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1
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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2
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Coelho D, Estêvão D, Oliveira MJ, Sarmento B. Radioresistance in rectal cancer: can nanoparticles turn the tide? Mol Cancer 2025; 24:35. [PMID: 39885557 PMCID: PMC11784129 DOI: 10.1186/s12943-025-02232-x] [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: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.
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Affiliation(s)
- Diogo Coelho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
| | - Diogo Estêvão
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute, Ghent University, Ghent, Belgium
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal.
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3
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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4
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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5
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Zhao P, Ning J, Huang J, Wei B, Wang Z, Huang X. High Expression of MORC2 is Associated with Poor Clinical Outcomes and Immune Infiltrates in Colon Adenocarcinoma. Int J Gen Med 2023; 16:4595-4615. [PMID: 37850194 PMCID: PMC10577261 DOI: 10.2147/ijgm.s420715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 09/07/2023] [Indexed: 10/19/2023] Open
Abstract
Purpose Microrchidia 2 (MORC2) is a universally expressed molecule that has recently been identified as a chromatin modulator and elevated in many malignancies. However, its prognostic value and immunological role of MORC2 in colon adenocarcinoma (COAD) have never been illustrated. Methods The clinical parameters and MORC2 expression datasets of COAD patients were obtained from The Cancer Genome Atlas (TCGA). Cancer and adjacent tissue specimens from surgically resected COAD patients were collected, and quantitative real-time PCR was used to detect MORC2 expression. Differentially expressed genes related to MORC2 were discovered and used for functional enrichment analysis. The diagnostic and prognostic values of MORC2 in COAD were conducted using receiver operating characteristics (ROC), Kaplan-Meier survival curve analysis, PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA) public databases and nomograms. Eventually, the association of MORC2 with tumor microenvironment was analyzed by using TIMER and GSVA package of R (v3.6.3). Results MORC2 expression was upregulated in COAD tissues, and the RT-qPCR results further verified the reliability of our differential analysis at the transcriptional level. Additionally, higher expression of MORC2 was correlated to a poor prognosis for COAD patients. MORC2 was an independent prognostic factor for COAD and could be a diagnostic factor for early COAD. Furthermore, MORC2 expression was positively correlated with immune cells such as NK cells, TFH cells and so on. Conclusion The findings demonstrated that overexpression of MORC2 was correlated with worse prognosis and immune infiltrates of COAD. MORC2 can serve as a reliable diagnostic and prognostic biomarker and a target of immunotherapy for COAD patients.
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Affiliation(s)
- Peizhuang Zhao
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jiajia Ning
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jun Huang
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Binqian Wei
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Zhen Wang
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Xue Huang
- Department of Geriatrics and Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
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6
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Malkomes P, Lunger I, Oppermann E, Lorenz J, Faqar-Uz-Zaman SF, Han J, Bothur S, Ziegler P, Bankov K, Wild P, Bechstein WO, Rieger MA. Transglutaminase 2 is associated with adverse colorectal cancer survival and represents a therapeutic target. Cancer Gene Ther 2023; 30:1346-1354. [PMID: 37443286 PMCID: PMC10581896 DOI: 10.1038/s41417-023-00641-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 05/29/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Molecular markers for predicting prognosis of colorectal cancer (CRC) patients are urgently needed for effective disease management. We reported previously that the multifunctional enzyme Transglutaminase 2 (TGM2) is essential for CRC cell survival by inactivation of the tumor suppressor p53. Based on these data, we determined the clinical relevance of TGM2 expression and explored its potential as prognostic marker and therapeutic target in CRC. We profiled TGM2 protein expression in tumor samples of 279 clinically characterized CRC patients using immunohistochemical staining. TGM2 expression was upregulated in matched tumor samples in comparison to normal tissue. A strong TGM2 expression was associated with advanced tumor stages and predicted worse prognosis regarding progression-free and overall-survival, even at early stages. Inhibition of TGM2 in CRC cell lines by the inhibitors LDN27219 and Tyrphostin resulted in a strong reduction of cancer cell proliferation and tumorsphere formation in vitro by induction of p53-mediated apoptosis. Primary patient-derived tumorsphere formation was significantly reduced by inhibition of TGM2. Treatment of mice with TGM2 inhibitors exhibited a significant deceleration of tumor progression. Our data indicate that high TGM2 expression in CRC is associated with worse prognosis and may serve as a therapeutic target in CRC patients with strong TGM2 expression.
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Affiliation(s)
- Patrizia Malkomes
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ilaria Lunger
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
- Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
| | - Elsie Oppermann
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
| | - Johannes Lorenz
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
| | - Sara Fatima Faqar-Uz-Zaman
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
| | - Jiaoyan Han
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
| | - Sabrina Bothur
- Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
| | - Paul Ziegler
- Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany
- University Cancer Center (UCT), Frankfurt am Main, Germany
| | - Katrin Bankov
- Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany
- University Cancer Center (UCT), Frankfurt am Main, Germany
| | - Peter Wild
- Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany
- University Cancer Center (UCT), Frankfurt am Main, Germany
| | - Wolf Otto Bechstein
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, Frankfurt am Main, Germany
| | - Michael A Rieger
- Frankfurt Cancer Institute, Frankfurt am Main, Germany.
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany.
- Cardio-Pulmonary-Institute, Frankfurt am Main, Germany.
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7
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Wakayama S, Ouchi K, Takahashi S, Yamada Y, Komatsu Y, Shimada K, Yamaguchi T, Shirota H, Takahashi M, Ishioka C. TP53 Gain-of-Function Mutation is a Poor Prognostic Factor in High-Methylated Metastatic Colorectal Cancer. Clin Colorectal Cancer 2023; 22:327-338. [PMID: 37355363 DOI: 10.1016/j.clcc.2023.06.001] [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: 03/30/2023] [Revised: 05/26/2023] [Accepted: 06/02/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND Neither TP53 mutation nor DNA methylation status has been established as a biomarker alone of metastatic colorectal cancer. We analyzed the association between TP53 mutation functional subtypes and genome-wide DNA methylation status (GWMS) as combined prognostic markers. METHODS Patient clinical data were obtained from the TRICOLORE study, a randomized phase III trial. The TP53 mutations were classified into wild-type, gain-of-function (GOF) mutations, and non-gain-of-function (non-GOF) mutations. GWMS of the tumor tissues classified them into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Overall survival (OS) was compared based on these subgroups. RESULTS Of the 209 patients, 60 (28.7%) were HMCC and 149 (71.3%) were LMCC, 35 (16.7%) were TP53 wild-type and 174 (83.3%) were TP53 mutants including 79 (45.4%) GOF mutations and 95 (54.6%) non-GOF mutations. The OS of the HMCC group was shorter than that of the LMCC group (median 25.3 vs. 40.3 months, P < .001, hazard ratio 1.87) in the total cohort. The combined subgroup analyses of GWMS and TP53 mutation subtypes showed that the HMCC/GOF group had significantly shorter OS than the HMCC/non-GOF group, the LMCC/GOF group, and the LMCC/non-GOF group (median 17.7; 35.3, 40.3, and 41.2 months, P = .007, P < .001, and P < .001, respectively), regardless of the primary tumor location. By the multivariate analysis, only HMCC (P = .009) was a poor prognostic factor in the GOF mutation group. CONCLUSIONS TP53 GOF with HMCC is a newly identified poorest prognostic molecular subset in metastatic colorectal cancer.
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Affiliation(s)
- Shonosuke Wakayama
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Kota Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Shin Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Yasuhide Yamada
- Comprehensive Cancer Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Yoshito Komatsu
- Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Hokkaido, Japan
| | - Ken Shimada
- Department of Internal Medicine, Division of Medical Oncology, Showa University Koto Toyosu Hospital, Koto-ku, Tokyo, Japan
| | - Tatsuro Yamaguchi
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Hidekazu Shirota
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Masanobu Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan; Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan
| | - Chikashi Ishioka
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan; Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan; Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
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8
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Epstein RJ, Lin FPY, Brink RA, Blackburn J. Synonymous alterations of cancer-associated Trp53 CpG mutational hotspots cause fatal developmental jaw malocclusions but no tumors in knock-in mice. PLoS One 2023; 18:e0284327. [PMID: 37053216 PMCID: PMC10101519 DOI: 10.1371/journal.pone.0284327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/28/2023] [Indexed: 04/14/2023] Open
Abstract
Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human TP53 tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence. We substituted the DNA-binding exons 5-8 of Trp53, the mouse ortholog of human TP53, with variant-CpG (either CpG-depleted or -enriched) sequences predicted to encode the normal p53 amino acid sequence; a control construct was also created in which all non-CpG sites were synonymously substituted. Homozygous Trp53-null mice were the only genotype to develop tumors. Mice with variant-CpG Trp53 sequences remained tumor-free, but were uniquely prone to dental anomalies causing jaw malocclusion (p < .0001). Since the latter phenotype also characterises murine Rett syndrome due to dysfunction of the trans-repressive MeCP2 methyl-CpG-binding protein, we hypothesise that CpG sites may exert non-coding phenotypic effects via pre-translational cis-interactions of 5-methylcytosine with methyl-binding proteins which regulate mRNA transcript initiation, expression or splicing, although direct effects on mRNA structure or translation are also possible.
