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Ma L, Huang G, Lin C, Li X, Liu C, Huang W, Zhang Q, Luo Y. LACTB promotes cell differentiation and inhibits cell proliferation in colorectal cancer. Biochim Biophys Acta Gen Subj 2025; 1869:130816. [PMID: 40354832 DOI: 10.1016/j.bbagen.2025.130816] [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: 12/18/2024] [Revised: 04/23/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
This study aims at exploring the role of LACTB on colorectal cancer (CRC) cell differentiation. In this study, 143 colorectal cancer tissue samples were collected for analyzing the correlation between LACTB level and clinical information. Another 24 recent cases and adjacent tissues underwent qPCR, Western blot, and immunohistochemistry (IHC) to detect LACTB expression. The differentiation and proliferation of CRC cells were evaluated by AKP levels, E-cadherin expression, cell viability, colony formation, EdU assay, and cell cycle. Subcutaneous models explored LACTB's pro-differentiation effects. The glandular-like structures of tumor were observed by HE staining, immunofluorescence detection of microvilli proteins, and transmission electron microscopy. Our results showed that LACTB expression in colorectal cancer tissues was lower than that in adjacent normal tissues. Higher LACTB expression was correlated with slower tumor progression, better prognosis and higher differentiation degree. Overexpressing LACTB in CRC cells enhanced differentiation markers level (AKP and E-cadherin), while inhibited cell proliferation and colony formation, induced cell cycle arrest. Conversely, LACTB knockdown had an opposite effect. Subcutaneous xenograft tumor model suggested that LACTB overexpression inhibited tumor growth, induced tissue differentiation and glandular-like structures formation. Collectively, our results show that LACTB overexpression promotes cell differentiation and inhibits cell proliferation in CRC cells, which may serve as a therapy target for CRC.
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Affiliation(s)
- Lili Ma
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Guan Huang
- Department of Pathology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, Guangdong, China
| | - Chun Lin
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Xiaoqing Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chao Liu
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Weiye Huang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Qingling Zhang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
| | - Yang Luo
- Department of Urology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
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Gioacchini FM, Di Stadio A, De Luca P, Camaioni A, Pace A, Iannella G, Rubini C, Santarelli M, Tomassetti M, Scarpa A, Olivieri F, Re M. A pilot study to evaluate the expression of microRNA‑let‑7a in patients with intestinal‑type sinonasal adenocarcinoma. Oncol Lett 2024; 27:69. [PMID: 38192674 PMCID: PMC10773186 DOI: 10.3892/ol.2023.14202] [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: 07/10/2023] [Accepted: 10/25/2023] [Indexed: 01/10/2024] Open
Abstract
Despite its histological resemblance to colorectal adenocarcinoma, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinoma (ITAC). The present study investigated the possible role and clinical value of microRNA (miR)-let-7a, a head and neck squamous cell carcinoma-related miR, in a well-characterized and homogeneous cohort of patients with ethmoidal ITAC associated with occupational exposure, treated by primary surgery. miR-let-7a expression levels were analyzed in 23 pairs of ethmoidal ITAC and adjacent normal formalin-fixed paraffin-embedded tissues by reverse transcription-quantitative PCR. The expression was evaluated in tumor and healthy tissues according to: Tumor grade (G) of differentiation and extension, and pTNM stage, and presence/absence of recurrence. Comparisons within and between groups were performed using two-tailed Student's paired t-test and one-way ANOVA with Tukey's post hoc test. P<0.05 was considered to indicate a statistically significant difference. miR-let-7a expression in ethmoidal ITAC tissues was significantly lower than that in adjacent normal tissues (P<0.05; mean expression level ± SD, 1.452707±1.4367189 vs. 4.094017±2.7465375). miR expression varied with pT stage. miR-let-7a was downregulated (P<0.05) in advanced stages (pT3-pT4) compared with earlier stages (pT1-pT2). Furthermore, downregulation of miR-let-7a in ITAC was associated with poorly-differentiated (G3) cancer (P<0.05). No other associations were observed between miR-let-7a expression and the other clinicopathological parameters, including disease-free survival. In conclusion, downregulation of miR-let-7a in ITAC was associated with advanced-stage (pT3 and pT4) and poorly-differentiated (G3) disease, suggesting that the mutation of this gene, combined with additional genetic events, could serve a role in ITAC pathogenesis.
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Affiliation(s)
- Federico Maria Gioacchini
- Ear, Nose and Throat Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona Joint Hospitals, I-60020 Ancona, Italy
| | - Arianna Di Stadio
- Gian Filippo Ingrassia Department, Otolaryngology Unit, University of Catania, I-95121 Catania, Italy
| | - Pietro De Luca
- Department of Otolaryngology, Fatebenefratelli Isola Tiberina-Gemelli Hospital, I-00100 Rome, Italy
| | - Angelo Camaioni
- Head and Neck Department, San Giovanni-Addolorata Hospital, I-00189 Rome, Italy
| | - Annalisa Pace
- Department of Sense Organs, University La Sapienza of Rome, I-00161 Rome, Italy
| | - Giannicola Iannella
- Department of Sense Organs, University La Sapienza of Rome, I-00161 Rome, Italy
| | - Corrado Rubini
- Pathology and Histopathology Division, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, I-60020 Ancona, Italy
| | - Marco Santarelli
- Pathology and Histopathology Division, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, I-60020 Ancona, Italy
| | - Marco Tomassetti
- Department of Clinical and Molecular Sciences, Section of Occupational Medicine, Polytechnic University of Marche, I-60020 Ancona, Italy
| | - Alfonso Scarpa
- Department of Medicine and Surgery, University of Salerno, I-84084 Fisciano, Italy
| | - Fabiola Olivieri
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, I-60121 Ancona, Italy
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, I-60126 Ancona, Italy
| | - Massimo Re
- Ear, Nose and Throat Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona Joint Hospitals, I-60020 Ancona, Italy
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Deshmukh R, Prajapati M, Harwansh RK. Management of Colorectal Cancer Using Nanocarriers-based Drug Delivery for Herbal Bioactives: Current and Emerging Approaches. Curr Pharm Biotechnol 2024; 25:599-622. [PMID: 38807329 DOI: 10.2174/0113892010242028231002075512] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 05/30/2024]
Abstract
Colorectal cancer (CRC) is a complex and multifactorial disorder in middle-aged people. Several modern medicines are available for treating and preventing it. However, their therapeutic uses are limited due to drawbacks, such as gastric perforation, diarrhea, intestinal bleeding, abdominal cramps, hair loss, nausea, vomiting, weight loss, and adverse reactions. Hence, there is a continuous quest for safe and effective medicines to manage human health problems, like CRC. In this context, herbal medicines are considered an alternative disease control system. It has become popular in countries, like American, European, and Asian, due to its safety and effectiveness, which has been practiced for 1000 years. During the last few decades, herbal medicines have been widely explored through multidisciplinary fields for getting active compounds against human diseases. Several herbal bioactives, like curcumin, glycyrrhizin, paclitaxel, chlorogenic acid, gallic acid, catechin, berberine, ursolic acid, betulinic acid, chrysin, resveratrol, quercetin, etc., have been found to be effective against CRC. However, their pharmacological applications are limited due to low bioavailability and therapeutic efficacy apart from their several health benefits. An effective delivery system is required to increase their bioavailability and efficacy. Therefore, targeted novel drug delivery approaches are promising for improving these substances' solubility, bioavailability, and therapeutic effects. Novel carrier systems, such as liposomes, nanoparticles, micelles, microspheres, dendrimers, microbeads, and hydrogels, are promising for delivering poorly soluble drugs to the target site, i.e., the colon. Thus, the present review is focused on the pathophysiology, molecular pathways, and diagnostic and treatment approaches for CRC. Moreover, an emphasis has been laid especially on herbal bioactive-based novel delivery systems and their clinical updates.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Mahendra Prajapati
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
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Shechter S, Ya'ar Bar S, Khattib H, Gage MJ, Avni D. Riok1, A Novel Potential Target in MSI-High p53 Mutant Colorectal Cancer Cells. Molecules 2023; 28:molecules28114452. [PMID: 37298928 DOI: 10.3390/molecules28114452] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/23/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
The vulnerabilities of cancer cells constitute a promising strategy for drug therapeutics. This paper integrates proteomics, bioinformatics, and cell genotype together with in vitro cell proliferation assays to identify key biological processes and potential novel kinases that could account, at least in part, for the clinical differences observed in colorectal cancer (CRC) patients. This study started by focusing on CRC cell lines stratified by their microsatellite (MS) state and p53 genotype. It shows that cell-cycle checkpoint, metabolism of proteins and RNA, signal transduction, and WNT signaling processes are significantly more active in MSI-High p53-WT cell lines. Conversely, MSI-High cell lines with a mutant (Mut) p53 gene showed hyperactivation of cell signaling, DNA repair, and immune-system processes. Several kinases were linked to these phenotypes, from which RIOK1 was selected for additional exploration. We also included the KRAS genotype in our analysis. Our results showed that RIOK1's inhibition in CRC MSI-High cell lines was dependent on both the p53 and KRAS genotypes. Explicitly, Nintedanib showed relatively low cytotoxicity in MSI-High with both mutant p53 and KRAS (HCT-15) but no inhibition in p53 and KRAS WT (SW48) MSI-High cells. This trend was flipped in CRC MSI-High bearing opposite p53-KRAS genotypes (e.g., p53-Mut KRAS-WT or p53-WT KRAS-Mut), where observed cytotoxicity was more extensive compared to the p53-KRAS WT-WT or Mut-Mut cells, with HCT 116 (KRAS-Mut and p53-WT) being the most sensitive to RIOK1 inhibition. These results highlight the potential of our in silico computational approach to identify novel kinases in CRC sub-MSI-High populations as well as the importance of clinical genomics in determining drug potency.
