapeutic biomarkers in colorectal cancer: a review. Am J Cancer Res 2022; 12:661-680. [PMID: 35261794 PMCID: PMC8900002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/22/2022] [Indexed: 06/14/2023] Open
Abstract
Colorectal cancer (CRC) is a public health concern and the second most common type of cancer among men and women causing a significant mortality. Biomarkers closely linked to the disease morbidity could holds potential as diagnostic and/or prognostic biomarker for the disease. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through genomics and proteomics according to clinical function and application. Specifically, a number of biomarkers were identified and discussed. Emphasis was placed on their clinical applications relative to the diagnosis and prognosis of CRC. The discovery of more sensitive and specific markers for CRC is an urgent need, and the study of molecular targets is extremely important in this process, as they will allow for a better understanding of colorectal carcinogenesis, identification and validation of potential genetic signatures.
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Affiliation(s)
- Jéssica Vieira de Assis
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
| | - Lucélia Antunes Coutinho
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
| | | | - Oyetunde Timothy Oyeyemi
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
- Department of Biological Sciences, University of Medical SciencesOndo, Ondo State, Nigeria
| | - Rafaella Fortini e Queiroz Grenfell
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
- Department of Infectious Diseases, College of Veterinary Medicine, University of GeorgiaAthens, Georgia, United States of America
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Al-Joufi FA, Setia A, Salem-Bekhit MM, Sahu RK, Alqahtani FY, Widyowati R, Aleanizy FS. Molecular Pathogenesis of Colorectal Cancer with an Emphasis on Recent Advances in Biomarkers, as Well as Nanotechnology-Based Diagnostic and Therapeutic Approaches. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:169. [PMID: 35010119 PMCID: PMC8746463 DOI: 10.3390/nano12010169] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a serious disease that affects millions of people throughout the world, despite considerable advances in therapy. The formation of colorectal adenomas and invasive adenocarcinomas is the consequence of a succession of genetic and epigenetic changes in the normal colonic epithelium. Genetic and epigenetic processes associated with the onset, development, and metastasis of sporadic CRC have been studied in depth, resulting in identifying biomarkers that might be used to predict behaviour and prognosis beyond staging and influence therapeutic options. A novel biomarker, or a group of biomarkers, must be discovered in order to build an accurate and clinically useful test that may be used as an alternative to conventional methods for the early detection of CRC and to identify prospective new therapeutic intervention targets. To minimise the mortality burden of colorectal cancer, new screening methods with higher accuracy and nano-based diagnostic precision are needed. Cytotoxic medication has negative side effects and is restricted by medication resistance. One of the most promising cancer treatment techniques is the use of nano-based carrier system as a medication delivery mechanism. To deliver cytotoxic medicines, targeted nanoparticles might take advantage of differently expressed molecules on the surface of cancer cells. The use of different compounds as ligands on the surface of nanoparticles to interact with cancer cells, enabling the efficient delivery of antitumor medicines. Formulations based on nanoparticles might aid in early cancer diagnosis and help to overcome the limitations of traditional treatments, including low water solubility, nonspecific biodistribution, and restricted bioavailability. This article addresses about the molecular pathogenesis of CRC and highlights about biomarkers. It also provides conceptual knowledge of nanotechnology-based diagnostic techniques and therapeutic approaches for malignant colorectal cancer.
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Affiliation(s)
- Fakhria A. Al-Joufi
- Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia;
| | - Aseem Setia
- Department of Pharmacy, Shri Rawatpura Sarkar University, Raipur 492015, India
| | - Mounir M. Salem-Bekhit
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Ram Kumar Sahu
- Department of Pharmaceutical Science, Assam University (A Central University), Silchar 788011, India
| | - Fulwah Y. Alqahtani
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
| | - Retno Widyowati
- Department of Pharmaceutical Science, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia;
| | - Fadilah Sfouq Aleanizy
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
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17
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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18
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Almuzzaini B, Alghamdi J, Alomani A, AlGhamdi S, Alsharm AA, Alshieban S, Sayed A, Alhejaily AG, Aljaser FS, Abudawood M, Almajed F, Samman A, Balwi MAA, Aziz MA. Identification of Novel Mutations in Colorectal Cancer Patients Using AmpliSeq Comprehensive Cancer Panel. J Pers Med 2021; 11:jpm11060535. [PMID: 34207827 PMCID: PMC8230213 DOI: 10.3390/jpm11060535] [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: 04/14/2021] [Revised: 05/25/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023] Open
Abstract
Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate high-quality sequencing data from local colorectal cancer patients and understand the pattern of occurrence of variants. In this report, we used archived samples from Saudi Arabia and used the AmpliSeq comprehensive cancer panel to identify novel somatic variants. We report a comprehensive analysis of next-generation sequencing results with a coverage of >300X. We identified 466 novel variants which were previously unreported in COSMIC and ICGC databases. We analyzed the genes associated with these variants in terms of their frequency of occurrence, probable pathogenicity, and clinicopathological features. Among pathogenic somatic variants, 174 were identified for the first time in the large intestine. APC, RET, and EGFR genes were most frequently mutated. A higher number of variants were identified in the left colon. Occurrence of variants in ERBB2 was significantly correlated with those of EGFR and ATR genes. Network analyses of the identified genes provide functional perspective of the identified genes and suggest affected pathways and probable biomarker candidates. This report lays the ground work for biomarker discovery and identification of driver gene mutations in local population.
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Affiliation(s)
- Bader Almuzzaini
- King Abdullah International Medical Research Center, Medical Genomics Research Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia;
- Correspondence: (B.A.); (M.A.A.); Tel.: +966-11-429-4533 (B.A.); +966-11-429-4582 (M.A.A.)
| | - Jahad Alghamdi
- King Abdullah International Medical Research Center, Saudi Biobank, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia; (J.A.); (A.S.)
| | - Alhanouf Alomani
- Department of Pathology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia;
| | - Saleh AlGhamdi
- Clinical Research Department, Research Center, King Fahad Medical City, Riyadh 11564, Saudi Arabia;
| | - Abdullah A. Alsharm
- Comprehensive Cancer Center, King Fahad Medical City, Riyadh 11564, Saudi Arabia;
| | - Saeed Alshieban
- King Abdul Aziz Medical City-National Guard Health Affairs (NGHA), King Abdullah International Medical Research Center, King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Riyadh 14611, Saudi Arabia;
| | - Ahood Sayed
- King Abdullah International Medical Research Center, Saudi Biobank, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia; (J.A.); (A.S.)
| | | | - Feda S. Aljaser
- Department of Clinical Laboratory Sciences, Chair of Medical and Molecular Genetics Research, College of Applied Medical Sciences, King Saud University Riyadh, Riyadh 11564, Saudi Arabia; (F.S.A.); (M.A.)
| | - Manal Abudawood
- Department of Clinical Laboratory Sciences, Chair of Medical and Molecular Genetics Research, College of Applied Medical Sciences, King Saud University Riyadh, Riyadh 11564, Saudi Arabia; (F.S.A.); (M.A.)
| | - Faisal Almajed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia;
| | - Abdulhadi Samman
- Department of Pathology, Faculty of Medicine, University of Jeddah, Jeddah 23218, Saudi Arabia;
| | - Mohammed A. Al Balwi
- King Abdullah International Medical Research Center, Medical Genomics Research Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia;
| | - Mohammad Azhar Aziz
- King Abdullah International Medical Research Center, Colorectal Cancer Research Program, Department of Cellular Therapy and Cancer Research, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia
- Correspondence: (B.A.); (M.A.A.); Tel.: +966-11-429-4533 (B.A.); +966-11-429-4582 (M.A.A.)
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Kang B, Lee HS, Jeon SW, Park SY, Choi GS, Lee WK, Heo S, Lee DH, Kim DS. Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development. Cancer Biomark 2021; 32:231-236. [PMID: 34092617 DOI: 10.3233/cbm-203259] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.