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Affiliation(s)
- Richard J Epstein
- University of New South Wales, St Vincent's Hospital Campus, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
| | - Frank P Y Lin
- University of New South Wales, St Vincent's Hospital Campus, Sydney, Australia
- Centre for Clinical Genomics, The Kinghorn Cancer Centre, Sydney, Australia
| | - Robert A Brink
- University of New South Wales, St Vincent's Hospital Campus, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
| | - James Blackburn
- University of New South Wales, St Vincent's Hospital Campus, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
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Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Genet Res (Camb) 2022; 2022:5338956. [PMID: 36072013 PMCID: PMC9402361 DOI: 10.1155/2022/5338956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS. Conclusions The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.
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10
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Luo K, Song Y, Guan Z, Ou S, Ye J, Ran S, Wang H, Tao Y, Gong Z, Ma T, Jin Y, Huang R, Gao F, Yu S. A KRAS-Associated Signature for Prognostic, Immune and Chemical Anti-Cancer Drug-Response Prediction in Colon Cancer. Front Pharmacol 2022; 13:899725. [PMID: 35774610 PMCID: PMC9237412 DOI: 10.3389/fphar.2022.899725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background: KRAS mutation, one of the most important biological processes in colorectal cancer, leads to poor prognosis in patients. Although studies on KRAS have concentrated for a long time, there are currently no ideal drugs against KRAS mutations. Methods: Different expression analysis and weighted gene coexpression network analysis was conducted to select candidate genes. Log-rank tests and Cox regression picked out the prognostic genes to build a KRAS-related gene prognostic score (KRGPS). A nomogram based on KRGPS was built to predict survival of clinical patients. Comprehensive analysis showed the prognosis, immune microenvironment and response to immune therapy and chemotherapy in KRGPS subgroups. Results: We collected a KRGPS from the set of two genes GJB6 and NTNG1, with low-KRGSP patients having better progression-free survival (PFS). Low KRGPS is correlated with high infiltration of activated NK cells, plasma cells and activated memory CD4 T cells and that these cells benefit more from immune checkpoint inhibitor therapy. However, high KRGPS is associated with high infiltration of activated mast cells, pathways of immune dysregulation and a high ratio of TP53 and KRAS mutations. KRGPS subgroups are also sensitive to chemotherapy differently. A nomogram, established based on the KRGPS and pathological stage, predict 3- and 5-years PFS well. Conclusions: The KRAS-associated score acts as a promising signature to distinguish prognosis, molecular and immune characteristics, and benefits from immune and chemical therapy. These KRAS-associated genes could be promising targets for drug design.
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Affiliation(s)
- Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanni Song
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zilong Guan
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Suwen Ou
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinhua Ye
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Songlin Ran
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hufei Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zijian Gong
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of General Surgery, The People’s Hospital of Duerbert Mongolian Autonomous County, Harbin, China
| | - Tianyi Ma
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yinghu Jin
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Feng Gao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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11
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Li X, Li X, Fu R, Ng D, Yang T, Zhang Y, Zhang M, Shi Y, Gu Y, Lv C, Chen G. Efficacy of Neoadjuvant Therapy in Improving Long-Term Survival of Patients with Resectable Rectal Cancer: A Meta-Analysis. Anticancer Agents Med Chem 2021; 22:1068-1079. [PMID: 34315397 DOI: 10.2174/1871520621666210726134809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/02/2021] [Accepted: 05/30/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The impact of neoadjuvant therapy on long-term prognosis of patients with resectable rectal cancer is currently unknown. OBJECTIVE This study aimed to explore the long-term prognosis of patients with resectable rectal cancer following treatment with neoadjuvant therapy. METHODS Four major databases (PubMed, Web of Science, Embase, Cochrane library) were searched to identify relevant articles published between January 2000 and July 2020. The main outcome indicators were the 5-year overall survival (OS) and disease-free survival (DFS). RESULTS The meta-analysis revealed that 5-year OS (HR: 0.88, 95% Cl: 0.83-0.93) and DFS (HR: 0.95, 95% Cl: 0.91-0.98) were higher in patients with resectable rectal cancer after receiving neoadjuvant therapy than those treated with upfront surgery. Subgroup analysis demonstrated that the long-term survival of patients in Asia and Europe could benefit from neoadjuvant therapy. The neoadjuvant short-course radiotherapy (SCRT) and neoadjuvant chemo-radiotherapy (CRT) improved the 5-year OS and DFS of patients with stage Ⅱ-Ⅲ rectal cancer and mid/low rectal cancer. Further research found that patients with stage Ⅱ only had an increase in OS, while patients with stage Ⅲ have improved 5-year OS and DFS. CONCLUSION Neoadjuvant therapy improved the long-term survival of patients with mid/low rectal cancer in stage Ⅱ-Ⅲ (especially stage Ⅲ). Additionally, patients in Asia and Europe seemed to be more likely to benefit from neoadjuvant therapy. For the treatment, we recommend neoadjuvant SCRT and neoadjuvant CRT for resectable rectal cancer.
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Affiliation(s)
- Xinlong Li
- Department of Anesthesiology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Rongrong Fu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Derry Ng
- Medical College of Ningbo University, Ningbo, Zhejiang, China
| | - Tong Yang
- Department of Tumor HIFU Therapy, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Yu Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yixuan Gu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chenhui Lv
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Gang Chen
- Department of Anesthesiology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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12
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Basnet U, Patil AR, Kulkarni A, Roy S. Role of Stress-Survival Pathways and Transcriptomic Alterations in Progression of Colorectal Cancer: A Health Disparities Perspective. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:5525. [PMID: 34063993 PMCID: PMC8196775 DOI: 10.3390/ijerph18115525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 12/09/2022]
Abstract
Every year, more than a million individuals are diagnosed with colorectal cancer (CRC) across the world. Certain lifestyle and genetic factors are known to drive the high incidence and mortality rates in some groups of individuals. The presence of enormous amounts of reactive oxygen species is implicated for the on-set and carcinogenesis, and oxidant scavengers are thought to be important in CRC therapy. In this review, we focus on the ethnicity-based CRC disparities in the U.S., the negative effects of oxidative stress and apoptosis, and gene regulation in CRC carcinogenesis. We also highlight the use of antioxidants for CRC treatment, along with screening for certain regulatory genetic elements and oxidative stress indicators as potential biomarkers to determine the CRC risk and progression.
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Affiliation(s)
- Urbashi Basnet
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
| | - Abhijeet R. Patil
- Computational Science Program, University of Texas at El Paso, El Paso, TX 79968, USA;
| | - Aditi Kulkarni
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
| | - Sourav Roy
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
- The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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13
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The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction. Cancers (Basel) 2021; 13:cancers13030479. [PMID: 33513745 PMCID: PMC7865496 DOI: 10.3390/cancers13030479] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/18/2021] [Accepted: 01/23/2021] [Indexed: 12/12/2022] Open
Abstract
The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.
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14
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Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications. Oncogene 2020; 40:1555-1569. [PMID: 33323976 DOI: 10.1038/s41388-020-01587-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 11/02/2020] [Accepted: 11/24/2020] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, however, the molecular mechanisms underlying the pathogenesis of CRC remain largely unclear. Recent studies have revealed crucial roles of transcription factors in CRC development. Transcription factors essential for the regulation of gene expression by interacting with transcription corepressor/enhancer complexes and they orchestrate downstream signal transduction. Deregulation of transcription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expression profiles play fundamental roles in multistep process of tumorigenesis, from cellular transformation, disease progression to metastatic disease. Herein, we summarized current and emerging key transcription factors that participate in CRC tumorigenesis, and highlighted their oncogenic or tumor suppressive functions. Moreover, we presented critical transcription factors of CRC, emphasized the major molecular mechanisms underlying their effect on signal cascades associated with tumorigenesis, and summarized of their potential as molecular biomarkers for CRC prognosis therapeutic response, as well as drug targets for CRC treatment. A better understanding of transcription factors involved in the development of CRC will provide new insights into the pathological mechanisms and reveal novel prognostic biomarkers and therapeutic strategies for CRC.