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Affiliation(s)
- Sharon Shechter
- Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854-2874, USA
| | - Sapir Ya'ar Bar
- Department of Natural Compound, Nutrition, and Health, MIGAL Galilee Research Institute, Kiryat Shmona 1101600, Israel
| | - Hamdan Khattib
- Department of Natural Compound, Nutrition, and Health, MIGAL Galilee Research Institute, Kiryat Shmona 1101600, Israel
| | - Matthew J Gage
- Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854-2874, USA
| | - Dorit Avni
- Department of Natural Compound, Nutrition, and Health, MIGAL Galilee Research Institute, Kiryat Shmona 1101600, Israel
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Akanuma N, Rabinovitch PS, Mattis AN, Lauwers GY, Choi WT. Fundic Gland Polyps Lack DNA Content Abnormality Characteristic of Other Adenomatous Precursor Lesions in the Gastrointestinal Tract. Mod Pathol 2023; 36:100117. [PMID: 36805791 DOI: 10.1016/j.modpat.2023.100117] [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: 12/12/2022] [Revised: 01/15/2023] [Accepted: 01/22/2023] [Indexed: 02/04/2023]
Abstract
Fundic gland polyps (FGPs) develop sporadically (frequently after proton pump inhibitor therapy) or in the setting of a hereditary polyposis syndrome, such as familial adenomatous polyposis (FAP). FAP-related FGPs often demonstrate low-grade dysplasia (LGD) and are frequently associated with APC mutations, even in the absence of dysplasia. Sporadic FGPs with dysplasia are molecularly similar to FAP-related FGPs and demonstrate frequent mutations in APC gene. Despite having similar molecular alterations with colorectal and other adenomatous precursor lesions in the gastrointestinal (GI) tract, FGPs rarely progress to advanced gastric neoplasia (high-grade dysplasia [HGD] or adenocarcinoma), and their role in gastric tumorigenesis remains unclear but likely limited. The clinicopathologic features of 192 patients diagnosed with FGPs, including 86 with FAP-related FGPs (33 with dysplastic FGPs and 53 with nondysplastic FGPs) and 106 with sporadic FGPs (12 with dysplastic FGPs and 94 with nondysplastic FGPs), were analyzed. DNA flow cytometry was performed on 111 FAP-related FGP biopsies, including 32 FGPs with LGD and 79 nondysplastic FGPs, to assess the presence of abnormal DNA content (ie, aneuploidy or elevated 4N fraction). Moreover, 40 sporadic FGP biopsies, including 14 dysplastic (13 LGD and 1 HGD) and 26 nondysplastic FGPs, were examined for DNA content abnormality. Patients with FAP and nondysplastic FGPs were more likely to be younger (mean age, 32 years) and present with multiple FGPs (92%, defined as having ≥2 FGPs) than those with sporadic nondysplastic FGPs (61 years and 65%, respectively; P < .001). They also recorded higher rates of previous or concurrent gastric epithelial dysplasia not occurring in a FGP (8%, P = .016), nongastric GI dysplasia (96%, P < .001), and nongastric GI malignancy (17%, P = .001) compared with those with sporadic nondysplastic FGPs (0%, 52%, and 2%, respectively). The sporadic group was more frequently associated with proton pump inhibitor therapy (78%, P < .001), gastric intestinal metaplasia (24%, P = .004), and a family history of gastric cancer (10%, P = .027) than the FAP group (19%, 6%, and 0%, respectively). Almost all FAP-related FGPs had a polypoid endoscopic appearance (98% vs 84% for sporadic FGPs; P = .009). The mean size of the largest FAP-related FGPs (0.5 cm) was similar to that of sporadic FGPs (0.7 cm) (P = .069). None of the 147 patients with FAP-related or sporadic nondysplastic FGPs were associated with subsequent detection of advanced gastric neoplasia within a mean follow-up time of 54 months (range, <1 to 277 months). However, 2 (4%) of the 45 patients with FAP-related or sporadic dysplastic FGPs developed advanced gastric neoplasia within a mean follow-up time of 59 months (range, <1 to 236 months). One (3%) of the 33 patients with FAP and dysplastic FGPs developed signet ring cell adenocarcinoma, whereas 1 (8%) of the 12 patients with sporadic dysplastic FGPs developed HGD (P = .445). However, none of the FAP-related and sporadic FGP biopsies, regardless of the presence or absence of dysplasia, demonstrated DNA content abnormality. In conclusion, FGPs lack large-scale chromosomal changes that are characteristic of the typical adenoma-carcinoma sequence involved in the development of other GI malignancies. Progression to advanced gastric neoplasia is rare in FGPs, which may be partly explained by the apparent lack of the chromosomal instability phenotype in these lesions.
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Affiliation(s)
- Naoki Akanuma
- Department of Pathology, University of California at San Francisco, San Francisco, California
| | - Peter S Rabinovitch
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Aras N Mattis
- Department of Pathology, University of California at San Francisco, San Francisco, California
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, California.
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Pu Y, Wu W, Xiang H, Chen Y, Xu H. CRISPR/Cas9-based genome editing for multimodal synergistic cancer nanotherapy. NANO TODAY 2023; 48:101734. [DOI: 10.1016/j.nantod.2022.101734] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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Ganesan H, Nandy SK, Banerjee A, Pathak S, Zhang H, Sun XF. RNA-Interference-Mediated miR-122-Based Gene Regulation in Colon Cancer, a Structural In Silico Analysis. Int J Mol Sci 2022; 23:ijms232315257. [PMID: 36499586 PMCID: PMC9739210 DOI: 10.3390/ijms232315257] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/18/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
The role of microRNA 122 (miR-122) in colorectal cancer (CRC) has not been widely investigated. In the current study, we aimed to identify the prominent gene and protein interactors of miR122 in CRC. Based on their binding affinity, these targets were chosen as candidate genes for the creation of miR122-mRNA duplexes. Following this, we examined the miRNA-mediated silencing mechanism using the gene-silencing complex protein Argonaute (AGO). Public databases, STRING, and GeneMANIA were utilized to identify major proteins and genes interacting with miR-122. DAVID, PANTHER, UniProt, FunRich, miRwalk, and KEGG were used for functional annotation, pathway enrichment, binding affinity analysis, and expression of genes in different stages of cancer. Three-dimensional duplexes of hub genes and miR-122 were created using the RNA composer, followed by molecular interaction analysis using molecular docking with the AGO protein. We analyzed, classified, and scrutinized 93 miR-122 interactors using various bioinformatic approaches. A total of 14 hub genes were categorized as major interactors of miR-122. The study confirmed the role of various experimentally documented miR-122 interactors such as MTDH (Q86UE4), AKT1 (P31749), PTPN1 (P18031), MYC (P01106), GSK3B (P49841), RHOA (P61586), and PIK3CG (P48736) and put forth several novel interactors, with AKT3 (Q9Y243), NCOR2 (Q9Y618), PIK3R2 (O00459), SMAD4 (P61586), and TGFBR1 (P36897). Double-stranded RNA duplexes of the strongest interactors were found to exhibit higher binding affinity with AGO. In conclusions, the study has explored the role of miR-122 in CRC and has identified a closely related group of genes influencing the prognosis of CRC in multiple ways. Further, these genes prove to be targets of gene silencing through RNA interference and might serve as effective therapeutic targets in understanding and treating CRC.
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Affiliation(s)
- Harsha Ganesan
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai 603103, Tamil Nadu, India
| | - Suman K. Nandy
- BioNEST Bioincubator Facility, North-Eastern Hill University, Tura Campus, Chasingre, Tura 793022, Meghalaya, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai 603103, Tamil Nadu, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai 603103, Tamil Nadu, India
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Correspondence: (S.P.); (X.-F.S.)
| | - Hong Zhang
- School of Medical Sciences, Faculty of Medicine and Health, Orebro University, 702 81 Örebro, Sweden
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Correspondence: (S.P.); (X.-F.S.)
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Bagaria J, Kim KO, Bagyinszky E, An SSA, Baek JH. Discriminating Potential Genetic Markers for Complete Response and Non-Complete Response Patients to Neoadjuvant Chemotherapy with Locally Advanced Rectal Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19074008. [PMID: 35409691 PMCID: PMC8997875 DOI: 10.3390/ijerph19074008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 02/07/2023]
Abstract
Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is considered standard therapy for locally advanced rectal cancer. Unfortunately, most patients with rectal cancer are resistant to radiotherapy. This might be a genetic cause. The role of certain rectal cancer-causing genes has not been completely elucidated. This study aims to investigate the genes responsible for locally advanced rectal cancer patients not reacting to radiotherapy. Methods: Whole exome sequencing of the DNA samples was performed on the samples. Bioinformatic analysis on the subjects was established. Individual genetic information was screened to identify differently expressed genes that more frequently appeared in non-complete response (NCR) compared to complete response (CR) patients after nCRT. All variations were verified by Sanger sequencing. Results: Genotyping information and pathway analyses of the samples indicated genes such as FLCN, CALML5, and ANTXR1 to be commonly mutated in CR group, whereas genes such as GALNTL14, CNKSR1, ACD, and CUL3 were more commonly mutated in the NCR group. Chi-square test revealed some significant variants (<0.05) such as rs3744124 (FLCN), rs28365986 (ANTXR1), rs10904516 (CALML5), rs3738952 (CUL3), rs13394 and rs2293013 (PIH1D1), rs2274531 (GPA33), rs4963048 (BRSK2), rs17883366 (IL3RA), rs2297575 (PSMD5), rs2288101 (GALNT14), and rs11954652 (DCTN4). Conclusion: Identifying an array of genes that separate NCRs from CRs would lead to finding genetic biomarkers for early detection of rectal cancer patients that are resistant to nCRT. A further investigation to validate the significance of genetic biomarkers to segregate NCRs from CRs should be performed with a larger CRC dataset. Protein expression levels, as well as transcriptomic analysis, would also help us understand the mechanism of how these genes could play a role in preventing radiation therapy to patients. This would be essential to prevent redundant radiation therapy.
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Affiliation(s)
- Jaya Bagaria
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
| | - Kyung-Ok Kim
- Gachon Medical Research Institute, Gil Medical Center, Gachon University, Incheon 21565, Korea;
| | - Eva Bagyinszky
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
| | - Seong Soo A. An
- Department of Bionano Technology, Gachon University, Seongnam-si 13120, Korea; (J.B.); (E.B.)
- Correspondence: (S.S.A.A.); (J.-H.B.); Tel.: +82-10-4344-9633 (S.S.A.A.); +82-10-5248-6656 (J.-H.B.)
| | - Jeong-Heum Baek
- Division of Colon and Rectal Surgery, Department of Surgery, Gil Medical Center, College of Medicine, Gachon University, Incheon 21565, Korea
- Correspondence: (S.S.A.A.); (J.-H.B.); Tel.: +82-10-4344-9633 (S.S.A.A.); +82-10-5248-6656 (J.-H.B.)