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Affiliation(s)
- Ben Kang
- Department of Pediatrics and Bio-medical Research Institute, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Seong Woo Jeon
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Soo Yeun Park
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Gyu Seog Choi
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Won Kee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Somi Heo
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Duk Hee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Dong Sun Kim
- Department of Anatomy, School of Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
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20
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Sun J, Xu J, Sun C, Zheng M, Li Y, Zhu S, Zhang S. Screening and Prognostic Value of Methylated Septin9 and its Association With Clinicopathological and Molecular Characteristics in Colorectal Cancer. Front Mol Biosci 2021; 8:568818. [PMID: 34095214 PMCID: PMC8173126 DOI: 10.3389/fmolb.2021.568818] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 04/22/2021] [Indexed: 12/24/2022] Open
Abstract
Screening of CRC continues to show poor compliance of endoscopy examination. The detection of mSEPT9 in peripheral blood is among the safe and simple early screening methods for CRC. The issue of how to elucidate whether detection of mSEPT9 in peripheral blood can effectively improve compliance of endoscopy and increase the early diagnosis rate of CRC and the relationship between levels of mSEPT9 in the peripheral blood and clinical stage, pathological classification, and expression of characteristic molecules in CRC remains unsolved. A total of 7759 individuals participated in the study that was performed using a questionnaire for screening of high-risk CRC. The endoscopic detection compliance of individuals with high-risk CRC who underwent the fecal occult blood test (FOBT) or mSEPT9 test was compared based on the results of the questionnaire. Additionally, correlation of mSEPT9 levels in the peripheral blood with clinicopathological features, mutation status of TP53, mismatch repair deficiency (dMMR), and KRAS/NRAS/BRAF/PIK3CA genotype was analyzed, and association of biomarkers with cancer-specific survival (CSS) and time to recurrence (TTR) was compared. We also detected levels of mSEPT9 in the peripheral blood of patients with CRC 7 days after surgery and compared the prognostic value of mSEPT9 with CEA. Results of our study showed that the mSEPT9 test could improve compliance of endoscopy and indicated a higher percentage of patients with positive mSEPT9 willing to undergo endoscopy detection than in those with positive FOBT. The specificity and sensitivity of mSEPT9 were better than that of FOBT for the detection of CRC. mSEPT9 was associated with the TNM stage, dMMR, and mutations in TP53, BRAF, and PIK3CA. A Ct value of mSEPT9 ≤ 37.5 was significantly related to poor CSS. mSEPT9 could affect association of dMMR and BRAF and PIK3CA mutations with CSS in a specific stage of CRC. The positive rate of mSEPT9 after surgery was found to correlate with poor TTR, and sensitivity was higher than CEA. The combination of mSEPT9 with CEA had a better prognostic value than that of mSEPT9 alone. The level of mSEPT9 was related to dMMR, mutations in TP53, BRAF, and PIK3CA, and was an effective biomarker for the prognosis of patients with CRC.
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Affiliation(s)
- Jie Sun
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Jinling Xu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Chao Sun
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Siwei Zhu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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21
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Zhang W, Huang Z, Zhao J, He D, Li M, Yin H, Tian S, Zhang H, Song B. Development and validation of magnetic resonance imaging-based radiomics models for preoperative prediction of microsatellite instability in rectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:134. [PMID: 33569436 PMCID: PMC7867944 DOI: 10.21037/atm-20-7673] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/02/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Microsatellite instability (MSI) is a predictive biomarker for response to chemotherapy and a prognostic biomarker for clinical outcomes of rectal cancer. The purpose of this study was to develop and validate radiomics models for preoperative prediction of the MSI status of rectal cancer based on magnetic resonance (MR) images. METHODS This study retrospectively recruited 491 rectal cancer patients with pathologically confirmed MSI status. Patients were randomly divided into a training cohort (n=327) and a validation cohort (n=164). The most predictive radiomics features were selected using intraclass correlation coefficient (ICC) analysis, the two-sample t test, and the least absolute shrinkage and selection operator (LASSO) method. XGBoost models were constructed in the training cohort to discriminate the MSI status using clinical factors, radiomics features, or a combined model incorporating both the radiomics signature and independent clinical characteristics. The diagnostic performance of these three models was evaluated in the validation cohort based on their area under the curve (AUC), sensitivity, specificity, and accuracy. RESULTS Among the 491 rectal cancer patients, the prevalence of MSI was 10.39% (51/491). Following ICC analysis, two-sample t test, and LASSO regression, six radiomics features were selected for subsequent analysis. The combined model, which incorporated both the clinical factors and radiomics features achieved an AUC of 0.895 [95% confidence interval (CI), 0.838-0.938] in the validation cohort, and showed better performance in predicting MSI status than the other two models using either clinical factors (P=0.015) or radiomics features (P=0.204) alone. CONCLUSIONS Radiomics features based on preoperative T2-weighted MR imaging (MRI) are associated with the MSI status of rectal cancer. Combinational analysis of clinical factors and radiomics features may improve predictive performance and potentially contribute to noninvasive personalized therapy selection.
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Affiliation(s)
- Wei Zhang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People’s Armed Police Forces, Leshan, China
| | - Zixing Huang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Zhao
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People’s Armed Police Forces, Leshan, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Mou Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongkun Yin
- Institute of Advanced Research, InferVision, Beijing, China
| | - Song Tian
- Institute of Advanced Research, InferVision, Beijing, China
| | - Huiling Zhang
- Institute of Advanced Research, InferVision, Beijing, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
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22
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Assessment of circulating tumor cells in peripheral blood using flow cytometry in patients with surgery for colorectal cancer – review. REV ROMANA MED LAB 2020. [DOI: 10.2478/rrlm-2020-0033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Introduction: Colorectal cancer (CRC) is the third most common neoplasia in the world. Circulating tumor cells (CTC) have a prognostic value and can be useful in monitoring solid neoplasia. Only one method for CTC identification has received the approval and this is the CellSearch® system based on the immunomagnetic separation. Multiple markers are used in CTC identification, as epithelial markers and cytokeratines. CTC identification in peripheral blood is associated with a worse prognostic and reduced free survival in CRC.
Material and methods: We performed a systematic search in PubMed database for articles that reports the circulating tumor cells in CRC until July 2019. We selected studies in English and French and the main words used for search were ‘circulating tumor cells’, ‘colorectal cancer’, ‘colon cancer’, ‘rectal cancer’, ‘flow cytometry’, ‘peripheral blood’. We included studies with more than 10 patients, where samples were collected from the blood in relation with surgery and flow cytometry was used as analyzing technique.
Results: We included 7 studies in final analysis, that showed in flow cytometry analysis a cut-off value of CTC that can vary from 2-4 CTC/ 7.5 ml peripheral blood with a sensitivity of 50.8% and specificity of 95%. Patients with positive CTC were associated with higher T stage and positive lymph nodes, with a worse overall survival (OS) and disease free survival (DFS) comparing with negative patients.
Conclusion: CTC are considered to be a prognostic factor who needs more validation studies in order to be included in the clinical practice.