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15
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Roy KR, Uddin MB, Roy SC, Hill RA, Marshall J, Li Y, Chamcheu JC, Lu H, Liu Y. Gb3-cSrc complex in glycosphingolipid-enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β-catenin-activated RNA methylation. FASEB Bioadv 2020; 2:653-667. [PMID: 33205006 PMCID: PMC7655095 DOI: 10.1096/fba.2020-00044] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 12/11/2022] Open
Abstract
Glucosylceramide synthase (GCS) is a key enzyme catalyzing ceramide glycosylation to generate glucosylceramide (GlcCer), which in turn serves as the precursor for cells to produce glycosphingolipids (GSLs). In cell membranes, GSLs serve as essential components of GSL-enriched microdomains (GEMs) and mediate membrane functions and cell behaviors. Previous studies showed that ceramide glycosylation correlates with upregulated expression of p53 hotspot mutant R273H and cancer drug resistance. Yet, the underlying mechanisms remain elusive. We report herewith that globotriaosylceramide (Gb3) is associated with cSrc kinase in GEMs and plays a crucial role in modulating expression of p53 R273H mutant and drug resistance. Colon cancer cell lines, either WiDr homozygous for missense-mutated TP53 (R273H+/+) or SW48/TP53-Dox bearing heterozygous TP53 mutant (R273H/+), display drug resistance with increased ceramide glycosylation. Inhibition of GCS with Genz-161 (GENZ 667161) resensitized cells to apoptosis in these p53 mutant-carrying cancer cells. Genz-161 effectively inhibited GCS activity, and substantially suppressed the elevated Gb3 levels seen in GEMs of p53-mutant cells exposed to doxorubicin. Complex formation between Gb3 and cSrc in GEMs to activate β-catenin was detected in both cultured cells and xenograft tumors. Suppression of ceramide glycosylation significantly decreased Gb3-cSrc in GEMs, β-catenin, and methyltransferase-like 3 for m6A RNA methylation, thus altering pre-mRNA splicing, resulting in upregulated expression of wild-type p53 protein, but not mutants, in cells carrying p53 R273H. Altogether, increased Gb3-cSrc complex in GEMs of membranes in response to anticancer drug induced cell stress promotes expression of p53 mutant proteins and accordant cancer drug resistance.
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Affiliation(s)
- Kartik R. Roy
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
| | - Mohammad B. Uddin
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
| | - Sagor C. Roy
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
| | - Ronald A. Hill
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
| | - John Marshall
- Department of Rare Genetic Disease ResearchSanofi‐Genzyme R&D CenterGenzyme, FraminghamMassachusettsUSA
| | - Yu‐Teh Li
- Department of Biochemistry and Molecular BiologyTulane University School of MedicineNew OrleansLouisianaUSA
| | - Jean Christopher Chamcheu
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
| | - Hua Lu
- Department of Biochemistry and Molecular BiologyTulane University School of MedicineNew OrleansLouisianaUSA
| | - Yong‐Yu Liu
- School of Basic Pharmaceutical and Toxicological SciencesCollege of PharmacyUniversity of Louisiana at MonroeMonroeLouisianaUSA
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16
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival. Nat Commun 2020; 11:3644. [PMID: 32686686 PMCID: PMC7371703 DOI: 10.1038/s41467-020-17386-z] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
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17
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González-González M, Gutiérrez ML, Sayagués JM, Muñoz-Bellvís L, Orfao A. Genomic profiling of sporadic liver metastatic colorectal cancer. Semin Cancer Biol 2020; 71:98-108. [PMID: 32485312 DOI: 10.1016/j.semcancer.2020.05.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023]
Abstract
Sporadic colorectal cancer (sCRC) is the third leading cause of cancer death in the Western world. Approximately, a quarter of sCRC patients present metastatic dissemination at the moment of diagnosis, the liver being the most frequently affected organ. Additionally, this group of CRC patients is characterized by a worse prognosis. In the last decades, significant technological developments for genome analysis have fostered the identification and characterization of genetic alterations involved in the pathogenesis of sCRC. However, genetic alterations involved in the metastatic process through which tumor cells are able to colonize other tissues with a different microenvironment, still remain to be fully identified. Here, we review current knowledge about the most relevant genomic alterations involved in the liver metastatic process of sCRC, including detailed information about the genetic profile of primary colorectal tumors vs. their paired liver metastases.
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Affiliation(s)
- María González-González
- Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain; Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium-CIBER-CIBERONC, Spain
| | - María Laura Gutiérrez
- Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain; Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium-CIBER-CIBERONC, Spain
| | - José María Sayagués
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain; Department of Pathology, Universidad de Salamanca, Salamanca, Spain
| | - Luis Muñoz-Bellvís
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium-CIBER-CIBERONC, Spain; Department of General and Gastrointestinal Surgery, University Hospital of Salamanca, Salamanca, Spain
| | - Alberto Orfao
- Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain; Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium-CIBER-CIBERONC, Spain.
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18
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Bürtin F, Mullins CS, Linnebacher M. Mouse models of colorectal cancer: Past, present and future perspectives. World J Gastroenterol 2020; 26:1394-1426. [PMID: 32308343 PMCID: PMC7152519 DOI: 10.3748/wjg.v26.i13.1394] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining, reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical in vivo models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models (GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity, they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development - even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.
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Affiliation(s)
- Florian Bürtin
- Department of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock 18057, Germany
| | - Christina S Mullins
- Department of Thoracic Surgery, University Medical Center Rostock, University of Rostock, Rostock 18057, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Department of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock 18057, Germany
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19
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Max Ma X, Bendell JC, Hurwitz HI, Ju C, Lee JJ, Lovejoy A, Mancao C, Nicholas A, Price R, Sommer N, Tikoo N, Yao L, Yaung SJ, Palma JF. Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer. Clin Cancer Res 2020; 26:4010-4017. [PMID: 32220893 DOI: 10.1158/1078-0432.ccr-19-1209] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 11/22/2019] [Accepted: 03/23/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy. EXPERIMENTAL DESIGN The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date. RESULTS Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC, and KRAS. Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17-0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other (ρ = 0.987, P < 0.0001). CONCLUSIONS ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
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Affiliation(s)
- Xiaoju Max Ma
- Medical Scientific Affairs, Roche Sequencing Solutions, Inc., Pleasanton, California.
| | - Johanna C Bendell
- Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee
| | - Herbert I Hurwitz
- Project Development Oncology, Genentech, Inc., South San Francisco, California
| | - Christine Ju
- Clinical Operations and Biometrics, Roche Molecular Systems, Pleasanton, California
| | - John J Lee
- Medical Scientific Affairs, Roche Sequencing Solutions, Inc., Pleasanton, California
| | - Alex Lovejoy
- Assay Development, Roche Sequencing Solutions, Inc., Pleasanton, California
| | - Christoph Mancao
- Oncology Biomarker Development, Genentech, Inc., Basel, Switzerland
| | - Alan Nicholas
- US Medical Affairs and Biometrics, Genentech, Inc., South San Francisco, California
| | - Richard Price
- Oncology Biomarker Development, Genentech, Inc., Basel, Switzerland
| | - Nicolas Sommer
- Medical Affairs BioOncology, Genentech, Inc., South San Francisco, California
| | - Nalin Tikoo
- Clinical Operations and Biometrics, Roche Molecular Systems, Pleasanton, California
| | - Lijing Yao
- Bioinformatics Research and Early Development, Roche Sequencing Solutions, Inc., Pleasanton, California
| | - Stephanie J Yaung
- Medical and Scientific Affairs Bioinformatics, Roche Sequencing Solutions, Inc., Pleasanton, California
| | - John F Palma
- Medical Scientific Affairs, Roche Sequencing Solutions, Inc., Pleasanton, California.
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20
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Ding X, Duan H, Luo H. Identification of Core Gene Expression Signature and Key Pathways in Colorectal Cancer. Front Genet 2020; 11:45. [PMID: 32153633 PMCID: PMC7046836 DOI: 10.3389/fgene.2020.00045] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/15/2020] [Indexed: 12/17/2022] Open
Abstract
Objective Colorectal cancer (CRC) is considered the most prevalent malignant tumor that contributes to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We sought to discover a novel biomarker in CRC. Materials and Methods All clinical CRC samples (n = 20) were from Renmin Hospital of Wuhan University. We first selected MAD2L1 by integrated bioinformatics analysis of a GSE dataset. Next, the expression of MAD2L1 in tissues and cell lines was verified by quantitative real-time PCR. The effects of MAD2L1 on cell growth, proliferation, the cell cycle, and apoptosis were examined by in vitro assays. Results We identified 683 shared DEGs (420 upregulated and 263 downregulated), and the top twenty genes (CDK1, CCNA2, TOP2A, PLK1, MAD2L1, AURKA, BUB1B, UBE2C, TPX2, RRM2, KIF11, NCAPG, MELK, NUSAP1, MCM4, RFC4, PTTG1, CHEK1, CEP55, DTL) were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of MAD2L1 in CRC tissues is higher than that in normal tissues. MAD2L1 knockdown significantly suppressed CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. Conclusion MAD2L1, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis and could be used as a new biomarker for diagnosis and therapy in CRC.
