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Li Y, Chen K, Li Q, Liu Q, Han H, Liu H, Wang S. Exploring the therapeutic potential of "Zhi-Zhen" formula for oxaliplatin resistance in colorectal cancer: an integrated study combining UPLC-QTOF-MS/MS, bioinformatics, network pharmacology, and experimental validation. Front Med (Lausanne) 2025; 12:1516307. [PMID: 40078400 PMCID: PMC11897289 DOI: 10.3389/fmed.2025.1516307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Background Chemoresistance is a critical factor compromising the survival of patients with colorectal cancer (CRC). The "Zhi-Zhen" formula (ZZF), a traditional prescription developed by Chinese national medicine masters, has been extensively used in clinical practice to treat gastrointestinal cancer. Notably, ZZF has the potential to enhance tumor sensitivity to chemotherapy. Although previous in vitro studies have demonstrated the efficacy of ZZF in overcoming chemoresistance in colorectal cancer (CRC), its precise molecular mechanisms remain poorly understood. Materials and methods We used an integrated approach of bioinformatics and network pharmacology to predict the potential active ingredients and targets of ZZF in alleviating chemoresistance. The top five active ingredients identified by degree in the network analysis were validated using mass spectrometry. We then established an oxaliplatin-resistant CRC cell model to explore the potential targets and regulatory mechanisms through which ZZF overcomes chemoresistance at the cellular level. Results Network pharmacology and bioinformatics analyses jointly identified 29 active compounds and 13 potential key targets of ZZF, associated with chemoresistance. Among these targets, the differential expression of CASP7 significantly affected the progression-free survival of patients with CRC. We established two oxaliplatin-resistant CRC cell lines and observed an upregulation of CASP7 expression in these resistant cells. Furthermore, ZZF increases the expression and activation of CASP7 in resistant cells, promoting apoptosis, and thereby ameliorating chemoresistance. Additionally, β-catenin knockdown led to an upregulation of CASP7 expression, whereas activation of the Wnt/β-catenin signaling pathway reduced CASP7 protein levels. ZZF decreases the activity of the Wnt/β-catenin signaling pathway by decreasing β-catenin transcription and nuclear localization. Conclusion ZZF has potential clinical value in the treatment of chemoresistance in CRC by inhibiting the transcription and nuclear localization of β-catenin, thereby increasing the expression of CASP7 and enhancing the apoptotic response in chemoresistant CRC cells.
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Affiliation(s)
- Yongjing Li
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Chen
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Li
- Department of Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiaoli Liu
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijie Han
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Liu
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Songpo Wang
- Department of Traditional Chinese Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Abula A, Ma SQ, Wang S, Peng W, Pei X, Hu ZY. Case report: Pilomatrix carcinoma with PDL1 expression and CDKN2A aberrant. Front Immunol 2024; 15:1337400. [PMID: 38873609 PMCID: PMC11170102 DOI: 10.3389/fimmu.2024.1337400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/30/2024] [Indexed: 06/15/2024] Open
Abstract
Case report A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.
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Affiliation(s)
- Ayinuer Abula
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
- Department of Oncology, Turpan City People’s Hospital, Tulufan, China
| | - Sheng-Qiang Ma
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
- Department of Oncology, Turpan City People’s Hospital, Tulufan, China
| | - Sisi Wang
- Department of Oncology, Turpan City People’s Hospital, Tulufan, China
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Peng
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
- Department of General Surgery, Turpan City People’s Hospital, Tulufan, China
| | - Xiaming Pei
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
- Department of Urinary Surgery, Turpan City People’s Hospital, Tulufan, China
| | - Zhe-Yu Hu
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
- Department of Oncology, Turpan City People’s Hospital, Tulufan, China
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Rossetti LZ, Bekheirnia MR, Lewis AM, Mefford HC, Golden‐Grant K, Tarczy‐Hornoch K, Briere LC, Sweetser DA, Walker MA, Kravets E, Stevenson DA, Bruenner G, Sebastian J, Knapo J, Rosenfeld JA, Marcogliese PC, Wangler MF. Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. Mol Genet Genomic Med 2021; 9:e1542. [PMID: 33350591 PMCID: PMC7963417 DOI: 10.1002/mgg3.1542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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Affiliation(s)
- Linda Z. Rossetti
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Mir Reza Bekheirnia
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Andrea M. Lewis
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Heather C. Mefford
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | - Katie Golden‐Grant
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | | | - Lauren C. Briere
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - David A. Sweetser
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Melissa A. Walker
- Department of NeurologyDivision of NeurogeneticsChild NeurologyMassachusetts General HospitalBostonMAUSA
| | - Elijah Kravets
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - David A. Stevenson
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - Georgette Bruenner
- Division of Medical GeneticsDepartment of PediatricsCohen Children’s Medical CenterQueensNYUSA
| | - Jessica Sebastian
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Julia Knapo
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Jill A. Rosenfeld
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Paul C. Marcogliese
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
| | | | - Michael F. Wangler
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
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Rabban JT, Karnezis AN, Devine WP. Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli-Leydig cell tumour, microcystic stromal tumour and their mimics. Histopathology 2020; 76:11-24. [PMID: 31846522 DOI: 10.1111/his.13978] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord-stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli-Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord-stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.