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Jung S, Lee JL, Kim TW, Lee J, Yoon YS, Lee KY, Song KH, Yu CS, Cho YB. Molecular characterization of dysplasia-initiated colorectal cancer with assessing matched tumor and dysplasia samples. Ann Coloproctol 2022; 38:72-81. [PMID: 34788527 PMCID: PMC8898627 DOI: 10.3393/ac.2021.00290.0041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/29/2021] [Accepted: 07/20/2021] [Indexed: 10/26/2022] Open
Abstract
PURPOSE Ulcerative colitis (UC) is known to have an association with the increased risk of colorectal cancer (CRC), and UC-associated CRC does not follow the typical progress pattern of adenoma-carcinoma. The aim of this study is to investigate molecular characteristics of UC-associated CRC and further our understanding of the association between UC and CRC. METHODS From 5 patients with UC-associated CRC, matched normal, dysplasia, and tumor specimens were obtained from formalin-fixed paraffin-embedded (FFPE) samples for analysis. Genomic DNA was extracted and whole exome sequencing was conducted to identify somatic variations in dysplasia and tumor samples. Statistical analysis was performed to identify somatic variations with significantly higher frequencies in dysplasia-initiated tumors, and their relevant functions were investigated. RESULTS Total of 104 tumor mutation genes were identified with higher mutation frequencies in dysplasia-initiated tumors. Four of the 5 dysplasia-initiated tumors (80.0%) have TP53 mutations with frequent stop-gain mutations that were originated from matched dysplasia. APC and KRAS are known to be frequently mutated in general CRC, while none of the 5 patients have APC or KRAS mutation in their dysplasia and tumor samples. Glycoproteins including mucins were also frequently mutated in dysplasia-initiated tumors. CONCLUSION UC-associated CRC tumors have distinct mutational characteristics compared to typical adenoma-carcinoma tumors and may have different cancer-driving molecular mechanisms that are initiated from earlier dysplasia status.
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Affiliation(s)
- Sungwon Jung
- Department of Genome Medicine and Science, Gachon University College of Medicine, Incheon, Korea
- Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Korea
| | - Jong Lyul Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae Won Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea
| | - Jongmin Lee
- Department of Genome Medicine and Science, Gachon University College of Medicine, Incheon, Korea
| | - Yong Sik Yoon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kil Yeon Lee
- Department of Surgery, Kyung Hee University College of Medicine, Seoul, Korea
| | - Ki-hwan Song
- Department of Surgery, Koo Hospital, Daegu, Korea
| | - Chang Sik Yu
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Beom Cho
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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11
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Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2022; 117:57-69. [PMID: 34962727 DOI: 10.14309/ajg.0000000000001548] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 12/11/2022]
Abstract
This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.
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12
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Patel SG, May FP, Anderson JC, Burke CA, Dominitz JA, Gross SA, Jacobson BC, Shaukat A, Robertson DJ. Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2022; 162:285-299. [PMID: 34794816 DOI: 10.1053/j.gastro.2021.10.007] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.
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Affiliation(s)
- Swati G Patel
- University of Colorado Anschutz Medical Center, Aurora, Colorado; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado.
| | - Folasade P May
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Joseph C Anderson
- VA Medical Center, White River Junction, Vermont, and the Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; University of Connecticut School of Medicine, Farmington, Connecticut
| | | | - Jason A Dominitz
- VA Puget Sound Health Care System and the University of Washington, Seattle, Washington
| | | | | | - Aasma Shaukat
- GI Section, Minneapolis VA Medical Center and University of Minnesota, Minneapolis, Minnesota
| | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont, and the Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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13
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Patel SG, May FP, Anderson JC, Burke CA, Dominitz JA, Gross SA, Jacobson BC, Shaukat A, Robertson DJ. Updates on age to start and stop colorectal cancer screening: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2022; 95:1-15. [PMID: 34794803 DOI: 10.1016/j.gie.2021.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.
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Affiliation(s)
- Swati G Patel
- University of Colorado Anschutz Medical Center, Aurora, Colorado, USA; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, USA
| | - Folasade P May
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA; Vatche and Tamar Manoukian Division of Digestive Diseases and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Joseph C Anderson
- VA Medical Center, White River Junction, Vermont, USA and the Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA; University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | | | - Jason A Dominitz
- VA Puget Sound Health Care System and the University of Washington, Seattle, Washington, USA
| | | | | | - Aasma Shaukat
- GI Section, Minneapolis VA Medical Center and University of Minnesota, Minneapolis, Minnesota, USA
| | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont, USA and the Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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14
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Larasati Y, Boudou C, Koval A, Katanaev VL. Unlocking the Wnt pathway: Therapeutic potential of selective targeting FZD 7 in cancer. Drug Discov Today 2021; 27:777-792. [PMID: 34915171 DOI: 10.1016/j.drudis.2021.12.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/09/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
Abstract
The Wnt signaling is of paramount pathophysiological importance. Despite showing promising anticancer activities in pre-clinical studies, current Wnt pathway inhibitors face complications in clinical trials resulting from on-target toxicity. Hence, the targeting of pathway component(s) that are essential for cancer but dispensable for normal physiology is key to the development of a safe Wnt signaling inhibitor. Frizzled7 (FZD7) is a Wnt pathway receptor that is redundant in healthy tissues but crucial in various cancers. FZD7 modulates diverse aspects of carcinogenesis, including cancer growth, metastasis, maintenance of cancer stem cells, and chemoresistance. In this review, we describe state-of-the-art knowledge of the functions of FZD7 in carcinogenesis and adult tissue homeostasis. Next, we overview the development of small molecules and biomolecules that target FZD7. Finally, we discuss challenges and possibilities in developing FZD7-selective antagonists.
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Affiliation(s)
- Yonika Larasati
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Cédric Boudou
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Alexey Koval
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Vladimir L Katanaev
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; School of Biomedicine, Far Eastern Federal University, 690922 Vladivostok, Russia.
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15
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Wan T, Pan Q, Liu C, Guo J, Li B, Yan X, Cheng Y, Ping Y. A Duplex CRISPR-Cas9 Ribonucleoprotein Nanomedicine for Colorectal Cancer Gene Therapy. NANO LETTERS 2021; 21:9761-9771. [PMID: 34767372 DOI: 10.1021/acs.nanolett.1c03708] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Based on the high frequency of concurrent adenomatous polyposis coli (APC) and KRAS mutations and their strong cooperative interaction in human colorectal cancer (CRC) promotion, we herein develop a CRISPR-Cas9-based genome-editing nanomedicine to target both APC and KRAS mutations for the treatment of CRC. To this end, a hyaluronic acid (HA)-decorated phenylboronic dendrimer (HAPD) was designed for the targeted delivery of Cas9 ribonucleoprotein (RNP), by which both APC and KRAS genetic mutations harboring in CRC cells can be synergistically disrupted. Systemic administration of Cas9 RNP targeting APC and KRAS enabled by HAPD significantly inhibits tumor growth on xenografted and orthotopic CRC mouse models and also greatly prevents CRC-induced liver metastasis and lung metastasis. Thus, this duplex genome-editing system provides a promising gene therapy strategy for the treatment of human CRC and can be extended to other types of cancers with activated Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways.
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Affiliation(s)
- Tao Wan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
| | - Qi Pan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chongyi Liu
- Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China
| | - Jiajing Guo
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bowen Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaojie Yan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yiyun Cheng
- Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China
| | - Yuan Ping
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
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16
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Leystra AA, Harvey KN, Kaunga E, Hensley H, Vanderveer LA, Devarajan K, Clapper ML. High Variability in Cellular Proliferation, Gene Expression, and Cytokine Production in the Nonneoplastic Colonic Epithelium of Young Apc+/Min-FCCC Mice. Front Oncol 2021; 11:705562. [PMID: 34513688 PMCID: PMC8429936 DOI: 10.3389/fonc.2021.705562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/09/2021] [Indexed: 12/31/2022] Open
Abstract
An urgent need exists to identify efficacious therapeutic preventive interventions for individuals who are at high risk of developing colorectal cancer. To maximize the benefits of preventive intervention, it is vital to identify the time interval during which the initiation of a preventive intervention will lead to an optimal outcome. The goal of the present study was to determine if oncogenic events can be detected in the nonneoplastic colonic mucosa of Apc+/Min-FCCC mice prior to formation of the first adenoma, thus defining an earlier point of intervention along the cancer continuum. Tissues taken at three potential points of intervention were characterized: prior to Apc mutation (wild type Apc+/+-FCCC mice); after initiation but prior to colon adenoma formation (tumor-free Apc+/Min-FCCC mice); and after formation of the first colon adenoma (tumor-bearing Apc+/Min-FCCC mice). Experimentation focused on molecular processes that are dysregulated in early colon lesions: 1) cellular proliferation (proliferative index and size of the proliferative zone); 2) cellular stemness (expression of Ascl2, Grem1, Lgr5 and Muc2); 3) EGFR signaling (expression of Ereg); and 4) inflammation (expression of Mmp9, Ptsg2, and Reg4, as well as secretion of 18 cytokines involved in immune activation and response). Interestingly, the nonneoplastic colonic mucosa of wild type, tumor-free Apc+/Min-FCCC , and tumor-bearing Apc+/Min-FCCC mice did not display significant differences in average epithelial cell proliferation (fold change 0.8-1.3, p≥0.11), mucosal gene expression (fold change 0.8-1.4, p≥0.22), or secretion of specific cytokines from colonic mucosa (fold change 0.2-1.5, p≥0.06). However, the level of cytokine secretion was highly variable, with many (22% of wild type, 31% of tumor-free Apc+/Min-FCCC , and 31% of tumor-bearing Apc+/Min-FCCC ) mice categorized as outliers (> 1.5 x interquartile ranges below the first quartile or above the third quartile) due to elevated expression of at least one cytokine. In summary, no differences were observed in proliferation, stemness, and EGFR signaling in the colonic mucosa of wild type vs Apc+/Min-FCCC mice, with low baseline cytokine expression, prior to the formation of the first colon adenoma. The results of this study provide valuable baseline data to inform the design of future cancer prevention studies.
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Affiliation(s)
- Alyssa A. Leystra
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Kristen N. Harvey
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Esther Kaunga
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Harvey Hensley
- Biological Imaging Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Lisa A. Vanderveer
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Karthik Devarajan
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Margie L. Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
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17
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Noe O, Filipiak L, Royfman R, Campbell A, Lin L, Hamouda D, Stanbery L, Nemunaitis J. Adenomatous polyposis coli in cancer and therapeutic implications. Oncol Rev 2021; 15:534. [PMID: 34267890 PMCID: PMC8256374 DOI: 10.4081/oncol.2021.534] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APCmutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an APC mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.