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Affiliation(s)
- Xiang Ding
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Houyu Duan
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
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21
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Hasakova K, Reis R, Vician M, Zeman M, Herichova I. Expression of miR-34a-5p is up-regulated in human colorectal cancer and correlates with survival and clock gene PER2 expression. PLoS One 2019; 14:e0224396. [PMID: 31658284 PMCID: PMC6816564 DOI: 10.1371/journal.pone.0224396] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer represents a leading cause of cancer death. MicroRNAs (miRNAs) are small non-coding RNA molecules that have been extensively studied in tumours, since changes in their levels can reveal patient prognosis. Cancer progression is also influenced by the circadian system whose functioning is based on the rhythmic expression of clock genes. Therefore, we performed macroarray screening of tumour and adjacent tissues in patients undergoing surgery for colorectal carcinoma. We identified 17 miRNAs showing expression that was more than 100 times higher in tumour tissue compared to adjacent tissue. From in silico analysis, miR-34a-5p was selected as showing a computer-predicted interaction with PER2. Real-time PCR revealed a negative correlation between expression of PER2 mRNA and miR-34a in patients with more advanced cancer stage. Expression of miR-34a was up-regulated in cancer tissue compared to adjacent tissue. High miR-34a expression was associated with better survival of patients. miR-34a showed lower expression levels in male patients with lymph node involvement, and a trend towards decreased expression in male patients with distant metastases. Male patients, but not female patients, with high expression of miR-34a and who were free of distant metastases and/or lymph node involvement showed better survival. Therefore, we proposed that expression of miR-34a was regulated in a sex-dependent manner and could be considered a marker of prognosis in earlier cancer stages in male patients.
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Affiliation(s)
- Kristina Hasakova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Richard Reis
- First Surgery Department, University Hospital, Comenius University Bratislava, Bratislava, Slovak Republic
| | - Marian Vician
- Fourth Surgery Department, University Hospital, Comenius University Bratislava, Bratislava, Slovak Republic
| | - Michal Zeman
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Iveta Herichova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
- * E-mail:
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22
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Khiste SK, Liu Z, Roy KR, Uddin MB, Hosain SB, Gu X, Nazzal S, Hill RA, Liu YY. Ceramide-Rubusoside Nanomicelles, a Potential Therapeutic Approach to Target Cancers Carrying p53 Missense Mutations. Mol Cancer Ther 2019; 19:564-574. [PMID: 31645443 DOI: 10.1158/1535-7163.mct-19-0366] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 07/24/2019] [Accepted: 10/14/2019] [Indexed: 12/15/2022]
Abstract
Ceramide (Cer) is an active cellular sphingolipid that can induce apoptosis or proliferation-arrest of cancer cells. Nanoparticle-based delivery offers an effective approach for overcoming bioavailability and biopharmaceutics issues attributable to the pronounced hydrophobicity of Cer. Missense mutations of the protein p53, which have been detected in approximately 42% of cancer cases, not only lose the tumor suppression activity of wild-type p53, but also gain oncogenic functions promoting tumor progression and drug resistance. Our previous works showed that cellular Cer can eradicate cancer cells that carry a p53 deletion-mutation by modulating alternative pre-mRNA splicing, restoring wild-type p53 protein expression. Here, we report that new ceramide-rubusoside (Cer-RUB) nanomicelles considerably enhance Cer in vivo bioavailability and restore p53-dependent tumor suppression in cancer cells carrying a p53 missense mutation. Natural RUB encapsulated short-chain C6-Cer so as to form Cer-RUB nanomicelles (∼32 nm in diameter) that substantially enhanced Cer solubility and its levels in tissues and tumors of mice dosed intraperitoneally. Intriguingly, Cer-RUB nanomicelle treatments restored p53-dependent tumor suppression and sensitivity to cisplatin in OVCAR-3 ovarian cancer cells and xenograft tumors carrying p53 R248Q mutation. Moreover, Cer-RUB nanomicelles showed no signs of significant nonspecific toxicity to noncancerous cells or normal tissues, including bone marrow. Furthermore, Cer-RUB nanomicelles restored p53 phosphorylated protein and downstream function to wild-type levels in p53 R172H/+ transgenic mice. Altogether, this study, for the first time, indicates that natural Cer-RUB nanomicelles offer a feasible approach for efficaciously and safely targeting cancers carrying p53 missense mutations.
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Affiliation(s)
- Sachin K Khiste
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana
| | - Zhijun Liu
- School of Renewable Natural Resources, Louisiana State University Agricultural Center, Baton Rouge, Louisiana
| | - Kartik R Roy
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana
| | - Mohammad B Uddin
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana
| | - Salman B Hosain
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana
| | - Xin Gu
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Sami Nazzal
- Department of Pharmaceutical Sciences, Texas Tech University Health Science Center, Dallas, Texas
| | - Ronald A Hill
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana
| | - Yong-Yu Liu
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana.
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23
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Codrich M, Comelli M, Malfatti MC, Mio C, Ayyildiz D, Zhang C, Kelley MR, Terrosu G, Pucillo CEM, Tell G. Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway. DNA Repair (Amst) 2019; 82:102675. [PMID: 31450087 PMCID: PMC7092503 DOI: 10.1016/j.dnarep.2019.102675] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 12/13/2022]
Abstract
The pathogenesis of colorectal cancer (CRC) involves different mechanisms, such as genomic and microsatellite instabilities. Recently, a contribution of the base excision repair (BER) pathway in CRC pathology has been emerged. In this context, the involvement of APE1 in the BER pathway and in the transcriptional regulation of genes implicated in tumor progression strongly correlates with chemoresistance in CRC and in more aggressive cancers. In addition, the APE1 interactome is emerging as an important player in tumor progression, as demonstrated by its interaction with Nucleophosmin (NPM1). For these reasons, APE1 is becoming a promising target in cancer therapy and a powerful prognostic and predictive factor in several cancer types. Thus, specific APE1 inhibitors have been developed targeting: i) the endonuclease activity; ii) the redox function and iii) the APE1-NPM1 interaction. Furthermore, mutated p53 is a common feature of advanced CRC. The relationship between APE1 inhibition and p53 is still completely unknown. Here, we demonstrated that the inhibition of the endonuclease activity of APE1 triggers p53-mediated effects on cell metabolism in HCT-116 colon cancer cell line. In particular, the inhibition of the endonuclease activity, but not of the redox function or of the interaction with NPM1, promotes p53 activation in parallel to sensitization of p53-expressing HCT-116 cell line to genotoxic treatment. Moreover, the endonuclease inhibitor affects mitochondrial activity in a p53-dependent manner. Finally, we demonstrated that 3D organoids derived from CRC patients are susceptible to APE1-endonuclease inhibition in a p53-status correlated manner, recapitulating data obtained with HCT-116 isogenic cell lines. These findings suggest the importance of further studies aimed at testing the possibility to target the endonuclease activity of APE1 in CRC.
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Affiliation(s)
- Marta Codrich
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Marina Comelli
- Laboratory of Bioenergetics, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Matilde Clarissa Malfatti
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Catia Mio
- Institute of Medical Genetics, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Dilara Ayyildiz
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University, School of Medicine, Indianapolis, IN 46202, USA
| | - Mark R Kelley
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and Pharmacology & Toxicology, Indiana University, School of Medicine, Indianapolis, IN 46202, USA
| | - Giovanni Terrosu
- General Surgery and Transplantation Unit, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Carlo E M Pucillo
- Laboratory of Immunology, Department of Medicine, University of Udine, Udine, 33100, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, 33100, Italy.
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24
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CRISPR-Cas9-mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes. Proc Natl Acad Sci U S A 2019; 116:15635-15644. [PMID: 31300537 DOI: 10.1073/pnas.1904714116] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Several genome sequencing studies have provided comprehensive CRC genomic datasets. Likewise, in our previous study, we performed genome-wide Sleeping Beauty transposon-based mutagenesis screening in mice and provided comprehensive datasets of candidate CRC driver genes. However, functional validation for most candidate CRC driver genes, which were commonly identified from both human and mice, has not been performed. Here, we describe a platform for functionally validating CRC driver genes that utilizes CRISPR-Cas9 in mouse intestinal tumor organoids and human CRC-derived organoids in xenograft mouse models. We used genetically defined benign tumor-derived organoids carrying 2 frequent gene mutations (Apc and Kras mutations), which act in the early stage of CRC development, so that we could clearly evaluate the tumorigenic ability of the mutation in a single gene. These studies showed that Acvr1b, Acvr2a, and Arid2 could function as tumor suppressor genes (TSGs) in CRC and uncovered a role for Trp53 in tumor metastasis. We also showed that co-occurrent mutations in receptors for activin and transforming growth factor-β (TGF-β) synergistically promote tumorigenesis, and shed light on the role of activin receptors in CRC. This experimental system can also be applied to mouse intestinal organoids carrying other sensitizing mutations as well as organoids derived from other organs, which could further contribute to identification of novel cancer driver genes and new drug targets.