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Affiliation(s)
- Joseph T Rabban
- Pathology Department, University of California San Francisco, San Francisco, CA, USA
| | - Anthony N Karnezis
- Pathology Department, University of California Davis, Sacramento, CA, USA
| | - W Patrick Devine
- Clinical Cancer Genomics Laboratory and Pathology Department, University of California San Francisco, San Francisco, CA, USA
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Hahn E, Putra J. Hepatocellular adenoma in the paediatric population: Molecular classification and clinical associations. World J Gastroenterol 2020; 26:2294-2304. [PMID: 32476794 PMCID: PMC7243640 DOI: 10.3748/wjg.v26.i19.2294] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular adenomas (HCAs) represent rare, benign liver tumours occurring predominantly in females taking oral contraceptives. In children, HCAs comprise less than 5% of hepatic tumours and demonstrate association with various conditions. The contemporary classification of HCAs, based on their distinctive genotypes and clinical phenotypes, includes hepatocyte nuclear factor 1 homeobox alpha-inactivated HCAs, beta-catenin-mutated HCAs, inflammatory HCAs, combined beta-catenin-mutated and inflammatory HCAs, sonic hedgehog-activated HCAs, and unclassified HCAs. In children, there is a lack of literature on the characteristics and distribution of HCA subtypes. In this review, we summarized different HCA subtypes and the clinicopathologic spectrum of HCAs in the paediatric population.
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Affiliation(s)
- Elan Hahn
- Division of Pathology, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto M5G 1X8, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, ON, Canada
| | - Juan Putra
- Division of Pathology, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto M5G 1X8, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, ON, Canada
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Abstract
This article links the understanding of developmental physiology of the adrenal cortex to adrenocortical tumor formation. Many molecular mechanisms that lead to formation of adrenocortical tumors have been discovered via next-generation sequencing approaches. The most frequently mutated genes in adrenocortical tumors are also factors in normal adrenal development and homeostasis, including those that alter the p53 and Wnt/β-catenin pathways. In addition, dysregulated protein kinase A signaling and ARMC5 mutations have been identified as key mediators of adrenocortical tumorigenesis. The growing understanding of genetic changes that orchestrate adrenocortical development and disease pave the way for potential targeted treatment strategies.
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Affiliation(s)
- Maya Lodish
- Pediatric Endocrinology Fellowship, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive, MSC 1830, Bethesda, MD 20892-1830, USA.