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Affiliation(s)
- Olivia Noe
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Louis Filipiak
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Rachel Royfman
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Austin Campbell
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Leslie Lin
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Danae Hamouda
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Laura Stanbery
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
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18
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Gomaa W, Al-Maghrabi H, Al-Maghrabi J. The prognostic significance of immunostaining of Wnt signalling pathway molecules, E-cadherin and β-catenin in colorectal carcinomacolorectal carcinoma. Arab J Gastroenterol 2021; 22:137-145. [PMID: 34088623 DOI: 10.1016/j.ajg.2021.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND STUDY AIMS Colorectal carcinoma (CRC) is associated with high morbidity and mortality. The E-cadherin-catenin complex is crucial in the development and progression of carcinomas. This study was conducted to evaluate the relation between E-cadherin and β-catenin immunostaining and CRC outcome. PATIENTS AND METHODS Tissue microarrays were constructed from CRC, nodal metastases, adenomas, and normal mucosa. E-cadherin and β-catenin immunostaining was performed, and results were analyzed. RESULTS For E-cadherin, the membranous fraction (MF) was higher in normal mucosa, adenoma, CRC, and nodal metastasis than the cytoplasmic fraction (CF), but no difference in nodal metastasis was observed. A low MF in CRC was associated with disease relapse. For β-catenin, high MF and CF in normal mucosa, adenoma, CRC, and nodal metastasis were observed, whereas the nuclear fraction (NF) was high only in CRC. In CRC, a high CF was associated with nodal metastasis and the incidence of relapse and predicted nodal metastasis. A high NF could predict distance metastasis. A high CF in CRC was associated with favorable disease-free survival and overall survival. CONCLUSION Reduced E-cadherin and β-catenin immunostaining in CRC is related to prognostic factors. The Wnt/β-catenin pathway may play a crucial role in CRC progression and help identify the high risk of adverse outcomes and indicate close follow-up.
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Affiliation(s)
- Wafaey Gomaa
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pathology, Faculty of Medicine, Minia University, Al-Minia, Egypt
| | - Haneen Al-Maghrabi
- Department of Pathology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Jaudah Al-Maghrabi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pathology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia.
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19
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San Miguel Y, Demb J, Martinez ME, Gupta S, May FP. Time to Colonoscopy After Abnormal Stool-Based Screening and Risk for Colorectal Cancer Incidence and Mortality. Gastroenterology 2021; 160:1997-2005.e3. [PMID: 33545140 PMCID: PMC8096663 DOI: 10.1053/j.gastro.2021.01.219] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/18/2021] [Accepted: 01/23/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The optimal time interval for diagnostic colonoscopy completion after an abnormal stool-based colorectal cancer (CRC) screening test is uncertain. We examined the association between time to colonoscopy and CRC outcomes among individuals who underwent diagnostic colonoscopy after abnormal stool-based screening. METHODS We performed a retrospective cohort study of veterans age 50 to 75 years with an abnormal fecal occult blood test (FOBT) or fecal immunochemical test (FIT) between 1999 and 2010. We used multivariable Cox proportional hazards to generate CRC-specific incidence and mortality hazard ratios (HRs) and 95% confidence intervals (CI) for 3-month colonoscopy intervals, with 1 to 3 months as the reference group. Association of time to colonoscopy with late-stage CRC diagnosis was also examined. RESULTS Our cohort included 204,733 patients. Mean age was 61 years (SD 6.9). Compared with patients who received a colonoscopy at 1 to 3 months, there was an increased CRC risk for patients who received a colonoscopy at 13 to 15 months (HR 1.13; 95% CI 1.00-1.27), 16 to 18 months (HR 1.25; 95% CI 1.10-1.43), 19 to 21 months (HR 1.28; 95% CI: 1.11-1.48), and 22 to 24 months (HR 1.26; 95% CI 1.07-1.47). Compared with patients who received a colonoscopy at 1 to 3 months, mortality risk was higher in groups who received a colonoscopy at 19 to 21 months (HR 1.52; 95% CI 1.51-1.99) and 22 to 24 months (HR 1.39; 95% CI 1.03-1.88). Odds for late-stage CRC increased at 16 months. CONCLUSIONS Increased time to colonoscopy is associated with higher risk of CRC incidence, death, and late-stage CRC after abnormal FIT/FOBT. Interventions to improve CRC outcomes should emphasize diagnostic follow-up within 1 year of an abnormal FIT/FOBT result.
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Affiliation(s)
- Yazmin San Miguel
- Division of Gastroenterology, Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California; Moores Cancer Center and Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California
| | - Joshua Demb
- Division of Gastroenterology, Department of Internal Medicine, University of California San Diego, La Jolla, California
| | - Maria Elena Martinez
- Moores Cancer Center and Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California
| | - Samir Gupta
- Division of Gastroenterology, Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California; Division of Gastroenterology, Department of Internal Medicine, University of California San Diego, La Jolla, California.
| | - Folasade P May
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California.
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20
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Jiang H, Tang J, Qiu L, Zhang Z, Shi S, Xue L, Kui L, Huang T, Nan W, Zhou B, Zhao C, Yu M, Sun Q. Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways. Oncol Rep 2021. [PMID: 33649851 DOI: 10.3892/or.2021.8021/html] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2023] Open
Abstract
Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL‑1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL‑1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knocked‑down Jurkat and BALL‑1 cells, and the phosphorylation level of ERK was decreased in Sema4D knocked‑down BALL‑1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.
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MESH Headings
- Adolescent
- Antigens, CD/biosynthesis
- Antigens, CD/blood
- Biomarkers, Tumor/biosynthesis
- Biomarkers, Tumor/blood
- Case-Control Studies
- Cell Line, Tumor
- Cell Proliferation/physiology
- Child
- Child, Preschool
- Female
- Humans
- Infant
- Jurkat Cells
- Leukemia, Myeloid, Acute/blood
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukocytes, Mononuclear/metabolism
- MAP Kinase Signaling System
- Male
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphorylation
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Proto-Oncogene Proteins c-akt/metabolism
- Semaphorins/biosynthesis
- Semaphorins/blood
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Affiliation(s)
- Hongchao Jiang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Jiaolian Tang
- Institute of Pediatrics, Children's Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650228, P.R. China
| | - Lijuan Qiu
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Zhen Zhang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Shulan Shi
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Li Xue
- Institute of Medicine, Dali University, Dali, Yunnan 671000, P.R. China
| | - Liyue Kui
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Tilong Huang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Weiwei Nan
- Institute of Medicine, Dali University, Dali, Yunnan 671000, P.R. China
| | - Bailing Zhou
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Canchun Zhao
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Ming Yu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Biomedical Engineering Research Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Qiangming Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan 650118, P.R. China
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Jiang H, Tang J, Qiu L, Zhang Z, Shi S, Xue L, Kui L, Huang T, Nan W, Zhou B, Zhao C, Yu M, Sun Q. Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways. Oncol Rep 2021; 45:1. [PMID: 33649851 PMCID: PMC7877000 DOI: 10.3892/or.2021.7952] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/18/2020] [Indexed: 12/18/2022] Open
Abstract
Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL-1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL-1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knocked-down Jurkat and BALL-1 cells, and the phosphorylation level of ERK was decreased in Sema4D knocked-down BALL-1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.
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Affiliation(s)
- Hongchao Jiang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Jiaolian Tang
- Institute of Pediatrics, Children's Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650228, P.R. China
| | - Lijuan Qiu
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Zhen Zhang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Shulan Shi
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Li Xue
- Institute of Medicine, Dali University, Dali, Yunnan 671000, P.R. China
| | - Liyue Kui
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Tilong Huang
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Weiwei Nan
- Institute of Medicine, Dali University, Dali, Yunnan 671000, P.R. China
| | - Bailing Zhou
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Canchun Zhao
- Institute of Pediatrics, The Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Ming Yu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Biomedical Engineering Research Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Qiangming Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan 650118, P.R. China
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Badic B, Tixier F, Cheze Le Rest C, Hatt M, Visvikis D. Radiogenomics in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13050973. [PMID: 33652647 PMCID: PMC7956421 DOI: 10.3390/cancers13050973] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/07/2021] [Accepted: 02/20/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal carcinoma is characterized by intratumoral heterogeneity that can be assessed by radiogenomics. Radiomics, high-throughput quantitative data extracted from medical imaging, combined with molecular analysis, through genomic and transcriptomic data, is expected to lead to significant advances in personalized medicine. However, a radiogenomics approach in colorectal cancer is still in its early stages and many problems remain to be solved. Here we review the progress and challenges in this field at its current stage, as well as future developments. Abstract The steady improvement of high-throughput technologies greatly facilitates the implementation of personalized precision medicine. Characterization of tumor heterogeneity through image-derived features—radiomics and genetic profile modifications—genomics, is a rapidly evolving field known as radiogenomics. Various radiogenomics studies have been dedicated to colorectal cancer so far, highlighting the potential of these approaches to enhance clinical decision-making. In this review, a general outline of colorectal radiogenomics literature is provided, discussing the current limitations and suggested further developments.
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Affiliation(s)
- Bogdan Badic
- National Institute of Health and Medical Research, LaTIM—Laboratory of Medical Information Processing (INSERM LaTIM), UMR 1101, Université Bretagne Occidentale, 29238 Brest, France; (F.T.); (C.C.L.R.); (M.H.); (D.V.)
- Correspondence: ; Tel.: +33-298-347-215
| | - Florent Tixier
- National Institute of Health and Medical Research, LaTIM—Laboratory of Medical Information Processing (INSERM LaTIM), UMR 1101, Université Bretagne Occidentale, 29238 Brest, France; (F.T.); (C.C.L.R.); (M.H.); (D.V.)
| | - Catherine Cheze Le Rest
- National Institute of Health and Medical Research, LaTIM—Laboratory of Medical Information Processing (INSERM LaTIM), UMR 1101, Université Bretagne Occidentale, 29238 Brest, France; (F.T.); (C.C.L.R.); (M.H.); (D.V.)
- Department of Nuclear Medicine, University Hospital of Poitiers, 86021 Poitiers, France
| | - Mathieu Hatt
- National Institute of Health and Medical Research, LaTIM—Laboratory of Medical Information Processing (INSERM LaTIM), UMR 1101, Université Bretagne Occidentale, 29238 Brest, France; (F.T.); (C.C.L.R.); (M.H.); (D.V.)
| | - Dimitris Visvikis
- National Institute of Health and Medical Research, LaTIM—Laboratory of Medical Information Processing (INSERM LaTIM), UMR 1101, Université Bretagne Occidentale, 29238 Brest, France; (F.T.); (C.C.L.R.); (M.H.); (D.V.)