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23
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Karn R, Emerson IA. Molecular dynamic study on PTEN frameshift mutations in breast cancer provide c2 domain as a potential biomarker. J Biomol Struct Dyn 2020; 40:3132-3143. [PMID: 33183179 DOI: 10.1080/07391102.2020.1845802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PTEN is a tumour suppressor gene known for regulating apoptosis, cell growth, and many other pathways. It is one of the most frequently mutated genes comprising the phosphatase domain (PD) and C terminal domain (C2). Direct therapeutic methods are not applicable for targeting PTEN because once gets mutated, it needs restoration. For mutant detection and restoration using PTEN mRNA there is a need to explore various mutations taking place in PTEN, identify their particular domains, and study their interactions within the cellular system. Here, we have tried to highlight a few such regions in the mutated PTEN of breast cancer patients. In this study, we have selected the top-most-occurring PTEN mutation in breast cancer and compared them to determine the specific properties of each mutation and its effect on functionality. Molecular dynamic simulation for 50 ns was performed on five structures to compare the structural behaviour of mutated PTEN in the system. Our finding suggests that frameshift mutations are more damaging and affect the c2 domain. Frameshift mutant fs_ACTT is the highest occurring as well as the most damaging mutation in all the compared structures. Docking study shows that substitution mutations D92H and R130Q causes loss of binding ability towards PIP2 in normal PTEN, interfering the dephosphorylation process. Overall, the C2 domain is more frequently mutated, and the amino acid residues in the C2 domain show more fluctuations compared to the other regions. Our study can provide the basis for selecting frequently mutated C2 domain as a potential therapeutic marker.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Rohit Karn
- Bioinformatics Programming Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT, Vellore, India
| | - Isaac Arnold Emerson
- Bioinformatics Programming Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT, Vellore, India
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24
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Forster S, Radpour R. Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells. Front Oncol 2020; 10:569017. [PMID: 33240813 PMCID: PMC7680905 DOI: 10.3389/fonc.2020.569017] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/08/2020] [Indexed: 12/17/2022] Open
Abstract
The immune system is able to recognize and eliminate tumor cells. Some tumors, including colorectal cancer (CRC), induce immune tolerance via different mechanisms of “immunoediting” and “immune evasion” and can thus escape immune surveillance. The impact of immunotherapy on cancer has been investigated for many years, but so far, the application was limited to few cancer types. Immuno-oncological therapeutic strategies against metastatic colorectal cancer (mCRC), the adaptive immune system activating approaches, offer a high potential for adaptation to the great heterogeneity of CRC. Moreover, novel treatment approaches are currently being tested that might specifically target the disease initiating and maintaining population of colorectal cancer stem cells (CSCs). In this review, we aim to summarize the current state of immune-oncology and tumor immunotherapy of patients with mCRC and discuss different therapeutic modalities that focus on the activation of tumor-specific T-cells and their perspectives such as tumor vaccination, checkpoint inhibition, and adoptive T-cell transfer or on the eradication of colorectal CSCs.
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Affiliation(s)
- Stefan Forster
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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25
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Nebbia M, Yassin NA, Spinelli A. Colorectal Cancer in Inflammatory Bowel Disease. Clin Colon Rectal Surg 2020; 33:305-317. [PMID: 32968366 DOI: 10.1055/s-0040-1713748] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with inflammatory bowel disease (IBD) are at an increased risk for developing colorectal cancer (CRC). However, the incidence has declined over the past 30 years, which is probably attributed to raise awareness, successful CRC surveillance programs and improved control of mucosal inflammation through chemoprevention. The risk factors for IBD-related CRC include more severe disease (as reflected by the extent of disease and the duration of poorly controlled disease), family history of CRC, pseudo polyps, primary sclerosing cholangitis, and male sex. The molecular pathogenesis of inflammatory epithelium might play a critical role in the development of CRC. IBD-related CRC is characterized by fewer rectal tumors, more synchronous and poorly differentiated tumors compared with sporadic cancers. There is no significant difference in sex distribution, stage at presentation, or survival. Surveillance is vital for the detection and subsequently management of dysplasia. Most guidelines recommend initiation of surveillance colonoscopy at 8 to 10 years after IBD diagnosis, followed by subsequent surveillance of 1 to 2 yearly intervals. Traditionally, surveillance colonoscopies with random colonic biopsies were used. However, recent data suggest that high definition and chromoendoscopy are better methods of surveillance by improving sensitivity to previously "invisible" flat dysplastic lesions. Management of dysplasia, timing of surveillance, chemoprevention, and the surgical approaches are all areas that stimulate various discussions. The aim of this review is to provide an up-to-date focus on CRC in IBD, from laboratory to bedside.
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Affiliation(s)
- Martina Nebbia
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center IRCCS, Rozzano, Milano, Italy
| | - Nuha A Yassin
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center IRCCS, Rozzano, Milano, Italy
| | - Antonino Spinelli
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center IRCCS, Rozzano, Milano, Italy.,Deparment of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy
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26
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Liu L, Shao Z, Lv J, Xu F, Ren S, Jin Q, Yang J, Ma W, Xie H, Zhang D, Chen X. Identification of Early Warning Signals at the Critical Transition Point of Colorectal Cancer Based on Dynamic Network Analysis. Front Bioeng Biotechnol 2020; 8:530. [PMID: 32548109 PMCID: PMC7272579 DOI: 10.3389/fbioe.2020.00530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 05/04/2020] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Due to the lack of early diagnosis methods and warning signals of CRC and its strong heterogeneity, the determination of accurate treatments for CRC and the identification of specific early warning signals are still urgent problems for researchers. In this study, the expression profiles of cancer tissues and the expression profiles of tumor-adjacent tissues in 28 CRC patients were combined into a human protein–protein interaction (PPI) network to construct a specific network for each patient. A network propagation method was used to obtain a mutant giant cluster (GC) containing more than 90% of the mutation information of one patient. Next, mutation selection rules were applied to the GC to mine the mutation sequence of driver genes in each CRC patient. The mutation sequences from patients with the same type CRC were integrated to obtain the mutation sequences of driver genes of different types of CRC, which provide a reference for the diagnosis of clinical CRC disease progression. Finally, dynamic network analysis was used to mine dynamic network biomarkers (DNBs) in CRC patients. These DNBs were verified by clinical staging data to identify the critical transition point between the pre-disease state and the disease state in tumor progression. Twelve known drug targets were found in the DNBs, and 6 of them have been used as targets for anticancer drugs for clinical treatment. This study provides important information for the prognosis, diagnosis and treatment of CRC, especially for pre-emptive treatments. It is of great significance for reducing the incidence and mortality of CRC.
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Affiliation(s)
- Lei Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zhuo Shao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jiaxuan Lv
- School of Stomatology, Harbin Medical University, Harbin, China
| | - Fei Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Sibo Ren
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Qing Jin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jingbo Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Weifang Ma
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongbo Xie
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Denan Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiujie Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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27
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Mandhair HK, Arambasic M, Novak U, Radpour R. Molecular modulation of autophagy: New venture to target resistant cancer stem cells. World J Stem Cells 2020; 12:303-322. [PMID: 32547680 PMCID: PMC7280868 DOI: 10.4252/wjsc.v12.i5.303] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a highly regulated catabolic process in which superfluous, damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions. Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers. For instance, autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses, by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics. Autophagy has been implicated in a cross talk with apoptosis. Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients. In this review, we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Miroslav Arambasic
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland.
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28
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Bodén S, Myte R, Harbs J, Sundkvist A, Zingmark C, Löfgren Burström A, Palmqvist R, Harlid S, Van Guelpen B. C-reactive Protein and Future Risk of Clinical and Molecular Subtypes of Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:1482-1491. [PMID: 32317300 DOI: 10.1158/1055-9965.epi-19-1339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/27/2020] [Accepted: 04/17/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Inflammation has been implicated in colorectal cancer etiology, but the relationship between C-reactive protein (CRP) and colorectal cancer risk is unclear. We aimed to investigate the association between prediagnostic plasma CRP concentrations and the risk of clinical and molecular colorectal cancer subtypes. METHODS We used prospectively collected samples from 1,010 matched colorectal cancer case-control pairs from two population-based cohorts in Northern Sweden, including 259 with repeated samples. Conditional logistic regression and linear mixed models were used to estimate relative risks of colorectal cancer, including subtypes based on BRAF and KRAS mutations, microsatellite instability status, tumor location, stage, lag time, and (using unconditional logistic regression) body mass index. RESULTS CRP was not associated with colorectal cancer risk, regardless of clinical or molecular colorectal cancer subtype. For participants with advanced tumors and blood samples <5 years before diagnosis, CRP was associated with higher risk [OR per 1 unit increase in natural logarithm (ln) transformed CRP, 1.32; 95% confidence interval (CI), 1.01-1.73]. CRP levels increased over time, but average time trajectories were similar for cases and controls (P interaction = 0.19). CONCLUSIONS Our results do not support intertumoral heterogeneity as an explanation for previous inconsistent findings regarding the role of CRP in colorectal cancer etiology. The possible association in the subgroup with advanced tumors and shorter follow-up likely reflects undiagnosed cancer at baseline. IMPACT Future efforts to establish the putative role of chronic, low-grade inflammation in colorectal cancer development will need to address the complex relationship between systemic inflammatory factors and tumor microenvironment, and might consider larger biomarker panels than CRP alone.