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Zhang G, Xu Q, Liu J, Lv Z, Lu Y, Yang H, Sun L, Xing C, Yuan Y. Five P53 SNPs Involved in Low Rectal Cancer Risk and Prognosis in a Chinese Population. J Cancer 2019; 10:1772-1780. [PMID: 31205533 PMCID: PMC6547998 DOI: 10.7150/jca.26722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 10/05/2018] [Indexed: 12/29/2022] Open
Abstract
Although the impact and potential mechanisms of p53 polymorphisms on human malignancies have been intensively studied, analyses for association between p53 polymorphisms and colorectal cancer (CRC) risk were still limited to some common variants. Moreover, the majority of previous studies did not classify the specimens of CRC based on tumor location. This case-control study aimed to evaluate the association of five p53 polymorphisms (rs1042522, rs12947788, rs1625895, rs2909430 and rs12951053) with the risk of low rectal cancer (LRC) and investigate the prognostic significance. A total of 347 cases and 353 controls from a Chinese population were recruited and genotyped using KASP assay. Individuals carrying the variant rs12947788 A allele were observed to associate with an increased risk of LRC. After stratification for clinicopathological parameters, rs12947788 was significantly co-related with the histological type of LRC under a dominant model. Although none of the selected p53 polymorphisms was significantly associated with patient prognosis in total population, significant associations with the overall survival were revealed in the heterozygosis carriers vs. wild type carriers model through subgroup analyses based on clinical characteristics. Moreover, haplotype analyses showed that C-A-G-A-A haplotype was associated with a significantly higher LRC risk as compared to the other haplotypes. In low rectal cancer, P53 protein expression was obviously higher in p53 rs1042522 mutant carriers than in other genotypes. Our study further proves the involvement of p53 polymorphisms in pathogenesis of LRC and may provide potential therapeutic implications.
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Affiliation(s)
- Guangzhe Zhang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Zhi Lv
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Youzhu Lu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Huaiwei Yang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Chengzhong Xing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
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26
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p53 expression status is associated with cancer-specific survival in stage III and high-risk stage II colorectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy. Br J Cancer 2019; 120:797-805. [PMID: 30894685 PMCID: PMC6474280 DOI: 10.1038/s41416-019-0429-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC). METHODS We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression. RESULTS The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60-4.60, P < 0.001) and poor 5-year cancer-specific survival (HR: 2.90, 95% CI = 1.28-6.57, P = 0.011). CONCLUSIONS p53-mild expression status was found to be an independent prognostic marker in adjuvant FOLFOX-treated patients with stage III and high-risk stage II CRC.
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27
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Qi Y, Qi H, Liu Z, He P, Li B. Bioinformatics Analysis of Key Genes and Pathways in Colorectal Cancer. J Comput Biol 2019; 26:364-375. [PMID: 30810359 DOI: 10.1089/cmb.2018.0237] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer in the world. Although great progress has been made, the specific molecular mechanism remains unclear. This study aimed to explore the differentially expressed genes (DEGs) and underlying mechanisms of CRC using bioinformatics analysis. In this study, we identified a total of 1353 DEGs in the database of GSE113513, including 715 up- and 638 downregulated genes. Gene ontology analysis results showed that upregulated DEGs were significantly enriched in cell division, cell proliferation, and DNA replication. The downregulated DEGs were enriched in immune response, relation of cell growth and inflammatory response. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that upregulated DEGs were enriched in cell cycle and p53 signaling pathway, whereas the downregulated DEGs were enriched in drug metabolism, metabolism of xenobiotics by cytochrome P450, and nitrogen metabolism. A total of 124 up-key genes and 35 down-key genes were identified from the protein-protein interaction networks. Furthermore, we identified five up-modules (up-A, up-B, up-C, up-D, and up-E) and three down-modules (d-A, d-B, and d-C) by module analysis. The module up-A was enriched in sister chromatid cohesion, cell division, and mitotic nuclear division. Pathways associated with cell cycle, progesterone-mediated oocyte maturation, oocyte meiosis, and p53 signaling pathway. Whereas the d-A was mainly enriched in G-protein coupled receptor signaling pathway, cell chemotaxis, and chemokine-mediated signaling pathway. The pathways enriched in chemokine signaling pathway, cytokine-cytokine receptor interaction, and alcoholism. These key genes and pathways might be used as molecular targets and diagnostic biomarkers for the treatment of CRC.
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Affiliation(s)
- Yuewen Qi
- 1 Department of Gastroenterology, Affiliated Hospital of Chengde Medical College, Chengde, P.R. China
| | - Haowen Qi
- 2 Department of Acupuncture and Massage, Chengde Hospital of Traditional Chinese Medicine, Chengde, P.R. China
| | - Zeyuan Liu
- 3 Department of Special Medicine, Qingdao University Medical College, Qingdao, P.R. China
| | - Peiyuan He
- 1 Department of Gastroenterology, Affiliated Hospital of Chengde Medical College, Chengde, P.R. China
| | - Bingqing Li
- 1 Department of Gastroenterology, Affiliated Hospital of Chengde Medical College, Chengde, P.R. China
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28
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Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Semin Cancer Biol 2019; 58:65-79. [PMID: 30633978 DOI: 10.1016/j.semcancer.2019.01.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/29/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from almost a quarter century of research, it is obvious that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. High-throughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer.
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Affiliation(s)
- Ammad Ahmad Farooqi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
| | - Marc de la Roche
- Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom.
| | - Mustafa B A Djamgoz
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London, SW7 2AZ, United Kingdom; Cyprus International University, Biotechnology Research Centre, Haspolat, Mersin 10, North Cyprus, Turkey.
| | - Zahid H Siddik
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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Uddin MB, Roy KR, Hosain SB, Khiste SK, Hill RA, Jois SD, Zhao Y, Tackett AJ, Liu YY. An N 6-methyladenosine at the transited codon 273 of p53 pre-mRNA promotes the expression of R273H mutant protein and drug resistance of cancer cells. Biochem Pharmacol 2018; 160:134-145. [PMID: 30578766 DOI: 10.1016/j.bcp.2018.12.014] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/18/2018] [Indexed: 02/06/2023]
Abstract
Mutant p53 proteins that promote cancer cell invasive growth, metastasis and drug resistance emerge as therapeutic targets. Previously, we reported that suppression of ceramide glycosylation restored wild-type p53 protein and tumor suppressing function in cancer cells heterozygously carrying p53 R273H, a hot-spot missense mutation; however, the mechanisms underlying the control of mutant protein expression remain elusive. Herein, we report that an N6-methyladenosine (m6A) at the point-mutated codon 273 (G > A) of p53 pre-mRNA determines the mutant protein expression. Methylation of the transited adenosine was catalyzed by methyltransferase like 3 (METTL3), and this m6A-RNA promoted a preferential pre-mRNA splicing; consequently, the produced p53 R273H mutant protein resulted in acquired multidrug resistance in colon cancer cells. Furthermore, glycosphingolipids (particularly globotriaosylceramide) generated from serial ceramide glycosylation were seen to activate cSrc and β-catenin signaling so as to upregulate METTL3 expression, in turn promoting expression of p53 R273H mutant protein, with consequent drug resistance. Conversely, either silencing METTL3 expression by using small interfering RNA (siRNA) or inhibiting RNA methylation with neplanocin A suppressed m6A formation in p53 pre-mRNA, and substantially increased the level of phosphorylated p53 protein (Ser15) and its function in cells heterozygously carrying the R273H mutation, thereby re-sensitizing these cells to anticancer drugs. Concordantly, suppression of ceramide glycosylation repressed METTL3 expression and m6A formation in p53 pre-mRNA, thus sensitizing cells carrying R273H to anticancer drugs. This study uncovers a novel function of pre-mRNA m6A as a determinant of mutant protein expression in cancer cells heterozygously carrying the TP53 R273H mutation. Suppressing both RNA methylation and ceramide glycosylation might constitute an efficacious and specific approach for targeting TP53 missense mutations coding for a G > A transition, thereby improving cancer treatments.
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Affiliation(s)
- Mohammad B Uddin
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Kartik R Roy
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Salman B Hosain
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Sachin K Khiste
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Ronald A Hill
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Seetharama D Jois
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Yunfeng Zhao
- Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Yong-Yu Liu
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA.