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23
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Abolhasani H, Zarghi A, Komeili Movahhed T, Abolhasani A, Daraei B, Dastmalchi S. Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents. Bioorg Med Chem 2021; 32:115960. [DOI: 10.1016/j.bmc.2020.115960] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 11/27/2020] [Accepted: 12/14/2020] [Indexed: 01/06/2023]
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24
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Snitow ME, Bhansali RS, Klein PS. Lithium and Therapeutic Targeting of GSK-3. Cells 2021; 10:255. [PMID: 33525562 PMCID: PMC7910927 DOI: 10.3390/cells10020255] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.
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Affiliation(s)
| | | | - Peter S. Klein
- Department of Medicine, Perelman School of Medicine,
University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USA; (M.E.S.); (R.S.B.)
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25
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Ji Y, Tu X, Hu X, Wang Z, Gao S, Zhang Q, Zhang W, Zhang H, Chen W. The role and mechanism of action of RNF186 in colorectal cancer through negative regulation of NF-κB. Cell Signal 2020; 75:109764. [PMID: 32882406 DOI: 10.1016/j.cellsig.2020.109764] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/26/2020] [Accepted: 08/26/2020] [Indexed: 12/25/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers worldwide. RING finger protein 186 (RNF186) is a member of the RING finger protein family. RNF186 has been reported to be involved in the regulation of the intestinal homeostasis through the regulation of endoplasmic reticulum (ER) stress in colonic epithelial cells. However, its role in CRC remains unclear. In this study, we found that colorectal tumours from human patients had decreased levels of RNF186. We demonstrated that overexpression of RNF186 suppressed the growth and migration of CRC-derived cell lines in vitro and inhibited tumour proliferation in vivo. Further, our findings indicated that forced expression of RNF186 inhibited nuclear factor-κB (NF-κB) activation by reducing the phosphorylation of NF-κB. In addition, our results showed that RNF186-/- mice exhibited significantly increased tumour burden compared to the wild type (WT) mice following treatment with azoxymethane/dextran sulfate sodium (AOM/DSS). Compared to WT mice, the percentage of Ki67 positive cells was increased in the RNF186-/- mice, indicating that RNF186 is crucial for intestinal cell proliferation during tumorigenesis. Taken together, our data suggest that RNF186 inhibits the development of CRC, and that this effect is mediated through the suppression of NF-κB activity.
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Affiliation(s)
- Yizhong Ji
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Xucan Tu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Xiuqi Hu
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Zhenglin Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Sifan Gao
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Qifan Zhang
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Wei Zhang
- The Second Clinical Medical College of Anhui Medical University, Hefei 230032, China
| | - Huabing Zhang
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China.
| | - Wei Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
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Meng J, Zhou X, Yang J, Qu X, Cui S. Exposure to low dose ZnO nanoparticles induces hyperproliferation and malignant transformation through activating the CXCR2/NF-κB/STAT3/ERK and AKT pathways in colonic mucosal cells. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 263:114578. [PMID: 32325249 DOI: 10.1016/j.envpol.2020.114578] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/31/2020] [Accepted: 04/09/2020] [Indexed: 06/11/2023]
Abstract
As ZnO nanoparticles have been applied in many fields, their biological risks on human health, of course, are worthy of our attention. Whether ZnO NPs have the risk and how colonic cells respond to the invaded ZnO NPs are still unknown. Herein, we evaluated the biological effects of ZnO NPs on colonic mucosal cells by in vitro and in vivo methods. IMCE cells, with APC mutation but phenotypically normal, demonstrated hyperproliferation through activating the CXCR2/NF-κB/STAT3/ERK and AKT pathways when exposed to ZnO NPs for 24 h. Long-term exposure of ZnO NPs resulted in the malignant transformation of IMCE cells, showing the morphological changes, anchorage-independent cell growth ability. Importantly, IMCE cells exposed to ZnO NPs subcutaneously grew and induced tumorigenesis in nude mice. In conclusion, exposure of ZnO NPs could induce malignant transformation of colonic mucosal cells through the CXCR2/NF-κB/STAT3/ERK and AKT pathways. We suggest that it was necessary to consider using the precautionary principle for gastrointestinal contact nanomaterials.
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Affiliation(s)
- Jian Meng
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Xiaoling Zhou
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Juan Yang
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shuxiang Cui
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China.
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27
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Wan T, Chen Y, Pan Q, Xu X, Kang Y, Gao X, Huang F, Wu C, Ping Y. Genome editing of mutant KRAS through supramolecular polymer-mediated delivery of Cas9 ribonucleoprotein for colorectal cancer therapy. J Control Release 2020; 322:236-247. [PMID: 32169537 DOI: 10.1016/j.jconrel.2020.03.015] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 02/14/2020] [Accepted: 03/10/2020] [Indexed: 12/21/2022]
Abstract
CRISPR (clustered, regularly interspaced, short palindromic repeats)/CRISPR-associated protein 9 (Cas9) system has emerged as a powerful genome-editing tool to correct genetic disorders. However, successful intracellular delivery of CRISPR/Cas9, especially in the form of ribonucleoprotein (RNP), remains elusive for clinical translation. Herein, we describe a supramolecular polymer that can mediate efficient controlled delivery of Cas9 RNP in vitro and in vivo. This supramolecular polymer system is prepared by complexing disulfide-bridged biguanidyl adamantine (Ad-SS-GD) with β-cyclodextrin-conjugated low-molecular-weight polyethyleneimime (CP) through supramolecular assembly to generate CP/Ad-SS-GD. Due to multiple, strong hydrogen bonding and salt bridge effects, CP/Ad-SS-GD well interact with Cas9 RNP to form stable nanocomplex CP/Ad-SS-GD/RNP, which can be readily released in the reductive intracellular milieu as a result of the cleavage of disulfide bonds. The supramolecular polymer ensures the efficient intracellular delivery and the release of Cas9 RNP into 293T cells and colorectal cancer (CRC) cells, thus displaying high genome-editing activity in vitro. Importantly, we also found that hyaluronic acid (HA)-decorated CP/Ad-SS-GD/RNP nanocomplexes targeting mutant KRAS effectively inhibit tumor growth as well as metastasis in the tumor-bearing mouse models. Collectively, our findings provide a promising therapeutic strategy against mutant KRAS for the treatment of CRC-activated RAS pathways, offering a new therapeutic genome-editing modality for the colorectal cancer treatment.
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Affiliation(s)
- Tao Wan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, China; Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China
| | - Yuxuan Chen
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China
| | - Qi Pan
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China
| | - Xiaojie Xu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China
| | - Yu Kang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China
| | - Xue Gao
- Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, Houston, TX 77005, USA
| | - Feihe Huang
- State Key Laboratory of Chemical Engineering, Center for Chemistry of High Performance & Novel Materials, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
| | - Chuanbin Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Yuan Ping
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China.
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Vidri RJ, Fitzgerald TL. GSK-3: An important kinase in colon and pancreatic cancers. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118626. [PMID: 31987793 DOI: 10.1016/j.bbamcr.2019.118626] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 12/09/2019] [Accepted: 12/12/2019] [Indexed: 12/17/2022]
Abstract
In this review, the role of glycogen synthase kinase 3 (GSK-3) in pancreatic and colon cancers will be explored. GSK-3 plays a fundamental role in many metabolic processes, primarily as the final enzyme in glycogen synthesis. Active β-catenin represents the final step for the transcription of Wnt target genes. Both GSK-3 and β-catenin are key in the neoplastic transformation and tumorigenesis of human cells. Despite the advances in diagnosis and treatment of pancreatic malignancies, survival remains dismal. Continued poor outcomes are attributable to tumor cell resistance and high frequency of metastatic disease. Survival for patients diagnosed with colon cancer is often excellent, and many patients achieve long term remission. However, the incidence of colon cancers continues to increase, especially among the young. The future use of targeted therapy in pancreatic and colo-rectal cancer utilizing GSK-3 may be promising, pending a more thorough understanding of potential downstream effects. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.
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Affiliation(s)
- Roberto J Vidri
- Division of Surgical Oncology, Tufts University School of Medicine-Maine Medical Center, Portland, ME, United States of America
| | - Timothy L Fitzgerald
- Division of Surgical Oncology, Tufts University School of Medicine-Maine Medical Center, Portland, ME, United States of America.
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Kobayashi M, Matsubara N, Nakachi Y, Okazaki Y, Uchino M, Ikeuchi H, Song J, Kimura K, Yasuhara M, Babaya A, Yamano T, Ikeda M, Nishikawa H, Matsuda I, Hirota S, Tomita N. Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer. In Vivo 2020; 34:57-63. [PMID: 31882463 PMCID: PMC6984071 DOI: 10.21873/invivo.11745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM The difficulty of early diagnosis of colitis associated colorectal cancer (CACRC) due to colonic mucosal changes in long-standing ulcerative colitis (UC) patients is often experienced in daily clinical practice. Noninvasive objective monitoring for cancer development is advantageous for optimizing treatment strategies in UC patients. We aimed to examine the epigenetic alterations occurring in CACRC, focusing on DNA hypermethylation of CpG islands. MATERIALS AND METHODS The level of DNA methylation in CpG cites was compared between CACRC and the counterpart non-tumorous mucosa using Infinium HumanMethylation 450K BeadChip. RESULTS Our subjects included 3 males and 3 females (median age, 49.5 years). The 450K CpG site DNA methylation microarray revealed that the difference in β value (level of hypermethylation) was the highest for corcicotropin releasing hormone receptor 2 (CRHR2) between CACRC and counterpart non-tumorous mucosa. CONCLUSION Detection of hypermethylation of CRHR2 may be promising for cancer screening in UC patients.
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Affiliation(s)
- Masayoshi Kobayashi
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nagahide Matsubara
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yutaka Nakachi
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan
| | - Yasushi Okazaki
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jihyng Song
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kei Kimura
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Michiko Yasuhara
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Akihito Babaya
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoki Yamano
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masataka Ikeda
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Nishikawa
- Center for Clinical Research and Education, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ikuo Matsuda
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naohiro Tomita
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
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Shaib WL, Zakka K, Staley C, Roberts A, Akce M, Wu C, Alese OB, El-Rayes BF. Blood-Based Next-Generation Sequencing Analysis of Appendiceal Cancers. Oncologist 2019; 25:414-421. [PMID: 31784493 DOI: 10.1634/theoncologist.2019-0558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/16/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Appendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations. MATERIALS AND METHODS Molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. RESULTS A total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25-83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%). CONCLUSION Evaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC. IMPLICATIONS FOR PRACTICE The complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.