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Affiliation(s)
- Stina Bodén
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
| | - Robin Myte
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Justin Harbs
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Anneli Sundkvist
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Carl Zingmark
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | | | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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29
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Zhang X, Song H, Canup BSB, Xiao B. Orally delivered targeted nanotherapeutics for the treatment of colorectal cancer. Expert Opin Drug Deliv 2020; 17:781-790. [PMID: 32237921 DOI: 10.1080/17425247.2020.1748005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC), the third-most common malignancy, has high morbidity and mortality. Oral nanotherapeutics have emerged as a promising strategy to improve the therapeutic outcomes and alleviate the adverse effects of drugs in CRC treatment. AREAS COVERED In this review, we introduce the beneficial features of oral drug administration for CRC therapy, and further address the three basic elements of nanotherapeutics, namely, therapeutic agents, carrier materials, and targeting ligands. In addition, we also discuss the potentials of the new emerging technologies (e.g., immunotherapy, gene editing and microbiota manipulation) in the treatment of CRC. EXPERT OPINION Orally delivered targeted nanotherapeutics represent a promising strategy toward the efficient treatment of CRC. Although the current oral nanotherapeutics exert better therapeutic outcomes than the traditional drug formulations, their application has been restricted by drug resistance, tumor metastasis, and biosafety. Therefore, it is necessary to exploit new nanotherapeutics in the aspects of their three basic elements, and combine the new emerging technologies to those nanotherapeutics for CRC treatment.
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Affiliation(s)
- Xueqing Zhang
- State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University , Beibei, P. R. China
| | - Heliang Song
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, GA, USA
| | - Brandon S B Canup
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, GA, USA
| | - Bo Xiao
- State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University , Beibei, P. R. China.,Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture and Rural Affairs, College of Biotechnology, Southwest University , Chongqing, P. R. China
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30
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Xu M, Guo X, Wang RD, Zhang ZH, Jia YM, Sun X. Long non-coding RNA HANR as a biomarker for the diagnosis and prognosis of colorectal cancer. Medicine (Baltimore) 2020; 99:e19066. [PMID: 32049807 PMCID: PMC7035088 DOI: 10.1097/md.0000000000019066] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Previous work suggests that the long noncoding RNA HCC associated long non-coding RNA (HANR) is associated with hepatocellular carcinoma (HCC) progression, but its significance in the context of colorectal cancer (CRC) remains to be determined. Therefore, in this study we assessed the prognostic and diagnostic value of HANR in patients suffering from CRC.The HANR expression in 165 pairs of CRC cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of CRC patients.In this study, levels of HANR were significantly higher in CRC tumor samples relative to adjacent normal tissue samples (P < .001). A ROC analysis suggested HANR expression could be reliably used to differentiate between normal and CRC tumor tissue. In addition, elevated HANR expression was positively correlated with more advanced and aggressive CRC features, such as a larger tumor size (P = .003), increased invasion depth (P = .012), and more advanced TNM stage (P = .011). Survival analyses revealed that elevated HANR expression was correlated with worse overall survival (P = .002) and disease-free survival (P = .003). A multivariate analysis further confirmed the relevance of HANR as an independent predictor of CRC patient outcomes.In summary, these results indicate that the lncRNA HANR is a promising prognostic indicator in CRC patients.
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Affiliation(s)
- Meng Xu
- Department of Colorectal Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University
| | - Xu Guo
- Department of Colorectal Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University
| | - Rong-Di Wang
- Department of Colorectal Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University
| | - Zhi-Hang Zhang
- Department of Colorectal Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University
| | - Yi-Mo Jia
- Dalian Medical University, Dalian City, Liaoning Province, China
| | - Xu Sun
- Department of Colorectal Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University
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31
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Zhang L, Qiao X, Chen M, Li P, Wen X, Sun M, Ma X, Hou Y, Yang J. Ilexgenin A prevents early colonic carcinogenesis and reprogramed lipid metabolism through HIF1α/SREBP-1. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 63:153011. [PMID: 31301538 DOI: 10.1016/j.phymed.2019.153011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 06/21/2019] [Accepted: 07/01/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Ilexgenin A (IA), the main bioactive compound from Ilex hainanensis Merr., has significant hypolipidemic activities. However, the effects of IA on colitis-associated colorectal cancer (CRC) and its mechanisms are still unknown. PURPOSE The study was designed to evaluate the effect of IA on CRC and explore its underlying mechanisms. STUDY DESIGN The effect of IA on colitis related CRC were evaluated in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice and the underlying mechanisms were revealed by metabolomics, which were further validated in vivo and in vitro. METHODS The Balb/c mice were treated with AOM/DSS to induce CRC model and fed with normal diet with or without 0.02% IA. After the experimental period, samples of plasma were collected and analyzed by ultra-high-performance liquid chromatography/quadrupole time off light mass spectrometry (UHPLC-Q-TOF). Multivariate statistical tools were used to identify the changes of serum metabolites associated with CRC and responses to IA treatment. HT 29 and HCT 116 cells were stimulated by palmitate (PA) and cultured under hypoxia. Western blot, Q-PCR, and Immunofluorescence staining were performed to confirm the molecular pathway in vivo and in vitro. RESULTS Our results showed IA significantly inhibited the inflammatory colitis symptoms such as disease activity index score, shortening of colon tissues and the increase of inflammatory cytokines. In metabolomic study, 31 potential metabolites associated with CRC were identified and 24 of them were reversed by IA treatment. Most of biomarkers were associated with arachidonic acid metabolism, glycerophospholipid catabolism, and phospholipid metabolism, suggesting lipid metabolism might be involved in the beneficial effect of IA on CRC. Furthermore, we also found IA could decrease the expressions of SREBP-1 and its target gene in the colon tissues of AOM/DSS mice. It could down-regulate the triglyceride (TG) content and the expressions of HIF1α, SREBP-1, FASN, and ACC in HT 29 and HCT 116 cells. The inhibitory effect of IA on SREBP-1 was also attenuated by desferrioxamine (DFX), suggesting HIF1α is involved in the regulation of IA on SREBP-1. CONCLUSION IA prevents early colonic carcinogenesis in AOM/DSS mice and reprogramed lipid metabolism partly through HIF1α/SREBP-1.
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Affiliation(s)
- Li Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Xin Qiao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Meihong Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Xiaodong Wen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Minhui Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Xiaonan Ma
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Yingjian Hou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
| | - Jie Yang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China.
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Assidi M, Gomaa W, Jafri M, Hanbazazh M, Al-Ahwal M, Pushparaj P, Al-Harbi A, Al-Qahtani M, Buhmeida A, Al-Maghrabi J. Prognostic value of Osteopontin (SPP1) in colorectal carcinoma requires a personalized molecular approach. Tumour Biol 2019; 41:1010428319863627. [PMID: 31500540 DOI: 10.1177/1010428319863627] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Stratification of colorectal cancer for better management and tangible clinical outcomes is lacking in clinical practice. To reach this goal, the identification of reliable biomarker(s) is a prerequisite to deliver personalized colorectal cancer theranostics. Osteopontin (SPP1) is a key extracellular matrix protein involved in several pathophysiological processes including cancer progression and metastasis. However, the exact molecular mechanisms regulating its expression, localization, and molecular functions in cancer are still poorly understood. This study was designed to investigate the SPP1 expression profiles in Saudi colorectal cancer patients, and to assess its prognostic value. Hundred thirty-four (134) archival paraffin blocks of colorectal cancer were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed, and automated immunohistochemistry was performed to evaluate SPP1 protein expression patterns in colorectal cancer. About 20% and 23% of our colorectal cancer samples showed high SPP1 cytoplasmic and nuclear expression patterns, respectively. Cytoplasmic SPP1 did not correlate with age, gender, tumor size, and location. However, significant correlations were observed with tumor grade (p = 0.008), tumor invasion (p = 0.01), and distant metastasis (p = 0.04). Kaplan-Meier survival analysis showed a significantly lower recurrence rate in patients with higher SPP1 cytoplasmic expression (p = 0.05). At multivariate analysis, high SPP1 cytoplasmic expression was an independent favorable prognostic marker (p = 0.02). However, nuclear SPP1 expression did not show any prognostic value (p = 0.712). Our results showed a particular SPP1 prognostic relevance that is not in line with most colorectal cancer previous studies that may be attributed to the molecular pathophysiology of our colorectal cancer cohort. Saudi Arabia has both specific genomic makeup and particular environment that could lead to distinctive molecular roots of cancer. SPP1 has several isoforms, tissue localizations and molecular functions, signaling pathways, and downstream molecular functions. Therefore, a more individualized approach for CRC studies and particularly SPP1 prognosis outcomes' assessment is highly recommended toward precision oncology.