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30
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Fischer NW, Prodeus A, Gariépy J. Survival in males with glioma and gastric adenocarcinoma correlates with mutant p53 residual transcriptional activity. JCI Insight 2018; 3:121364. [PMID: 30089713 DOI: 10.1172/jci.insight.121364] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 06/21/2018] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant-specific residual transcriptional activity scores. RESULTS Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4-3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7-5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7-3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8-2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). CONCLUSION The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. FUNDING Canadian Institutes of Health Research (no. 148556).
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Affiliation(s)
- Nicholas W Fischer
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Aaron Prodeus
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Jean Gariépy
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
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31
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Zhong X, Guo Z, Gao P, Song Y, Sun J, Chen X, Sun Y, Wang Z. Racial/ethnic disparities in the adjuvant chemotherapy of locally advanced colon cancer patients. J Surg Res 2018; 228:27-34. [PMID: 29907221 DOI: 10.1016/j.jss.2018.02.054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/16/2018] [Accepted: 02/27/2018] [Indexed: 10/17/2022]
Abstract
BACKGROUND Most race/ethnicity-oriented investigations focus on Caucasian Americans (whites) and African Americans (blacks), leaving Asians, Hispanic white (Hispanics), and other minorities less well studied. Adjuvant chemotherapy (CT) after curative resection is critical to patients with locally advanced colon cancer (LACC). We studied the racial disparities in the adjuvant CT of LACC to aid in selecting optimal treatments for people from different races/ethnicities in this era of precision medicine. METHODS Patients with American Joint Committee on Cancer (AJCC) stage II or III colon cancer (CC) (together termed as LACC) were included based on Surveillance, Epidemiology, and End Results cancer registry-Medicare linked databases. The log-rank test and Cox multivariate regression analysis were performed to investigate the racial/ethnic disparities in cohorts divided according to the regimen of adjuvant CT. RESULTS In the LACC patients who did not receive adjuvant CT, Asian patients had better survival than other groups (all, P <0.05). For the fluoropyrimidine cohort, the survival of Asian patients was better than that of whites, blacks, and other minorities (all, P <0.05). For the fluoropyrimidine with oxaliplatin cohort, other minorities had superior survival to other groups (all, P <0.05). Similar findings were demonstrated for patients with AJCC stage II and III CC, and the observed better survival persisted after adjustments in the Cox models. CONCLUSIONS Among LACC patients not receiving adjuvant CT, Asians achieved better survival than other races/ethnicities. Superior survival was also observed for Asians in the fluoropyrimidine cohort and for other minorities in the fluoropyrimidine with oxaliplatin cohort for AJCC stage III CC.
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Affiliation(s)
- Xi Zhong
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Zhexu Guo
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Jingxu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Xiaowan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Yu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang City, PR China.
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Li AJ, Li HG, Tang EJ, Wu W, Chen Y, Jiang HH, Lin MB, Yin L. PIK3CA and TP53 mutations predict overall survival of stage II/III colorectal cancer patients. World J Gastroenterol 2018; 24:631-640. [PMID: 29434452 PMCID: PMC5799864 DOI: 10.3748/wjg.v24.i5.631] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/13/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the predictive value of PIK3CA and TP53 mutation status in colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy.
METHODS In this study, a total of 315 patients with histologically proven CRC were enrolled from Yangpu Hospital affiliated to Shanghai Tongji University between 2007 and 2011. Of these patients, 241 with stage II/III CRC received 5-fluorouracil-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded lesion samples of the patients with curatively resected CRC were collected. Next-generation sequencing was performed to identify somatic gene mutations. The correlation of PIK3CA and TP53 mutation status with overall survival (OS) was analyzed using a Cox proportional hazard model and the Kaplan-Meier method.
RESULTS Among the 241 patients with stage II/III in this cohort, the PIK3CA and/or TP53 mutation was detected in 177 patients, among which 54 patients had PIK3CA and TP53 double mutations. The PIK3CA or TP53 mutation was not significantly correlated with OS in univariate and multivariate analyses. Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations showed a significantly worse survival (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91). The PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052). The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041)
CONCLUSION Double mutation of PIK3CA and TP53 is correlated with a shorter OS in stage II/III CRC patients treated with 5-fluorouracil-based therapy.
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Affiliation(s)
- A-Jian Li
- Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Hua-Guang Li
- Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Er-Jiang Tang
- Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Wei Wu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Ying Chen
- Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hui-Hong Jiang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Mou-Bin Lin
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Lu Yin
- Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
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Hosain SB, Khiste SK, Uddin MB, Vorubindi V, Ingram C, Zhang S, Hill RA, Gu X, Liu YY. Inhibition of glucosylceramide synthase eliminates the oncogenic function of p53 R273H mutant in the epithelial-mesenchymal transition and induced pluripotency of colon cancer cells. Oncotarget 2018; 7:60575-60592. [PMID: 27517620 PMCID: PMC5312403 DOI: 10.18632/oncotarget.11169] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 07/26/2016] [Indexed: 01/06/2023] Open
Abstract
Missense mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF), not only promotes tumor progression, but also diminishes therapeutic efficacies of cancer treatments. However, it remains unclear how a p53 missense mutant contributes to induced pluripotency of cancer stem cells (CSCs) in tumors exposed to chemotherapeutic agents. More importantly, it may be possible to abrogate the GOF by restoring wild-type p53 activity, thereby overcoming the deleterious effects resulting from heterotetramer formation, which often compromises the efficacies of current approaches being used to reactivate p53 function. Herewith, we report that p53 R273H missense mutant urges cancer cells to spawn CSCs. SW48/TP53 cells, which heterozygously carry the p53 R273H hot-spot mutant (R273H/+, introduced by a CRISPR/Casp9 system), were subchronically exposed to doxorubicin in cell culture and in tumor-bearing mice. We found that p53-R273H (TP53-Dox) cells were drug-resistant and exhibited epithelial-mesenchymal transition (EMT) and increased numbers of CSCs (CD44v6+/CD133+), which resulted in enhanced wound healing and tumor formation. Inhibition of glucosylceramide synthase with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) sensitized p53-R273H cancer cells and tumor xenografts to doxorubicin treatments. Intriguingly, PDMP treatments restored wild-type p53 expression in heterozygous R273H mutant cells and in tumors, decreasing CSCs and sensitizing cells and tumors to treatments. This study demonstrated that p53-R273H promotes EMT and induced pluripotency of CSCs in cancer cells exposed to doxorubicin, mainly through Zeb1 and β-catenin transcription factors. Our results further indicate that restoration of p53 through inhibition of ceramide glycosylation might be an effective treatment approach for targeting cancers heterozygously harboring TP53 missense mutations.
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Affiliation(s)
- Salman B Hosain
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Sachin K Khiste
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Mohammad B Uddin
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Vindya Vorubindi
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Catherine Ingram
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Sifang Zhang
- Department of Integrated Chinese and Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ronald A Hill
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Xin Gu
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
| | - Yong-Yu Liu
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
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Yin J, Jiang XY, Qi W, Ji CG, Xie XL, Zhang DX, Cui ZJ, Wang CK, Bai Y, Wang J, Jiang HQ. piR-823 contributes to colorectal tumorigenesis by enhancing the transcriptional activity of HSF1. Cancer Sci 2017; 108:1746-1756. [PMID: 28618124 PMCID: PMC5581525 DOI: 10.1111/cas.13300] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 06/02/2017] [Accepted: 06/10/2017] [Indexed: 12/13/2022] Open
Abstract
Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, were first discovered in germline cells and are thought to silence transposons in spermatogenesis. Recently, piRNAs have also been identified in somatic tissues, and aberrant expression of piRNAs in tumor tissues may be implicated in carcinogenesis. However, the function of piR-823 in colorectal cancer (CRC) remains unclear. Here, we first found that piR-823 was significantly upregulated in CRC tissues compared with its expression in the adjacent tissues. Inhibition of piR-823 suppressed cell proliferation, arrested the cell cycle in the G1 phase and induced cell apoptosis in CRC cell lines HCT116 and DLD-1, whereas overexpression of piR-823 promoted cell proliferation in normal colonic epithelial cell line FHC. Interestingly, Inhibition of piR-823 repressed the expression of heat shock protein (HSP) 27, 60, 70. Furthermore, elevated HSPs expression partially abolished the effect of piR-823 on cell proliferation and apoptosis. In addition, we further demonstrated that piR-823 increased the transcriptional activity of HSF1, the common transcription factor of HSPs, by binding to HSF1 and promoting its phosphorylation at Ser326. Our study reveals that piR-823 plays a tumor-promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR-823 as a potential therapeutic target for CRC.