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Affiliation(s)
- Walid L Shaib
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Katerina Zakka
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Charles Staley
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Ali Roberts
- Guardant Health, Redwood City, California, USA
| | - Mehmet Akce
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Christina Wu
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Olatunji B Alese
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Zhou CB, Fang JY. The role of pyroptosis in gastrointestinal cancer and immune responses to intestinal microbial infection. Biochim Biophys Acta Rev Cancer 2019; 1872:1-10. [DOI: 10.1016/j.bbcan.2019.05.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 04/18/2019] [Accepted: 05/01/2019] [Indexed: 01/04/2023]
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WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. Cell Commun Signal 2019; 17:88. [PMID: 31362761 PMCID: PMC6668196 DOI: 10.1186/s12964-019-0403-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/22/2019] [Indexed: 12/22/2022] Open
Abstract
Background Stabilization of RAS is a key event for the hyper-activation of Wnt/β-catenin signaling and activation of cancer stem cell (CSC) in colorectal cancer (CRC). WD Repeat protein 76 (WDR76) mediates the polyubiquitination-dependent degradation of RAS in hepatocellular carcinoma (HCC). We investigated whether WDR76 destabilizes RAS and acts as a tumor suppressor inhibiting CSC activation in CRC. Methods We generated mice with deletion of Wdr76 (Wdr76−/−) and crosses of Wdr76−/− with ApcMin/+ (Wdr76−/−; ApcMin/+) and compared them with wildtype mice (Wdr76+/+) and ApcMin/+ mice (Wdr76+/+; ApcMin/+), respectively. Intestinal crypt lengthening, tumorigenesis and CSC activation were analyzed by histology, immunohistochemistry, and immunoblotting. CRC cell line was engineered to stably express or knockdown WDR76 or control vector and was analyzed after spheroid culture. Results Wdr76−/− mice, with increased Ras level, displayed crypt elongation and hyper-proliferation. Wdr76−/−; ApcMin/+ mice developed more tumors with bigger sizes than ApcMin/+ mice and their tumors showed increased proliferation and CSC activation with elevated RAS and β-catenin levels. In CRC cells, overexpression or knockdown of WDR76 decreased or increased the numbers and sizes of CRC spheroids with inhibition or activation of CSC markers, respectively. In human CRC, lower level of WDR76 was associated with poor patient survival. Conclusions In analyses of mice with deletion of Wdr76 and CRC spheroids, we found that RAS stability plays important roles in tumorigenesis by affecting proliferation and CSC activation. Our results suggest that destabilization of RAS by WDR76 is a potential strategy for targeting malignant CRC involving CSC activation. Graphic abstract ![]()
Electronic supplementary material The online version of this article (10.1186/s12964-019-0403-x) contains supplementary material, which is available to authorized users.
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Majumder S, Shah R, Elias J, Mistry Y, Coral K, Shah P, Maurya AK, Mittal B, D’Silva JK, Murugan S, Mahadevan L, Sathian R, Ramprasad VL, Chakraborty P, Gupta R, Chaudhuri A, Khanna-Gupta A. A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity. PLoS One 2018; 13:e0203845. [PMID: 30256815 PMCID: PMC6157866 DOI: 10.1371/journal.pone.0203845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/28/2018] [Indexed: 01/21/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35–60 years) carrying this mutation. The remaining four members (6–23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.
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Affiliation(s)
| | | | - Jisha Elias
- MedGenome Labs Pvt. Ltd., Bangalore, India
- KCHRC, Muni Seva Ashram, Goraj, Gujarat, India
| | | | | | | | | | | | | | | | | | | | | | | | - Ravi Gupta
- MedGenome Labs Pvt. Ltd., Bangalore, India
| | - Amitabha Chaudhuri
- MedGenome Labs Pvt. Ltd., Bangalore, India
- MedGenome Inc., Foster City, CA, United States of America
- * E-mail: (AKG); (AC)
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Venancio VP, Cipriano PA, Kim H, Antunes LMG, Talcott ST, Mertens-Talcott SU. Cocoplum (Chrysobalanus icaco L.) anthocyanins exert anti-inflammatory activity in human colon cancer and non-malignant colon cells. Food Funct 2018; 8:307-314. [PMID: 28009871 DOI: 10.1039/c6fo01498d] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Cocoplum (Chrysobalanus icaco L.) (CP) is an anthocyanin-rich fruit found in tropical areas around the globe. CP polyphenols are associated with beneficial effects on health, including reduction of inflammation and oxidative stress. Due to its functional properties, the consumption of this fruit may be beneficial in the promotion of human health and reduce the risk for chronic diseases. The objective of this study was to assess the anti-inflammatory and anti-proliferative activities of anthocyanins extracted from CP (1.0 to 20.0 μg ml-1 gallic acid equivalents [GAE]) in CCD-18Co non-malignant colonic fibroblasts and HT-29 colorectal adenocarcinoma cells. Tumor necrosis factor alpha (TNF-α, 10 ng mL-1) was used to induce inflammation in CCD-18Co cells. CP anthocyanins were identified and quantified using HPLC-ESI-MSn. The chemical analysis of CP extract identified delphinidin, cyanidin, petunidin and peonidin derivatives as major components. Cell proliferation was suppressed in HT-29 cells at 10.0 and 20.0 μg ml-1 GAE and this was accompanied by increased intracellular ROS production as well as decreased TNF-α, IL-1β, IL-6, and NF-κB1 expressions at 20.0 μg ml-1 GAE. Within the same concentration range, there was no cytotoxic effect of CP anthocyanins in CCD-18Co cells and TNF-α-induced intracellular ROS-production was decreased by 17.3%. IL-1β, IL-6 and TNF-α protein expressions were also reduced in TNF-α-treated CCD-18Co cells by CP anthocyanins at 20.0 μg ml-1 GAE. These results suggest that cocoplum anthocyanins possess cancer-cytotoxic and anti-inflammatory activities in both inflamed colon and colon cancer cells.
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Affiliation(s)
- Vinicius P Venancio
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843-2254, USA. and Department of Clinical Analyses, Toxicology and Food Science, University of São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil
| | - Paula A Cipriano
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843-2254, USA.
| | - Hyemee Kim
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843-2254, USA.
| | - Lusânia M G Antunes
- Department of Clinical Analyses, Toxicology and Food Science, University of São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil
| | - Stephen T Talcott
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843-2254, USA.
| | - Susanne U Mertens-Talcott
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843-2254, USA.
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Jafarov S, Link KH. COLON AND RECTAL CANCER ARE DIFFERENT TUMOR ENTITIES ACCORDING TO EPIDEMIOLOGY, CARCINOGENESIS, MOLECULAR- AND TUMOR BIOLOGY, PRIMARY AND SECONDARY PREVENTION: PRECLINICAL EVIDENCE. SIBERIAN JOURNAL OF ONCOLOGY 2018; 17:88-98. [DOI: 10.21294/1814-4861-2018-17-4-88-98] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Introduction.Colon and rectal cancer (CC, RC) are different entities from a clinical and tumor biological point of view. Up to now, both, CC and RC, are synonymously called “Colorectal Cancer” (CRC). With our experience in basic and clinical research and routine work in this field we now have come to the opinion, that the term “CRC” should definitely be questioned, and if justified, be abandoned.Materials/Methods.We analyzed the actual available data from the literature and our own results from the Ulm based study group FOGT to proof or reject our hypothesis.Results.The following evident differences were recognized: Anatomically, the risk to develop RC is 4× higher than for CC. Molecular changes in carcinogenesis in CC are different from RC. Physical activity helps to prevent CC, not RC. Pathologically there are differences between RC and CC. In addition, there are also major clinical differences between CC and RC, such as in surgical topography and– procedures, multimodal treatment (MMT) approaches (RC in MMT is less sensitive to chemotherapy than CC), and prognostic factors for the spontaneous course and for success of MMT (e.g. TS or DPD ). Discussion. CC ´sand RC´s definitely are different in parameters of causal and formal carcinogenesis, effectivity of primary prevention by physical activity, conventional and molecular pathology.According to our findings we can demand from the preclinical point of view that CC and RC are two different tumor entities in terms of various representative biological characteristics.CC and RC are also differing substantially in many clinical features, as outlined in a separate paper from our group.Conclusion.“CRC” should no longer be used in basic and clinical research and other fields of cancer classification as a single disease entity. CC is not the same as RC. CC might even be divided into right and left CC.
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Ashburn JH. Management of rectal neoplasia in hereditary colorectal cancer patients. SEMINARS IN COLON AND RECTAL SURGERY 2018. [DOI: 10.1053/j.scrs.2018.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Paschke S, Jafarov S, Staib L, Kreuser ED, Maulbecker-Armstrong C, Roitman M, Holm T, Harris CC, Link KH, Kornmann M. Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer. Int J Mol Sci 2018; 19:2577. [PMID: 30200215 PMCID: PMC6165083 DOI: 10.3390/ijms19092577] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/20/2018] [Indexed: 01/06/2023] Open
Abstract
Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term "CRC" should no longer be used as a single entity in basic and clinical research as well as other areas of classification.
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Affiliation(s)
- Stephan Paschke
- Department of General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany.
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
| | - Sakhavat Jafarov
- Surgical Clinic, University Hospital Duesseldorf, 40225 Duesseldorf, Germany.
| | - Ludger Staib
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Department of General and Visceral Surgery, Hospital Esslingen, 73730 Esslingen, Germany.
| | - Ernst-Dietrich Kreuser
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Department of Hematology and Oncology, KH Barmherzige Brueder, 93049 Regensburg, Germany.
| | - Catharina Maulbecker-Armstrong
- Department of Disease Prevention, Hessian Ministry for Social Affairs, Health, and Integration, Germany and Technical High School Giessen, 35390 Wiesbaden, Germany.
- Hessian and German Cancer Societies, 14057 Berlin, Germany.
| | - Marc Roitman
- Surgical Center and Asklepios Tumor Center, Asklepios Paulinen Klinik, 65197 Wiesbaden, Germany.
| | - Torbjörn Holm
- Department Molecular Medicine, Coloproctology, Centre of Surgical Gastroenterology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
| | - Curtis C Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
| | - Karl-Heinrich Link
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Surgical Center and Asklepios Tumor Center, Asklepios Paulinen Klinik, 65197 Wiesbaden, Germany.
- Hessian and German Cancer Societies, 14057 Berlin, Germany.
| | - Marko Kornmann
- Department of General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany.