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Affiliation(s)
- Mourad Assidi
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Medical Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wafaey Gomaa
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pathology, Faculty of Medicine, Minia University, Al Minia, Egypt
| | - Mohammad Jafri
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Medical Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mehenaz Hanbazazh
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Al-Ahwal
- Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Peter Pushparaj
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Medical Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Asia Al-Harbi
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Al-Qahtani
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdelbaset Buhmeida
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jaudah Al-Maghrabi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
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Liu YR, Hu Y, Zeng Y, Li ZX, Zhang HB, Deng JL, Wang G. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) as prognostic biomarkers for colorectal cancer. J Cell Biochem 2019; 120:18041-18052. [PMID: 31297877 DOI: 10.1002/jcb.29107] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/18/2019] [Indexed: 12/24/2022]
Abstract
Owing to the high morbidity and mortality, novel biomarkers in the occurrence and development of colorectal cancer (CRC) are needed nowadays. In this study, the CRC-related datasets were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. After screening the differentially expressed genes (DEGs) in R software, a total of 238 upregulated and 199 downregulated DEGs were revealed simultaneously. Then the Kaplan-Meier survival analysis and Cox regression analysis were used to reveal the prognostic function of these DEGs. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) were two outstanding independent overall survival (OS) and relapse-free survival (RFS) prognostic genes of CRC in TCGA database. We next verified the expression of NXPE4 and PARM1 messenger RNA (mRNA) levels were significantly lower in CRC tumor tissue than in the adjacent noncancerous tissue in our clinical samples, and NXPE4 mRNA expression level was related to the tumor location and tumor size, while PARM1 was related to tumor location, lymph nodes metastasis, and tumor size. This study demonstrated that NXPE4 and PARM1 might be two potential novel prognostic biomarkers for CRC.
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Affiliation(s)
- Ya-Rui Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Yang Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Ying Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Zhi-Xing Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Hai-Bo Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Jun-Li Deng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
| | - Guo Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, P.R. China
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Kim E, Jung S, Park WS, Lee JH, Shin R, Heo SC, Choe EK, Lee JH, Kim K, Chai YJ. Upregulation of SLC2A3 gene and prognosis in colorectal carcinoma: analysis of TCGA data. BMC Cancer 2019; 19:302. [PMID: 30943948 PMCID: PMC6446261 DOI: 10.1186/s12885-019-5475-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 03/14/2019] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Upregulation of SLC2A genes that encode glucose transporter (GLUT) protein is associated with poor prognosis in many cancers. In colorectal cancer, studies reporting the association between overexpression of GLUT and poor clinical outcomes were flawed by small sample sizes or subjective interpretation of immunohistochemical staining. Here, we analyzed mRNA expressions in all 14 SLC2A genes and evaluated the association with prognosis in colorectal cancer using data from the Cancer Genome Atlas (TCGA) database. METHODS In the present study, we analyzed the expression of SLC2A genes in colorectal cancer and their association with prognosis using data obtained from the TCGA for the discovery sample, and a dataset from the Gene Expression Omnibus for the validation sample. RESULTS SLC2A3 was significantly associated with overall survival (OS) and disease-free survival (DFS) in both the discovery sample (345 patients) and validation sample (501 patients). High SLC2A3 expression resulted in shorter OS and DFS. In multivariate analyses, high SLC2A3 levels predicted unfavorable OS (adjusted HR 1.95, 95% CI 1.22-3.11; P = 0.005) and were associated with poor DFS (adjusted HR 1.85, 95% CI 1.10-3.12; P = 0.02). Similar results were found in the discovery set. CONCLUSION Upregulation of the SLC2A3 genes is associated with decreased OS and DFS in colorectal cancer patients. Therefore, assessment of SLC2A3 gene expression may useful for predicting prognosis in these patients.
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Affiliation(s)
- Eunyoung Kim
- Department of Surgery, National Medical Center, Seoul, Republic of Korea
| | - Sohee Jung
- Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Won Seo Park
- Department of Surgery, Graduate College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Joon-Hyop Lee
- Department of Surgery, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Rumi Shin
- Department of Surgery, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 156-70, Republic of Korea
| | - Seung Chul Heo
- Department of Surgery, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 156-70, Republic of Korea
| | - Eun Kyung Choe
- Department of Surgery, Seoul National University Hospital Healthcare System, Gangnam Center, Seoul, Republic of Korea
| | - Jae Hyun Lee
- Department of Statistics, Korea University, Seoul, Republic of Korea
| | - Kwangsoo Kim
- Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
| | - Young Jun Chai
- Department of Surgery, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 156-70, Republic of Korea.
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Francavilla A, Tarallo S, Pardini B, Naccarati A. Fecal microRNAs as non-invasive biomarkers for the detection of colorectal cancer: a systematic review. MINERVA BIOTECNOL 2019; 31. [DOI: 10.23736/s1120-4826.18.02495-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Radpour R, Forouharkhou F. Single-cell analysis of tumors: Creating new value for molecular biomarker discovery of cancer stem cells and tumor-infiltrating immune cells. World J Stem Cells 2018; 10:160-171. [PMID: 30631391 PMCID: PMC6325074 DOI: 10.4252/wjsc.v10.i11.160] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Biomarker-driven individualized treatment in oncology has made tremendous progress through technological developments, new therapeutic modalities and a deeper understanding of the molecular biology for tumors, cancer stem cells and tumor-infiltrating immune cells. Recent technical developments have led to the establishment of a variety of cancer-related diagnostic, prognostic and predictive biomarkers. In this regard, different modern OMICs approaches were assessed in order to categorize and classify prognostically different forms of neoplasia. Despite those technical advancements, the extent of molecular heterogeneity at the individual cell level in human tumors remains largely uncharacterized. Each tumor consists of a mixture of heterogeneous cell types. Therefore, it is important to quantify the dynamic cellular variations in order to predict clinical parameters, such as a response to treatment and or potential for disease recurrence. Recently, single-cell based methods have been developed to characterize the heterogeneity in seemingly homogenous cancer cell populations prior to and during treatment. In this review, we highlight the recent advances for single-cell analysis and discuss the challenges and prospects for molecular characterization of cancer cells, cancer stem cells and tumor-infiltrating immune cells.