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Affiliation(s)
- Jie Yin
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Xiao-Yu Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Wei Qi
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Chen-Guang Ji
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Xiao-Li Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Dong-Xuan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Zi-Jin Cui
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Cun-Kai Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Yun Bai
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
| | - Jia Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei.,Ronghe Biotechnology Co., Ltd, Shijiazhuang, Hebei, China
| | - Hui-Qing Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei
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R M, P HA, Mahadevan V. HDAC inhibitors show differential epigenetic regulation and cell survival strategies on p53 mutant colon cancer cells. J Biomol Struct Dyn 2017; 36:938-955. [PMID: 28264628 DOI: 10.1080/07391102.2017.1302820] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Besides inactivating tumour suppressor activity in cells, mutations in p53 confer significant oncogenic functions and promote metastasis and resistance to anticancer therapy. A variety of therapies involving genetic and epigenetic signalling events regulate tumorogenesis and progression in such cases. Pharmacological interventions with HDAC inhibitors have shown promise in therapy. This work explores the changes in efficacy of the four HDAC inhibitors SAHA, MS-275, valproic acid and sodium butyrate on a panel of colon cancer cell lines - HCT116 (p53 wt), HCT116 p53-/-, HT29 and SW480 (with mutations in p53). Clonogenic assays, gene profiling and epigenetic expression done on these cells point to p53 dependent differential activity of the 4 HDAC inhibitors which also elevate methylation levels in p53 mutant cell lines. In silico modelling establishes the alterations in interactions that lead to such differential activity of valproic acid, one of the inhibitors considered for the work. Molecular Dynamic simulations carried out on the valproic acid complex ensure stability of the complex. This work establishes a p53 dependent epigenetic signalling mechanism triggered by HDAC inhibition expanding the scope of HDAC inhibitors in adjuvant therapy for p53 mutant tumours.
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Affiliation(s)
- Mahalakshmi R
- a Centre for Nanotechnology & Advanced Biomaterials (CeNTAB), School of Chemical & Biotechnology , SASTRA University , Thanjavur 613401 , India
| | - Husayn Ahmed P
- b Institute of Bioinformatics and Applied Biotechnology (IBAB) , Bangalore 560100 , India
| | - Vijayalakshmi Mahadevan
- a Centre for Nanotechnology & Advanced Biomaterials (CeNTAB), School of Chemical & Biotechnology , SASTRA University , Thanjavur 613401 , India.,b Institute of Bioinformatics and Applied Biotechnology (IBAB) , Bangalore 560100 , India
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A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer. Sci Rep 2016; 6:28083. [PMID: 27312428 PMCID: PMC4911576 DOI: 10.1038/srep28083] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 05/31/2016] [Indexed: 01/16/2023] Open
Abstract
Tumor-derived exosomes are important for cell-cell communication. However, the role of TP53 in the control of exosome production in colorectal cancer (CRC) is controversial and unclear. The features of exosomes secreted from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells were assessed. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A comprehensive proteomic analysis of exosomal proteins was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In conclusion, a novel HGS-dependent TP53 mechanism in exosome formation was identified in CRC. HGS may serve as a novel prognostic biomarker and a candidate target for therapeutic interventions.
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Lee DH, Ahn YJ, Shin R, Lee HW. Metastatic mucinous adenocarcinoma of the distal common bile duct, from transverse colon cancer presenting as obstructive jaundice. KOREAN JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2015; 19:125-8. [PMID: 26379735 PMCID: PMC4568601 DOI: 10.14701/kjhbps.2015.19.3.125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 07/06/2015] [Accepted: 08/01/2015] [Indexed: 12/04/2022]
Abstract
The patient was a 70-year-old male whose chief complaints were obstructive jaundice and weight loss. Abdominal imaging studies showed a 2.5 cm sized mass at the distal common bile duct, which was suggestive of bile duct cancer. Eccentric enhancing wall thickening in the transverse colon was also shown, suggesting concomitant colon cancer. A colonoscopy revealed a lumen-encircling ulcerofungating mass in the transverse colon, that was pathologically proven to be adenocarcinoma. The bile duct pathology was also adenocarcinoma. Pylorus-preserving pancreaticoduodenectomy and extended right hemicolectomy were performed under the diagnosis of double primary cancers. Postoperative histopathologic examination revealed moderately differentiated mucinous adenocarcinoma of transverse colon cancer, and mucinous adenocarcinoma of the distal common bile duct. Immunohistochemical staining studies showed that the bile duct cancer had metastasized from the colon cancer. The patient recovered uneventfully from surgery and will be undergoing chemotherapy for three months.
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Affiliation(s)
- Doo-Ho Lee
- Department of Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Young Joon Ahn
- Department of Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Rumi Shin
- Department of Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Hae Won Lee
- Department of Surgery, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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38
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Functional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer. Bull Cancer 2015; 102:117-25. [PMID: 25609485 DOI: 10.1016/j.bulcan.2014.12.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 03/24/2014] [Indexed: 01/28/2023]
Abstract
BACKGROUND Survival of metastatic colon cancer (mCC) patients has considerably improved with optimization of new drugs regimen. Inactivation of TP53 pathway by TP53 mutations is observed in nearly half of colorectal tumors. The impact of such mutations has been poorly studied in the metastatic setting. METHODS The files of 254 mCC treated in a single institution at Saint-Louis hospital between January 1999 and April 2011 were retrospectively reviewed. Tissue samples for analysis of TP53 mutations were available for 68 patients, performed using FASAY. The prognostic value of TP53 status was evaluated by comparing progression free survival (PFS) and overall survival (OS) in the group of TP53-mutated and wild type patients. RESULTS PFS was 6.9 months and OS 21.7 months in the whole population. There was no statistical difference in TP53-mutated and wild type groups in term of PFS (HR=1.04; IC 95%=0.6-1.79) and OS (HR=0.99; IC 95%=0.53-1.55) whatever the chemotherapy regimen (oxaliplatin- or irinotecan-based). Only BRAF V600 mutation was demonstrated to be a poor prognostic factor for PFS and OS, and CEA level for OS. CONCLUSIONS Routine determination of TP53 mutations, even with a highly sensitive method, cannot be recommended to predict chemotherapy response in mCC.
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Li XL, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol 2015; 21:84-93. [PMID: 25574081 PMCID: PMC4284363 DOI: 10.3748/wjg.v21.i1.84] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 08/20/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies with high prevalence and low 5-year survival. CRC is a heterogeneous disease with a complex, genetic and biochemical background. It is now generally accepted that a few important intracellular signaling pathways, including Wnt/β-catenin signaling, Ras signaling, and p53 signaling are frequently dysregulated in CRC. Patients with mutant p53 gene are often resistant to current therapies, conferring poor prognosis. Tumor suppressor p53 protein is a transcription factor inducing cell cycle arrest, senescence, and apoptosis under cellular stress. Emerging evidence from laboratories and clinical trials shows that some small molecule inhibitors exert anti-cancer effect via reactivation and restoration of p53 function. In this review, we summarize the p53 function and characterize its mutations in CRC. The involvement of p53 mutations in pathogenesis of CRC and their clinical impacts will be highlighted. Moreover, we also describe the current achievements of using p53 modulators to reactivate this pathway in CRC, which may have great potential as novel anti-cancer therapy.
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40
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Lee SL, Dempsey-Hibbert NC, Vimalachandran D, Wardle TD, Sutton P, Williams JHH. Targeting Heat Shock Proteins in Colorectal Cancer. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/978-3-319-17211-8_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Wei XL, Wang DS, Xi SY, Wu WJ, Chen DL, Zeng ZL, Wang RY, Huang YX, Jin Y, Wang F, Qiu MZ, Luo HY, Zhang DS, Xu RH. Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer. World J Gastroenterol 2014; 20:18404-18412. [PMID: 25561809 PMCID: PMC4277979 DOI: 10.3748/wjg.v20.i48.18404] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 06/29/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
METHODS: We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed.
RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51).
CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.