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
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A Novel Approach for Predicting Disease-lncRNA Associations Based on the Distance Correlation Set and Information of the miRNAs. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2018; 2018:6747453. [PMID: 30046354 PMCID: PMC6038663 DOI: 10.1155/2018/6747453] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 04/04/2018] [Accepted: 04/17/2018] [Indexed: 12/29/2022]
Abstract
Recently, accumulating laboratorial studies have indicated that plenty of long noncoding RNAs (lncRNAs) play important roles in various biological processes and are associated with many complex human diseases. Therefore, developing powerful computational models to predict correlation between lncRNAs and diseases based on heterogeneous biological datasets will be important. However, there are few approaches to calculating and analyzing lncRNA-disease associations on the basis of information about miRNAs. In this article, a new computational method based on distance correlation set is developed to predict lncRNA-disease associations (DCSLDA). Comparing with existing state-of-the-art methods, we found that the major novelty of DCSLDA lies in the introduction of lncRNA-miRNA-disease network and distance correlation set; thus DCSLDA can be applied to predict potential lncRNA-disease associations without requiring any known disease-lncRNA associations. Simulation results show that DCSLDA can significantly improve previous existing models with reliable AUC of 0.8517 in the leave-one-out cross-validation. Furthermore, while implementing DCSLDA to prioritize candidate lncRNAs for three important cancers, in the first 0.5% of forecast results, 17 predicted associations are verified by other independent studies and biological experimental studies. Hence, it is anticipated that DCSLDA could be a great addition to the biomedical research field.
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Abstract
The intestinal tract is a site of intense immune cell activity that is poised to mount an effective response against a pathogen and yet maintain tolerance toward commensal bacteria and innocuous dietary antigens. The role of cell death in gut pathologies is particularly important as the intestinal epithelium undergoes self-renewal every 4-7 days through a continuous process of cell death and cell division. Cell death is also required for removal of infected, damaged, and cancerous cells. Certain forms of cell death trigger inflammation through release of damage-associated molecular patterns. Further, molecules involved in cell death decisions also moonlight as critical nodes in immune signaling. The manner of cell death is, therefore, highly instructive of the immunological consequences that ensue. Perturbations in cell death pathways can impact the regulation of the immune system with deleterious consequences. In this review, we discuss the various forms of cell death with a special emphasis on lytic cell death pathways of pyroptosis and necroptosis and their implications in inflammation and cancer in the gut. Understanding the implications of distinct cell death pathways will help in the development of therapeutic interventions in intestinal pathologies.
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Affiliation(s)
- Deepika Sharma
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer. Oncotarget 2018; 7:81727-81740. [PMID: 27835580 PMCID: PMC5348425 DOI: 10.18632/oncotarget.13172] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/19/2016] [Indexed: 01/08/2023] Open
Abstract
APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.
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Aghdam R, Baghfalaki T, Khosravi P, Saberi Ansari E. The Ability of Different Imputation Methods to Preserve the Significant Genes and Pathways in Cancer. GENOMICS, PROTEOMICS & BIOINFORMATICS 2017; 15:396-404. [PMID: 29247873 PMCID: PMC5828654 DOI: 10.1016/j.gpb.2017.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 07/18/2017] [Accepted: 08/08/2017] [Indexed: 11/23/2022]
Abstract
Deciphering important genes and pathways from incomplete gene expression data could facilitate a better understanding of cancer. Different imputation methods can be applied to estimate the missing values. In our study, we evaluated various imputation methods for their performance in preserving significant genes and pathways. In the first step, 5% genes are considered in random for two types of ignorable and non-ignorable missingness mechanisms with various missing rates. Next, 10 well-known imputation methods were applied to the complete datasets. The significance analysis of microarrays (SAM) method was applied to detect the significant genes in rectal and lung cancers to showcase the utility of imputation approaches in preserving significant genes. To determine the impact of different imputation methods on the identification of important genes, the chi-squared test was used to compare the proportions of overlaps between significant genes detected from original data and those detected from the imputed datasets. Additionally, the significant genes are tested for their enrichment in important pathways, using the ConsensusPathDB. Our results showed that almost all the significant genes and pathways of the original dataset can be detected in all imputed datasets, indicating that there is no significant difference in the performance of various imputation methods tested. The source code and selected datasets are available on http://profiles.bs.ipm.ir/softwares/imputation_methods/.
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Affiliation(s)
- Rosa Aghdam
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran 19395-5746, Iran.
| | - Taban Baghfalaki
- Department of Statistics, Faculty of Mathematical Sciences, Tarbiat Modares University, Tehran 14115-111, Iran
| | - Pegah Khosravi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran 19395-5746, Iran; Department of Physiology and Biophysics, Institute for Computational Biomedicine and Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Elnaz Saberi Ansari
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran 19395-5746, Iran; Institut Cochin, Inserm U1016, CNRS UMR 8104, Universit Paris Descartes UMR-S1016, F-75014 Paris, France.
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Triki M, Ben Ayed-Guerfali D, Saguem I, Charfi S, Ayedi L, Sellami-Boudawara T, Cavailles V, Mokdad-Gargouri R. RIP140 and LCoR expression in gastrointestinal cancers. Oncotarget 2017; 8:111161-111175. [PMID: 29340045 PMCID: PMC5762313 DOI: 10.18632/oncotarget.22686] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/05/2017] [Indexed: 12/11/2022] Open
Abstract
The transcription coregulators RIP140 and LCoR are part of a same complex which controls the activity of various transcription factors and cancer cell proliferation. In this study, we have investigated the expression of these two genes in human colorectal and gastric cancers by immunohistochemistry. In both types of tumors, the levels of RIP140 and LCoR appeared highly correlated. Their expression tended to decrease in colorectal cancer as compared to adjacent normal tissues but was found higher in gastric cancer as compared to normal stomach. RIP140 and LCoR expression correlated with TNM and tumor differentiation. Significant correlations were observed with expression levels of key proteins involved in tumor progression and invasion namely E-cadherin and Cyclooxygenase-2. Survival analysis showed that patients with LCoRlow/RIP140high colorectal tumors have a significant prolonged overall and disease-free survival. In gastric cancer, high LCoR expression was identified as an independent marker of poor prognosis suggesting a key role in this malignancy. Altogether, these results demonstrate that RIP140 and LCoR have a prognostic relevance in gastrointestinal cancers and could represent new potential biomarkers in these tumors.
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Affiliation(s)
- Mouna Triki
- IRCM (Institute of Cancer Research of Montpellier), INSERM U1194, Montpellier University, Montpellier, France.,Center of Biotechnology of Sfax, Laboratory of Eukaryotic Molecular Biotechnology, Sfax University, Sfax, Tunisia
| | - Dorra Ben Ayed-Guerfali
- Center of Biotechnology of Sfax, Laboratory of Eukaryotic Molecular Biotechnology, Sfax University, Sfax, Tunisia
| | - Ines Saguem
- Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | - Slim Charfi
- Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | - Lobna Ayedi
- Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | | | - Vincent Cavailles
- IRCM (Institute of Cancer Research of Montpellier), INSERM U1194, Montpellier University, Montpellier, France
| | - Raja Mokdad-Gargouri
- Center of Biotechnology of Sfax, Laboratory of Eukaryotic Molecular Biotechnology, Sfax University, Sfax, Tunisia
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Smerdu V, Perše M. Effect of carcinogen 1,2-dimethylhydrazine treatment on fiber types in skeletal muscles of male Wistar rats. Physiol Res 2017; 66:845-858. [PMID: 28730826 DOI: 10.33549/physiolres.933508] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The cancerogen 1,2-dimethylhydrazine (DMH), widely used in the experimental animal model of carcinogenesis, affects various organs, but its effect on muscle fibers is unknown. To evaluate the effect of 15-week DMH treatment on the fiber size and myosin heavy chain (MyHC) isoforms, which substantially determine fiber types and their contractile characteristics, pure and hybrid fiber types were immunohistochemically determined according to the MyHC isoform expression in soleus, extensor digitorum longus, gastrocnemius medialis and lateralis muscles of DMH-treated and control male Wistar rats. Whereas the size of fibers was mostly unaffected, the MyHC isoform expression was partially affected in both gastrocnemius samples, but not in the soleus and extensor digitorum longus of DMH-treated rats. The lower proportions of hybrid fiber types and especially that of type 1/2x in most gastrocnemius samples of DMH-treated rats resulted in a shift towards a single MyHC isoform expression, but the extent and pattern of the MyHC isoform shift varied across the different gastrocnemius samples. Such variable response to DMH treatment across muscles indicates that each muscle possesses its own adaptive range. These findings are essential for an accurate evaluation of skeletal muscle characteristics in DMH animal model.
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MESH Headings
- 1,2-Dimethylhydrazine/toxicity
- Animals
- Carcinogens/toxicity
- Male
- Muscle Fibers, Fast-Twitch/drug effects
- Muscle Fibers, Fast-Twitch/metabolism
- Muscle Fibers, Fast-Twitch/pathology
- Muscle Fibers, Skeletal/drug effects
- Muscle Fibers, Skeletal/metabolism
- Muscle Fibers, Skeletal/pathology
- Muscle Fibers, Slow-Twitch/drug effects
- Muscle Fibers, Slow-Twitch/metabolism
- Muscle Fibers, Slow-Twitch/pathology
- Myosin Heavy Chains/biosynthesis
- Rats
- Rats, Wistar
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Affiliation(s)
- V Smerdu
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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Shaib WL, Assi R, Shamseddine A, Alese OB, Staley C, Memis B, Adsay V, Bekaii-Saab T, El-Rayes BF. Appendiceal Mucinous Neoplasms: Diagnosis and Management. Oncologist 2017; 22:1107-1116. [PMID: 28663356 PMCID: PMC5599200 DOI: 10.1634/theoncologist.2017-0081] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 05/09/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Appendiceal mucinous neoplasms (AMNs) are a rare and heterogeneous disease for which clinical management is challenging. We aim to review the literature regarding modalities of treatment to guide the management of AMNs. METHODS AND REVIEW CRITERIA We conducted a PubMed search in February 2016 for English-language publications, using the terms "appendiceal," "appendix," "carcinoma," "cancer," "mucinous," "treatment," "genes," "target," "genomic," and terms listed in the articles' subheadings. Published reports and abstracts from the American Society of Clinical Oncology meetings were also searched. RESULTS In this review, we summarize current data and controversies in AMN classification, clinical presentation, molecular alterations, treatment outcomes with regard to cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and the role of systemic chemotherapy. CONCLUSION Appendiceal mucinous neoplasms are a heterogeneous group of tumors with a rising incidence. Treatment is based on stage and histology. Low-grade tumors are treated surgically with resection of the primary site in early stage disease, or peritoneal debulking and HIPEC in patients with advanced stage disease. Treatment of high-grade tumors requires further prospective trials, and options include debulking surgery and HIPEC with or without preoperative chemotherapy. Trials evaluating novel therapies based on the molecular profiling of AMN tumors are needed to evaluate therapeutic options in patients who are not surgical candidates. IMPLICATIONS FOR PRACTICE This review provides a reference to guide gastroenterologists, pathologists, surgeons, and oncologists in the management of appendiceal mucinous neoplasms (AMNs), a rare and heterogeneous disease with no consensus on histologic classification or guidelines for treatment algorithms. This review summarizes all AMN classifications and proposes a treatment algorithm based on stage and histology of disease.