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Affiliation(s)
- Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Farzad Forouharkhou
- Department for Bioinformatics, Persian Bioinformatics System, Tehran 14166, Iran
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Franczak C, Filhine-Tressarieu P, Broséus J, Gilson P, Merlin JL, Harlé A. Clinical Interest of Circulating Tumor DNA in Oncology. Arch Med Res 2018; 49:297-305. [PMID: 30414710 DOI: 10.1016/j.arcmed.2018.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/25/2018] [Indexed: 12/18/2022]
Abstract
Genetic alterations in tumors, as predictor of response to targeted-therapies or as prognostic markers, are clinically relevant to determine adequate therapeutic management. Tumor biopsy is currently the golden standard for somatic alterations assessment, but this approach is invasive and does not consider tumor heterogeneity. In various body fluids like plasma, somatic mutations have been identified. Circulating tumor DNA (ctDNA) holds promises in tumor burden monitoring or malignancies early detection. Since allele frequencies of circulating somatic mutations are low, highly sensitive novel assays have been developed to allow the investigation of the tumor genome, leading to the emergence of the "liquid biopsy" concept. Despite these technological advances, other assays for identifying intratumor and intermetastases heterogeneity need to be developed. Before being applied to clinic, ctDNA analyses need to be harmonized and validated with well-powered, well-designed studies. One of the primary prerequisite to incorporation of ctDNA analysis in the follow-up strategy of malignancies is the checking of the concordance with golden standard detection methods, imaging, circulating proteins and biopsy. This review focuses on the clinical interest of ctDNA in solid tumors and hematological malignancies.
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Affiliation(s)
- Claire Franczak
- Institut de Cancérologie de Lorraine, Service de Biopathologie, Vandœuvre-lès-Nancy, France
| | | | - Julien Broséus
- Inserm U954, Faculté de Médecine de Nancy, Université de Lorraine, Vandœuvre-lès-Nancy, France; Service d'Hématologie Biologique, Pôle Laboratoires, Centre Hospitalier Régional et Universitaire de Nancy, Vandœuvre-lès-Nancy, France
| | - Pauline Gilson
- Université de Lorraine, CNRS UMR 7039 CRAN, Institut de Cancérologie de Lorraine, Service de Biopathologie, Nancy, France
| | - Jean-Louis Merlin
- Université de Lorraine, CNRS UMR 7039 CRAN, Institut de Cancérologie de Lorraine, Service de Biopathologie, Nancy, France
| | - Alexandre Harlé
- Université de Lorraine, CNRS UMR 7039 CRAN, Institut de Cancérologie de Lorraine, Service de Biopathologie, Nancy, France.
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Sun X, Tian Y, Zheng Q, Zheng R, Lin A, Chen T, Zhu Y, Lai M. A novel discriminating colorectal cancer model for differentiating normal and tumor tissues. Epigenomics 2018; 10:1463-1475. [DOI: 10.2217/epi-2018-0063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Xiaohui Sun
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Yiping Tian
- Key Laboratory of Disease Proteomics of Zhejiang Province & Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, PR China
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, PR China
| | - Qianqian Zheng
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Ruizhi Zheng
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Aifen Lin
- Human Tissue Bank/Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, PR China
| | - Tianhui Chen
- Group of Molecular Epidemiology & Cancer Precision Prevention, Zhejiang Academy of Medical Sciences, Hangzhou, PR China
| | - Yimin Zhu
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Maode Lai
- Key Laboratory of Disease Proteomics of Zhejiang Province & Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, PR China
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Aberrantly Expressed Genes and miRNAs in Slow Transit Constipation Based on RNA-Seq Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2617432. [PMID: 30186855 PMCID: PMC6112260 DOI: 10.1155/2018/2617432] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/26/2018] [Accepted: 07/18/2018] [Indexed: 02/06/2023]
Abstract
Background This study aims to identify the key genes and miRNAs in slow transit constipation (STC). Methods MRNA and miRNA expression profiling were obtained. Differentially expressed genes (DEGs) and miRNAs were identified followed by the regulatory network construction. Functional annotation analysis and protein-protein interaction (PPI) network were conducted. The electronic validation was performed. Results Hsa-miR-2116-3p, hsa-miR-3622a-5p, hsa-miR-424-5p, and hsa-miR-1273-3p covered most DEGs. HLA-DRB1, HLA-DRB5, C3, and ICAM were significantly involved in staphylococcus aureus infection. The PPI network generated several hub proteins including ZBTB16, FBN1, CCNF, and CDK1. Electronic validation of HLA-DRB1, PTGDR, MKI67, BIRC5, CCNF, and CDK1 was consistent with the RNA-sequencing analysis. Conclusion Our study might be helpful in understanding the pathology of STC at the molecular level.
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Application of Fecal Volatile Organic Compound Analysis in Clinical Practice: Current State and Future Perspectives. CHEMOSENSORS 2018. [DOI: 10.3390/chemosensors6030029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Increasing interest is noticed in the potential of volatile organic compound (VOC) analysis as non-invasive diagnostic biomarker in clinical medical practice. The spectrum of VOCs, originating from (patho)physiological metabolic processes in the human body and detectable in bodily excrements, such as exhaled breath, urine and feces, harbors a magnificent source of information. Thus far, the majority of studies have focused on VOC analysis in exhaled breath, aiming at identification of disease-specific VOC profiles. Recently, an increasing number of studies have evaluated the usability of VOC present in the headspace of feces in the diagnostic work-up of a wide range of gastrointestinal diseases. Promising results have been demonstrated particularly in those diseases in which microbiota alterations are considered to play a significant etiological role, such as colorectal carcinoma, inflammatory bowel disease, irritable bowel syndrome, celiac disease and infectious bowel diseases. In addition, fecal VOC analysis seems to have potential as a diagnostic biomarker for extra-intestinal diseases, including bronchopulmonary dysplasia and sepsis. Different methods for VOC analysis have been used in medical studies, such as gas-chromatography mass spectrometry, selected-ion flow tube-mass spectrometry, ion-mobility spectrometry, and electronic nose devices. In this review, the available literature on the potential of fecal VOCs as diagnostic biomarker, including an overview of relevant VOC detection techniques, is discussed. In addition, future hurdles, which need to be taken prior to implementation of VOC analysis in daily clinical practice, are outlined.
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Fang M, Wang C, Zheng C, Luo J, Hou S, Liu K, Li X. Mir-29b promotes human aortic valve interstitial cell calcification via inhibiting TGF-β3 through activation of wnt3/β-catenin/Smad3 signaling. J Cell Biochem 2018; 119:5175-5185. [PMID: 29227539 PMCID: PMC6001435 DOI: 10.1002/jcb.26545] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 11/30/2017] [Indexed: 01/08/2023]
Abstract
Herein, we hypothesized that pro-osteogenic MicroRNAs (miRs) could play functional roles in the calcification of the aortic valve and aimed to explore the functional role of miR-29b in the osteoblastic differentiation of human aortic valve interstitial cells (hAVICs) and the underlying molecular mechanism. Osteoblastic differentiation of hAVICs isolated from human calcific aortic valve leaflets obtained intraoperatively was induced with an osteogenic medium. Alizarin red S staining was used to evaluate calcium deposition. The protein levels of osteogenic markers and other proteins were evaluated using western blotting and/or immunofluorescence while qRT-PCR was applied for miR and mRNA determination. Bioinformatics and luciferase reporter assay were used to identify the possible interaction between miR-29b and TGF-β3. Calcium deposition and the number of calcification nodules were pointedly and progressively increased in hAVICs during osteogenic differentiation. The levels of osteogenic and calcification markers were equally increased, thus confirming the mineralization of hAVICs. The expression of miR-29b was significantly increased during osteoblastic differentiation. Furthermore, the osteoblastic differentiation of hAVICs was significantly inhibited by the miR-29b inhibition. TGF-β3 was markedly downregulated while Smad3, Runx2, wnt3, and β-catenin were significantly upregulated during osteogenic induction at both the mRNA and protein levels. These effects were systematically induced by miR-29b overexpression while the inhibition of miR-29b showed the inverse trends. Moreover, TGF-β3 was a direct target of miR-29b. Inhibition of miR-29b hinders valvular calcification through the upregulation of the TGF-β3 via inhibition of wnt/β-catenin and RUNX2/Smad3 signaling pathways.