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Abstract
Colorectal cancer (CRC) results from a stepwise accumulation of genetic and epigenetic alterations that transform the normal colonic epithelium into cancer. DNA methylation represents one of the most studied epigenetic marks in CRC, and three common epigenotypes have been identified characterized by high, intermediate and low methylation profiles, respectively. Combining DNA methylation data with gene mutations and cytogenetic alterations occurring in CRC is nowadays allowing the characterization of different CRC subtypes, but the crosstalk between DNA methylation and other epigenetic mechanisms, such as histone tail modifications and the deregulated expression of non-coding RNAs is not yet clearly defined. Epigenetic biomarkers are increasingly recognized as promising diagnostic and prognostic tools in CRC, and the potential of therapeutic applications aimed at targeting the epigenome is under investigation.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy
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43
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Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort. Tumour Biol 2014; 35:7163-75. [PMID: 24763823 DOI: 10.1007/s13277-014-1874-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
According to the multistep route of genetic alterations in the colorectal adenoma-carcinoma sequence, the complex K-ras/p53 mutation is one of the first alterations to occur and represent an important genetic event in colorectal cancer (CRC). An evaluation of the mutation spectra in K-ras and p53 gene was effected in 167 Tunisian patients with sporadic CRC to determine whether our populations have similar pattern of genetic alteration as in Maghrebin's population. Mutation patterns of codon 12-13 of K-ras and exon 5-8 of p53 were analyzed by immunohistochemistry and PCR-SSCP and confirmed by sequencing. Mutations in the K-ras gene were detected in 31.13 % and affect the women more than the men (p = 0.008). Immunostaining showed that expression of p21 ras was correlated with the advanced age (p = 0.004), whereas loss of signal was associated with mucinous histotype (p = 0.003). Kaplan-Meier survival curve found that patients with the K-ras mutation had a shorter survival compared with patients without mutation (p = 0.005). Alteration in p53 was seen in 17.4 % of patients and affects three hot spot codons such as 175, 245, and 248. Overexpression of p53 was seen in 34.1 % and correlated with tumor node metastasis (TNM) advanced stage (p = 0.037) and mucinous histotype (p = 0.001). A high concordance between p53 expression and alteration (p<0.005) was shown. Concomitant mutations in K-ras and p53 gene were detected in only 4 % of tumors. K-ras and p53 undergo separate pathways in colorectal tumorogenesis. Interestingly, mutations in the K-ras gene might be considered a valuable prognostic factor correlated to poor outcome. p53 gene alterations were rather low in our set, and methylation pattern of p53 is required to elucidate the molecular basis of this protein in CRC.
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Prognostic biomarkers in colorectal cancer: where do we stand? Virchows Arch 2014; 464:379-91. [PMID: 24487787 DOI: 10.1007/s00428-013-1532-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 12/03/2013] [Accepted: 12/23/2013] [Indexed: 12/13/2022]
Abstract
Colorectal cancer remains a major cause of cancer-related death worldwide. One way to reduce its staggering mortality rate and socio-economic burden is to predict outcome based on the aggressiveness of the tumor biology in order to treat patients accordingly to their risk profile. As such, it comes as no surprise that prognostic biomarker discovery is a hot topic in colorectal cancer research. The last two decades have literally produced tons of new data and an avalanche of potential clinically applicable biomarkers. This review explores and summarizes data concerning the prognostic strength and clinical utility of current and future tissue biomarkers in the diagnosis and treatment of colorectal cancer.
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45
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Zeilstra J, Joosten SPJ, Vermeulen L, Koster J, Medema JP, Versteeg R, Spaargaren M, Pals ST. CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status. PLoS One 2013; 8:e72849. [PMID: 24009708 PMCID: PMC3756983 DOI: 10.1371/journal.pone.0072849] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 07/15/2013] [Indexed: 11/18/2022] Open
Abstract
CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential. Previous data indicate that CD44 is a direct target of p53-mediated transcriptional repression in breast cancer. Since inactivating p53 mutations are frequent genetic events in CRC these could unleash expression of CD44. In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression. Interestingly, we observed that, in contrast to breast cancer, loss of function p53 mutations were not associated with elevated CD44 expression in colon cancer. Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells. Our data demonstrate that CD44 expression in normal and malignant intestinal epithelial cells is not regulated by p53, implying that regulation of this potentially important therapeutic target is tissue and cancer-type specific.
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Affiliation(s)
- Jurrit Zeilstra
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Sander P. J. Joosten
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Koster
- Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Rogier Versteeg
- Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Marcel Spaargaren
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Steven T. Pals
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- * E-mail:
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Warren RS, Atreya CE, Niedzwiecki D, Weinberg VK, Donner DB, Mayer RJ, Goldberg RM, Compton CC, Zuraek MB, Ye C, Saltz LB, Bertagnolli MM. Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803. Clin Cancer Res 2013; 19:5777-87. [PMID: 23983256 DOI: 10.1158/1078-0432.ccr-13-0351] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. EXPERIMENTAL DESIGN The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). RESULTS TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. CONCLUSIONS The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men.
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Affiliation(s)
- Robert S Warren
- Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California; Department of Biostatistics and Bioinformatics, Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina; Dana-Farber Cancer Institute; Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts; The Ohio State University, Columbus, Ohio; National Cancer Institute, Bethesda, Maryland; and Memorial Sloan-Kettering Cancer Center, New York, New York
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Sarasqueta AF, Forte G, Corver WE, de Miranda NF, Ruano D, van Eijk R, Oosting J, Tollenaar RAEM, van Wezel T, Morreau H. Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer. BMC Cancer 2013; 13:277. [PMID: 23739040 PMCID: PMC3682902 DOI: 10.1186/1471-2407-13-277] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 05/08/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence. TP53 is mutated in around 50% of human cancers. Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear. Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice. METHODS By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome. Moreover, survival effects of CSNK1A1 together with p53 were also studied.Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue. RESULTS Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0.009). Expression of CSNK1A1 modified p53 survival effects. Patients with low CSNK1A1 expression and non-functional p53 had a very poor survival both in the univariate (Log Rank p<0.001) and in the multivariate survival analysis (HR=4.74 95% CI 1.45 - 15.3 p=0.009). CONCLUSION The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients. This effect was specifically modified by CSKN1A1 expression.
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Santos C, Vilar E, Capella G, Salazar R. Molecular markers in colorectal cancer: clinical relevance in stage II colon cancer. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.24] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY Colorectal cancer is the second most common cause of cancer death in developed countries. Adjuvant chemotherapy is standard for stage III colorectal cancer but its use in stage II is controversial. Several clinicopathological factors have been described to define a high-risk group among stage II colon cancers, which can aid the selection of patients who may benefit from chemotherapy. Local tumor invasion (T4), high histological grade, obstruction and perforation at diagnosis, and number of lymph nodes removed are the most widely accepted factors. Several molecular factors have been also investigated as prognostic candidate biomarkers. DNA ploidy, KRAS and TP53 mutations, thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, loss of heterozygosity on chromosome 18q and microsatellite instability have been widely investigated. The aim of this review is to analyze the current evidence and clinical applications of the classical molecular biomarkers as well as new ones such as BRAF, circulating tumor cells, genome expression signatures and DNA methylation.
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Affiliation(s)
- Cristina Santos
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Capella
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Ramon Salazar
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
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Janouskova H, Ray AM, Noulet F, Lelong-Rebel I, Choulier L, Schaffner F, Lehmann M, Martin S, Teisinger J, Dontenwill M. Activation of p53 pathway by Nutlin-3a inhibits the expression of the therapeutic target α5 integrin in colon cancer cells. Cancer Lett 2013; 336:307-18. [PMID: 23523610 DOI: 10.1016/j.canlet.2013.03.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 03/01/2013] [Accepted: 03/15/2013] [Indexed: 12/11/2022]
Abstract
Integrins emerge nowadays as crucial actors of tumor aggressiveness and resistance to therapies. Integrin α5β1, the fibronectin receptor, determines malignant properties of colon carcinoma which is one of the most important causes of cancer-related deaths in the world. Here we show that inhibition of α5 integrin subunit expression by siRNA or α5β1 integrin function by specific antagonist affects the survival of HCT116 colon cancer cells. We also evidence that pharmacological reactivation of the tumor suppressor p53 by Nutlin-3a inhibits specifically the expression of the α5 integrin subunit both at the transcriptional and protein level. Inversely repression of α5 integrin modulates p53 activity. A clear relationship between p53 activation by Nutlin-3a, α5 repression and cell survival is shown. No such effects are obtained in cells lacking p53 or when another non-genotoxic activator of p53, RITA, is used. Our results emphasize the crucial role of α5β1 integrin in colon tumors. Data also suggest that interfering with the integrin α5β1 through the reactivation of p53 by Nutlin-3a may be of valuable interest as a new therapeutic option for colon tumors expressing high level of the integrin and a wild type p53.
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Affiliation(s)
- Hana Janouskova
- UMR7213 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
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Jiang WQ, Fu FF, Li YX, Wang WB, Wang HH, Jiang HP, Teng LS. Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice. J Zhejiang Univ Sci B 2013; 13:663-75. [PMID: 22949358 DOI: 10.1631/jzus.b1100340] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Colorectal cancer remains one of the most common types of cancer and leading causes of cancer death worldwide. Although we have made steady progress in chemotherapy and targeted therapy, evidence suggests that the majority of patients undergoing drug therapy experience severe, debilitating, and even lethal adverse drug events which considerably outweigh the benefits. The identification of suitable biomarkers will allow clinicians to deliver the most appropriate drugs to specific patients and spare them ineffective and expensive treatments. Prognostic and predictive biomarkers have been the subjects of many published papers, but few have been widely incorporated into clinical practice. Here, we want to review recent biomarker data related to colorectal cancer, which may have been ready for clinical use.
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Affiliation(s)
- Wei-qin Jiang
- Cancer Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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