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Affiliation(s)
- Walid L Shaib
- Department of Hematology and Oncology, Atlanta, Georgia, USA
- GI Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Rita Assi
- Division of Hematology and Oncology, American University of Beirut, Beirut, Lebanon
| | - Ali Shamseddine
- Division of Hematology and Oncology, American University of Beirut, Beirut, Lebanon
| | - Olatunji B Alese
- Department of Hematology and Oncology, Atlanta, Georgia, USA
- GI Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | | | - Bahar Memis
- Department of Pathology, Atlanta, Georgia, USA
| | | | | | - Bassel F El-Rayes
- Department of Hematology and Oncology, Atlanta, Georgia, USA
- GI Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Xu M, Liu X, Xu Y, Zhu S, Gao Y. Co‑expression of Axin and APC gene fragments inhibits colorectal cancer cell growth via regulation of the Wnt signaling pathway. Mol Med Rep 2017; 16:3783-3790. [PMID: 28731177 PMCID: PMC5646956 DOI: 10.3892/mmr.2017.7049] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/26/2017] [Indexed: 12/17/2022] Open
Abstract
Adenomatous polyposis coli (APC) and Axin interactions serve an important role in colorectal cancer (CRC) pathogenesis. The aim of the present study was to assess the combined effects of Axin and APC co-expression in CRC cells, and to determine the underlying mechanisms involved. SW480 cells were divided into the following groups: Untransfected (SW480 group), transfected with pEGFP-N3plus pCS2-MT (SW480/vector-vector), transfected with pEGFP-N3-APC5 (SW480/APC5), and transfected with pEGFP-N3-APC5 pluspCS2-MT-Axin (SW480/APC5-Axin). APC5 and Axin mRNA levels were determined by reverse transcription-polymerase chain reaction. MTT assays and flow cytometry analysis were performed to assess cell growth and cell cycle distribution, respectively. Quantitative PCR and western blot analyses were conducted to evaluate the mRNA and protein levels, respectively, of Wnt signaling effectors, including β-catenin, c-myc and survivin. Successful transfection of SW480 cells was determined with APC and APC-Axin plasmids as indicated by the green fluorescence signals. Notably, SW480/APC5 cell growth was inhibited by 40.33%, and cells co-expressing APC5 and Axin demonstrated 61.27% inhibition of cell growth compared with SW480 control cells. The results demonstrate that APC5 may induce G1/S arrest in SW480 cells, and Axin may enhance cell growth arrest induced by APC5. The mRNA and protein levels of β-catenin, c-myc and survivin were significantly reduced in SW480/APC-Axin cells when compared with the SW480/APC group. In conclusion, co-expression of APC5 and Axin genes significantly downregulated Wnt signaling in human SW480 CRC cells and inhibited cell growth, when compared with cells transfected with APC5 alone. These results may provide experimental evidence to support combined gene therapy in CRC.
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Affiliation(s)
- Meili Xu
- Department of Gerontology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Xianling Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yan Xu
- Department of Gerontology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Shicong Zhu
- Department of Gerontology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yawen Gao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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Saadallah-Kallel A, Abdelmaksoud-Dammak R, Triki M, Charfi S, Khabir A, Sallemi-Boudawara T, Mokdad-Gargouri R. Clinical and prognosis value of the CIMP status combined with MLH1 or p16 INK4a methylation in colorectal cancer. Med Oncol 2017; 34:147. [PMID: 28730335 DOI: 10.1007/s12032-017-1007-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 07/15/2017] [Indexed: 01/10/2023]
Abstract
Aberrant DNA methylation of CpG islands occurred frequently in CRC and associated with transcriptional silencing of key genes. In this study, the CIMP combined with MLH1 or p16 INK4a methylation status was determined in CRC patients and correlated with clinicopathological parameters and overall survival. Our data showed that CIMP+ CRCs were identified in 32.9% of cases and that CACNAG1 is the most frequently methylated promoter. When we combined the CIMP with the MLH1 or the p16 INK4a methylation status, we found that CIMP-/MLH1-U (37.8%) and CIMP-/p16 INK4a -U (35.4%) tumors were the most frequent among the four subtypes. Statistical analysis showed that tumor location, lymphovascular invasion, TNM stage, and MSI differed among the group of patients. Kaplan-Meier analyses revealed differences in overall survival according to the CIMP combined with MLH1 or p16 INK4a methylation status. In a multivariate analysis, CIMP/MLH1 and CIMP/p16 INK4a methylation statuses were predictive of prognosis, and the OS was longer for patients with tumors CIMP-/MLH1-M, as well as CIMP-/p16 INK4a -M. Furthermore, DNMT1 is significantly overexpressed in tumors than in normal tissues as well as in CIMP+ than CIMP- tumors. Our results suggest that tumor classification based on the CIMP status combined with MLH1 or p16 INK4a methylation is useful to predict prognosis in CRC patients.
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Affiliation(s)
- Amana Saadallah-Kallel
- Laboratory of Molecular Biotechnology of Eukaryotes, Department of Cancer Genetics, Center of Biotechnology of Sfax, University of Sfax, BPK1177, 3018, Sfax, Tunisia
| | - Rania Abdelmaksoud-Dammak
- Laboratory of Molecular Biotechnology of Eukaryotes, Department of Cancer Genetics, Center of Biotechnology of Sfax, University of Sfax, BPK1177, 3018, Sfax, Tunisia
| | - Mouna Triki
- Laboratory of Molecular Biotechnology of Eukaryotes, Department of Cancer Genetics, Center of Biotechnology of Sfax, University of Sfax, BPK1177, 3018, Sfax, Tunisia
| | - Slim Charfi
- Service of Pathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | | | | | - Raja Mokdad-Gargouri
- Laboratory of Molecular Biotechnology of Eukaryotes, Department of Cancer Genetics, Center of Biotechnology of Sfax, University of Sfax, BPK1177, 3018, Sfax, Tunisia.
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Adenomatous Polyposis Syndromes: Familial Adenomatous Polyposis and MutYH-Associated Polyposis. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0379-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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48
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Larki P, Gharib E, Yaghoob Taleghani M, Khorshidi F, Nazemalhosseini-Mojarad E, Asadzadeh Aghdaei H. Coexistence of KRAS and BRAF Mutations in Colorectal Cancer: A Case Report Supporting The Concept of Tumoral Heterogeneity. CELL JOURNAL 2017; 19:113-117. [PMID: 28580315 PMCID: PMC5448326 DOI: 10.22074/cellj.2017.5123] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 03/13/2017] [Indexed: 12/24/2022]
Abstract
The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor (EGFR)-targeted therapy resistance of colorectal carcinomas. The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers (CRCs) with the prevalence of less than 0.001% of the cases. In patients with KRAS-mutant tumors, BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor. The current report demonstrates a case with advanced adenocarcinoma of the colon showing the coexistence of KRAS and BRAF mutations and may have profound clinical implications for disease progression and therapeutic responses.
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Affiliation(s)
- Pegah Larki
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Gharib
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Yaghoob Taleghani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khorshidi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abdelmaksoud-Dammak R, Chamtouri N, Triki M, Saadallah-Kallel A, Ayadi W, Charfi S, Khabir A, Ayadi L, Sallemi-Boudawara T, Mokdad-Gargouri R. Overexpression of miR-10b in colorectal cancer patients: Correlation with TWIST-1 and E-cadherin expression. Tumour Biol 2017; 39:1010428317695916. [PMID: 28345456 DOI: 10.1177/1010428317695916] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
MicroRNAs are emergent players of epigenetics that function as oncogenes or tumor suppressors and that have been implicated in regulating diverse cellular pathways. MiR-10b is an oncogenic microRNA involved in tumor invasion and metastasis in various cancers. Our data have shown that miR-10b is overexpressed in colorectal cancer samples in comparison with non-tumorous adjacent mucosa (p = 0.0025) and that it is associated with severe features such as tumor size >5 cm (p = 0.023), distant metastasis (p = 0.0022), non-differentiated tumors (p = 0.016), and vascular invasion (p = 0.01). Regarding the regulation of its expression, positive correlation between the loss of miR-10b and aberrant DNA methylation (p = 0.02) as well as a loss of TWIST-1 messenger RNA (p = 0.018) have been observed. Furthermore, expression analysis of the downstream miR-10b targets has shown that there are associations between low HOXD10 messenger RNA and E-cadherin protein levels (p < 0.0001, p = 0.0008, respectively) and overexpression of miR-10b. Our data suggests that overexpression of miR-10b results from high levels of TWIST-1 and may induce a decrease of E-cadherin membranous protein levels, thus contributing to the acquisition of metastatic phenotypes in colorectal cancer.
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Affiliation(s)
- Rania Abdelmaksoud-Dammak
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Nour Chamtouri
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Mouna Triki
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Amena Saadallah-Kallel
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Wajdi Ayadi
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Slim Charfi
- 2 Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | - Abdelmajid Khabir
- 2 Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | - Lobna Ayadi
- 2 Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia
| | | | - Raja Mokdad-Gargouri
- 1 Laboratory of Eukaryotes Molecular Biotechnology, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
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Abstract
PURPOSE OF REVIEW Despite the large investment of resources from screening, the fact that colorectal cancer remains the second leading cause of cancer deaths among Americans underscores the need for alternative strategies. Thus, a major clinical and research imperative is personalize clinical care, while focusing on risk stratification for screening, surveillance, chemoprevention, and therapeutic intervention. RECENT FINDINGS A complicating factor that colorectal cancer is biologically heterogeneous for at least four consensus molecular subtypes presents clear challenges for developing robust molecular biomarkers. SUMMARY The purpose of the review is to discuss the genetics and molecular biology of colonic neoplasia, high and low penetrance, and racial disparities in colonic neoplasia. Finally, we put forth the emerging concept of greater genomic landscape and the idea of chromatin protection therapy as a novel adjuvant to chemotherapy.
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