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Affiliation(s)
- Ming Fang
- Department of CardiologyHainan General HospitalHaikouHainanP.R. China
- Department of CardiologyShanghai Zhoupu HospitalShanghaiP.R. China
| | - Cheng‐Guang Wang
- Laboratory of System BiologyShanghai Advanced Research InstituteChinese Academy of SciencesShanghaiP.R. China
| | - Changzhu Zheng
- Department of CardiologyShanghai Zhoupu HospitalShanghaiP.R. China
| | - Jun Luo
- Department of CardiologyShanghai Zhoupu HospitalShanghaiP.R. China
| | - Shiqiang Hou
- Department of CardiologyShanghai Zhoupu HospitalShanghaiP.R. China
| | - Kangyong Liu
- Department of NeurologyShanghai Zhoupu HospitalShanghaiP.R. China
| | - Xinming Li
- Department of CardiologyShanghai Zhoupu HospitalShanghaiP.R. China
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Nikolouzakis TK, Vassilopoulou L, Fragkiadaki P, Sapsakos TM, Papadakis GZ, Spandidos DA, Tsatsakis AM, Tsiaoussis J. Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review). Oncol Rep 2018; 39:2455-2472. [PMID: 29565457 PMCID: PMC5983921 DOI: 10.3892/or.2018.6330] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy. In that way, they will be able to decrease both morbidity and mortality of their patients. In accordance with that, colon cancer research has described numerous biomarkers for diagnostic, prognostic and predictive purposes that either alone or as part of a panel would help improve patient's clinical management. This review aims to describe the most accepted biomarkers among those proposed for use in CRC divided based on the clinical specimen that is examined (tissue, faeces or blood) along with their restrictions. Lastly, new insight in CRC monitoring will be discussed presenting promising emerging biomarkers (telomerase activity, telomere length and micronuclei frequency).
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Affiliation(s)
| | - Loukia Vassilopoulou
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Theodoros Mariolis Sapsakos
- Laboratory of Anatomy and Histology, Nursing School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Z. Papadakis
- Foundation for Research and Technology Hellas (FORTH), Institute of Computer Sciences (ICS), Computational Biomedicine Laboratory (CBML), 71003 Heraklion, Crete, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aristides M. Tsatsakis
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
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Bruno A, Bassani B, D'Urso DG, Pitaku I, Cassinotti E, Pelosi G, Boni L, Dominioni L, Noonan DM, Mortara L, Albini A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer. FASEB J 2018; 32:5365-5377. [PMID: 29763380 DOI: 10.1096/fj.201701103r] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56brightCD16dim/-CD9+CD49+ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.
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Affiliation(s)
- Antonino Bruno
- Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Barbara Bassani
- Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Davide Giuseppe D'Urso
- Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Ilvana Pitaku
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Elisa Cassinotti
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Luigi Boni
- Department of Medical-Surgical Physiopathology and Transplantation, University of Milan-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ca' Granda, Polyclinic Hospital, Milan, Italy
| | - Lorenzo Dominioni
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Douglas M Noonan
- Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy.,Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy; and
| | - Lorenzo Mortara
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy; and
| | - Adriana Albini
- Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy.,Department of Medicine and Surgery, University Milano-Bicocca, Monza, Italy
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Gao SJ, Chen L, Lu W, Zhang L, Wang L, Zhu HH. miR-888 functions as an oncogene and predicts poor prognosis in colorectal cancer. Oncol Lett 2018; 15:9101-9109. [PMID: 29928331 PMCID: PMC6004656 DOI: 10.3892/ol.2018.8461] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 06/06/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of tumor formation, progression and metastasis. The present study characterized a novel miRNA (miR)-888, as a potent oncomiR in human colorectal cancer (CRC). The clinicopathological investigation on 126 cases of CRC patients demonstrated that the expression level of miR-888 was significantly upregulated in tumors compared with adjacent healthy tissue, and was associated with tumor stage and histological differentiation. A Kaplan-Meier analysis and log-rank test demonstrated that CRC patients with increased miR-888 expression exhibited a decreased overall survival (OS) and disease-free survival (DFS) compared with patients with low miR-888 expression. Further univariate and multivariate analyses identified miR-888 as an independent prognostic factor for poor survival outcome in CRC patients. To determine the biological role of miR-888 in human CRC, in vitro Cell Counting kit-8, wound healing and transwell assays were performed and demonstrated that miR-888 contributed greatly to CRC cell proliferation, invasion and metastasis. Furthermore, potential targets of miR-888 were investigated using a luciferase reporter assay, followed by polymerase chain reaction and western blot analysis. The findings revealed that miR-888 directly bound to the 3′-untranslated region of mothers against decapentaplegic-4 and thus inhibited its expression and promoted the tumor growth factor-1-induced cancer metastasis signaling. The results of the present study identified miR-888 as an oncogenic miRNA in CRC and provide a foundation for promising research in the future regarding this predictive and prognostic biomarker.
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Affiliation(s)
- Su-Jun Gao
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Lei Chen
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Wei Lu
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Li Zhang
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Lu Wang
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Hai-Hang Zhu
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
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Buhmeida A, Assidi M, Al-Maghrabi J, Dallol A, Sibiany A, Al-Ahwal M, Chaudhary A, Abuzenadah A, Al-Qahtani M. Membranous or Cytoplasmic HER2 Expression in Colorectal Carcinoma: Evaluation of Prognostic Value Using Both IHC & BDISH. Cancer Invest 2018; 36:129-140. [PMID: 29504811 DOI: 10.1080/07357907.2018.1439054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Human epidermal growth factor recptor-2 (HER2) was identified as a driver gene in several types of cancers with both prognostic and predictive value. However, the molecular association of HER2 gene mutation with HER2 gene amplification and/or protein expression in cancer tissues has not been clearly defined. Moreover, there is little information available on HER2 status role in tumor progression and metastasis in colorectal carcinoma (CRC) compared to other solid tumors. The aim of this study was to evaluate both HER2 amplification and protein expression profiles using immunohistochemistry (IHC) and bright-field dual in situ hybridization (BDISH) techniques, respectively. PATIENTS AND METHODS Tissue microarray (TMA) was constructed to accommodate a total of 243 CRC formalin-fixed paraffin embedded (FFPE) samples of consent patients and stained by IHC and BDISH methods. The expression patterns of HER2 protein status were evaluated and correlated to HER2 gene amplification status and then assessed for its prognostic value. RESULTS The expression profile of 58% samples showed cytoplasmic expression patterns of different categories. Interestingly, only 1% showed strong (+3) membranous expression pattern of HER2 with perfect match with their corresponding gene amplification status (>2). However, the cytoplasmic HER2 protein status did not show significant correlation with most clinicopathological features and survival outcomes except with age (p = 0.04) and tumor size (p = 0.03). CONCLUSION We demonstrated that the membranous HER2 gene/protein status is infrequent, while the main fraction of HER2 overexpression was cytoplasmic and lacking prognostic value. This cytoplasmic HER2 overexpression was induced through a gene-amplification independent pathway, making the HER2 gene status evaluation approach in those cases not worthy. Further investigations about the molecular pathways of the cytoplasmic HER2 protein in CRC and its associations with survival outcomes are required to allow either a breakthrough in CRC management; or to confirm the hypothesis of a marginal role in CRC onset and progression.
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Affiliation(s)
- Abdelbaset Buhmeida
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mourad Assidi
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Jaudah Al-Maghrabi
- c Department of Pathology, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Ashraf Dallol
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Abdulrahman Sibiany
- d Department of Surgery, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mahmoud Al-Ahwal
- e Department of Internal Medicine, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adeel Chaudhary
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adel Abuzenadah
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mohammed Al-Qahtani
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
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Liu HN, Liu TT, Wu H, Chen YJ, Tseng YJ, Yao C, Weng SQ, Dong L, Shen XZ. Serum microRNA signatures and metabolomics have high diagnostic value in colorectal cancer using two novel methods. Cancer Sci 2018; 109:1185-1194. [PMID: 29363233 PMCID: PMC5891204 DOI: 10.1111/cas.13514] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/10/2018] [Accepted: 01/18/2018] [Indexed: 12/14/2022] Open
Abstract
Recently, many new diagnostic biomarkers have been developed for colorectal cancer. We chose 2 methods with high diagnostic efficiency, the detection of serum microRNA and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. We reviewed the diagnostic value of all microRNA identified by previous diagnostic tests. We selected appropriate microRNA to validate their diagnostic efficiency, and determined the optimal combination. We included 85 patients with colorectal cancer (CRC) and 78 healthy controls (HC) and detected the expression of the microRNA. GC/MS analysis was conducted, and we used 3 multivariate statistical methods to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) were detected for comparison with the novel models. Ultimately, 62 published studies and 63 microRNA were included in this review. MiR‐21, miR‐29a, miR‐92a, miR‐125b and miR‐223 were selected to further validate their diagnostic value. The serum levels of the 5 microRNA in CRC patients were significantly higher than those in the HC. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952, with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. With regard to traditional biomarkers, the AUC of CEA and CA19‐9 were 0.808 and 0.705, respectively. The application prospects are good for microRNA and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers.
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Affiliation(s)
- Hai-Ning Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hao Wu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yu-Jen Tseng
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Can Yao
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Shu-Qiang Weng
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ling Dong
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
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47
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Telechea-Fernández M, Rodríguez-Fernández L, García C, Zaragozá R, Viña J, Cervantes A, García-Trevijano ER. New localization and function of calpain-2 in nucleoli of colorectal cancer cells in ribosomal biogenesis: effect of KRAS status. Oncotarget 2018; 9:9100-9113. [PMID: 29507677 PMCID: PMC5823616 DOI: 10.18632/oncotarget.23888] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022] Open
Abstract
Calpain-2 belongs to a family of pleiotropic Cys-proteases with modulatory rather than degradative functions. Calpain (CAPN) overexpression has been controversially correlated with poor prognosis in several cancer types, including colorectal carcinoma (CRC). However, the mechanisms of substrate-recognition, calpain-2 regulation/deregulation and specific functions in CRC remain elusive. Herein, calpain subcellular distribution was studied as a key event for substrate-recognition and consequently, for calpain-mediated function. We describe a new localization for calpain-2 in the nucleoli of CRC cells. Calpain-2 nucleolar distribution resulted dependent on its enzymatic activity and on the mutational status of KRAS. In KRASWT/- cells serum-starvation induced CAPN2 expression, nucleolar accumulation and increased binding to the rDNA-core promoter and intergenic spacer (IGS), concomitant with a reduction in pre-rRNA levels. Depletion of calpain-2 by specific siRNA prevented pre-rRNA down-regulation after serum removal. Conversely, ribosomal biogenesis proceeded in the absence of serum in unresponsive KRASG13D/- cells whose CAPN2 expression, nucleolar localization and rDNA-occupancy remained unchanged during the time-course of serum starvation. We propose here that nucleolar calpain-2 might be a KRAS-dependent sensor to repress ribosomal biogenesis in growth limiting conditions. Under constitutive activation of the pathway commonly found in CRC, calpain-2 is deregulated and tumor cells become insensitive to the extracellular microenvironment.
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Affiliation(s)
- Marcelino Telechea-Fernández
- CIBERONC, Department of Medical Oncology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Lucia Rodríguez-Fernández
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Concha García
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Rosa Zaragozá
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain.,Department of Anatomy and Human Embriology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Juan Viña
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- CIBERONC, Department of Medical Oncology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
| | - Elena R García-Trevijano
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute/University of Valencia, Valencia, Spain
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Peluso G, Incollingo P, Calogero A, Tammaro V, Rupealta N, Chiacchio G, Sandoval Sotelo ML, Minieri G, Pisani A, Riccio E, Sabbatini M, Bracale UM, Dodaro CA, Carlomagno N. Current Tissue Molecular Markers in Colorectal Cancer: A Literature Review. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2605628. [PMID: 29214162 PMCID: PMC5682052 DOI: 10.1155/2017/2605628] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 09/18/2017] [Accepted: 10/03/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most spread neoplasia types all around the world, especially in western areas. It evolves from precancerous lesions and adenomatous polyps, through successive genetic and epigenetic mutations. Numerous risk factors intervene in its development and they are either environmental or genetic. AIM OF THE REVIEW Alongside common screening techniques, such as fecal screening tests, endoscopic evaluation, and CT-colonography, we have identified the most important and useful biomarkers and we have analyzed their role in the diagnosis, prevention, and prognosis of CRC. CONCLUSION Biomarkers can become an important tool in the diagnostic and therapeutic process for CRC. But further studies are needed to identify a noninvasive, cost-effective, and highly sensible and specific screening test for their detection and to standardize their use in clinical practice.
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Affiliation(s)
- Gaia Peluso
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Paola Incollingo
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Armando Calogero
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Vincenzo Tammaro
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Niccolò Rupealta
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Gaetano Chiacchio
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Maria Laura Sandoval Sotelo
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Gianluca Minieri
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Antonio Pisani
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Eleonora Riccio
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Massimo Sabbatini
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Umberto Marcello Bracale
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Concetta Anna Dodaro
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | - Nicola Carlomagno
- Department of Advanced Biomedical Science, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
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Radpour R. Tracing and targeting cancer stem cells: New venture for personalized molecular cancer therapy. World J Stem Cells 2017; 9:169-178. [PMID: 29104735 PMCID: PMC5661129 DOI: 10.4252/wjsc.v9.i10.169] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/14/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023] Open
Abstract
Tumors consist of a mixture of heterogeneous cell types. Cancer stem cells (CSCs) are a minor sub-population within the bulk cancer fraction which has been found to reconstitute and propagate the disease and to be frequently resistant to chemotherapy, irradiation, cytotoxic drugs and probably also against immune attack. CSCs are considered as the seeds of tumor recurrence, driving force of tumorigenesis and metastases. This underlines the urgent need for innovative methods to identify and target CSCs. However, the role and existence of CSCs in therapy resistance and cancer recurrence remains a topic of intense debate. The underlying biological properties of the tumor stem cells are extremely dependent on numerous signals, and the targeted inhibition of these stem cell signaling pathways is one of the promising approaches of the new antitumor therapy approaches. This perspective review article summarizes the novel methods of tracing CSCs and discusses the hallmarks of CSC identification influenced by the microenvironment or by having imperfect detection markers. In addition, explains the known molecular mechanisms of therapy resistance in CSCs as reliable and clinically predictive markers that could enable the use of new targeted antitumor therapy in the sense of personalized medicine.
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Affiliation(s)
- Ramin Radpour
- Tumor Immunology and Cancer Stem Cells, Inselspital, Bern University Hospital, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland.
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50
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The BET-Bromodomain Inhibitor JQ1 synergized ABT-263 against colorectal cancer cells through suppressing c-Myc-induced miR-1271-5p expression. Biomed Pharmacother 2017; 95:1574-1579. [PMID: 28950657 DOI: 10.1016/j.biopha.2017.09.087] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 09/17/2017] [Accepted: 09/18/2017] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) cells undergo apoptosis in the presence of the small-molecule inhibitor ABT-263 by up-regulating antiapoptotic Bcl-2 family members. However, the resistance to ABT-263 gradually developed in most solid tumors due to its low affinity to Mcl-1. Here, we found the BET-Bromodomain inhibitor JQ1, when combined with ABT-263, synergistically reduced Mcl-1 protein level, induced apoptosis, and decreased cell viability in the CRC HCT-15, HT-29 and SW620 cells. The subsequent mechanism study revealed that a pathway of c-Myc/miR-1271-5p/Noxa/Mcl-1 underlies the synergistic effect of such combination treatment. We discovered that miR-1271-5p, the key mediator for the synergistic effect, is transcriptionally activated by c-Myc, and binds to the 3'-UTR of noxa to inhibit its protein production. The combination treatment of JQ1 and ABT-263 inhibited c-Myc protein level and also c-Myc-driven expression of miR-1271-5p, subsequently increased the protein level of Noxa, and finally promotes the degradation of Mcl-1. Our findings provide an alternative strategy to resolve the resistance during treatment of CRC by JQ1, and also discovered a novel miR-1271-5p-dependent regulatory mechanism for gene expression of noxa.
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