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Li N, Xu Y, Li G, Yu T, Yao RE, Wang X, Wang J. Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review. Medicine (Baltimore) 2017; 96:e6914. [PMID: 28514307 PMCID: PMC5440144 DOI: 10.1097/md.0000000000006914] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
RATIONALE The CTNNB1 (β-catenin) gene is well known for its crucial role in cell adhesion and the Wnt-signaling pathway. Previous studies have shown that gain-of-function mutations in the CTNNB1 gene contribute to the occurrence and development of a variety of carcinomas in humans. Recently, de novo, heterozygous, loss-of-function mutations of the CTNNB1 gene were found that partially explain intellectual disability in some patients. Other major clinical symptoms in these patients included microcephaly, abnormal facial features, motor delays, speech impairments, and deformities of the hands and feet. In addition, approximately 75% of these patients had mild visual defects, such as astigmatism, hyperopia, or strabismus PATIENT CONCERNS:: A 15-month-old Chinese boy, presenting with retinal detachment, lens and vitreous opacities, hypertonia of the extremities, mild thumb adduction, microcephaly, and developmental delay, is described. Targeted gene sequencing using an ophthalmic gene panel was performed to test for familial exudative vitreoretinopathy; however, the pathogenic gene was not found. INTERVENTIONS Genomic DNA analysis was performed to search for causing mutations. DIAGNOSES AND OUTCOMES Whole-exome sequencing revealed a novel nonsense variation in exon 11 of the CTNNB1 gene (c.1672C>T, p.Gln558X). Sanger sequencing of the patient and his parent confirmed this mutation and demonstrated it to be de novo. To the best of our knowledge, this is the first case report of a loss-of-function mutation of the CTNNB1 gene in an Asian population. LESSONS Severe ophthalmic phenotype has not well been connected with loss of functional mutation of CTNNB1 gene. Our finding expands the mutant spectrum of CTNNB1 gene and adds new understanding of the phenotype.
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Affiliation(s)
- Niu Li
- Molecular Diagnostic Laboratory
| | | | | | | | | | - Xiumin Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
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High-fat diet feeding promotes stemness and precancerous changes in murine gastric mucosa mediated by leptin receptor signaling pathway. Arch Biochem Biophys 2016; 610:16-24. [PMID: 27693038 DOI: 10.1016/j.abb.2016.09.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/25/2016] [Accepted: 09/27/2016] [Indexed: 12/16/2022]
Abstract
Obesity increases the risk for gastric cancers. However, the occurrence and mechanisms of precancerous atrophic gastritis induced by high-fat diet (HFD) remain unclear. Here, we show that HFD-associated lipotoxicity induces precancerous lesions that are accompanied by the disruption of organelle homeostasis, tissue integrity, and deregulated expression of stemness genes in the gastric epithelium mediated by leptin receptor (ObR) signaling. Following HFD feeding, ectopic fat accumulated and expression of LAMP2A in lysosome and COX IV in mitochondria increased in the gastric mucosa. HFD feeding also led to enhanced expression of activated-Notch1 and stem cell markers Lgr5, CD44, and EpCAM. In addition, HFD-fed mice showed intracellular β-catenin accumulation in the gastric mucosa with increased expression of its target genes, Nanog, Oct4, and c-Myc. These observations were abrogated in the leptin-deficient ob/ob mice and ObR-mutated db/db mice, indicating that these HFD-induced changes were responsible for effects downstream of the ObR. Consistent with this, the expression of the Class IA and III PI3Ks was increased following ObR activation in the gastric mucosa of HFD-fed mice. Together, these results suggest that HFD-induced lipotoxicity and deregulated organelle biosynthesis confer cancer stem cell-like properties to the gastric mucosa via signaling pathway mediated by leptin, PI3K and β-catenin.
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Waghmare I, Kango-Singh M. Loss of Cell Adhesion Increases Tumorigenic Potential of Polarity Deficient Scribble Mutant Cells. PLoS One 2016; 11:e0158081. [PMID: 27327956 PMCID: PMC4915667 DOI: 10.1371/journal.pone.0158081] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 06/09/2016] [Indexed: 11/18/2022] Open
Abstract
Epithelial polarity genes are important for maintaining tissue architecture, and regulating growth. The Drosophila neoplastic tumor suppressor gene scribble (scrib) belongs to the basolateral polarity complex. Loss of scrib results in disruption of its growth regulatory functions, and downregulation or mislocalization of Scrib is correlated to tumor growth. Somatic scribble mutant cells (scrib-) surrounded by wild-type cells undergo apoptosis, which can be prevented by introduction of secondary mutations that provide a growth advantage. Using genetic tools in Drosophila, we analyzed the phenotypic effects of loss of scrib in different growth promoting backgrounds. We investigated if a central mechanism that regulates cell adhesion governs the growth and invasive potential of scrib mutant cells. Here we show that increased proliferation, and survival abilities of scrib- cells in different genetic backgrounds affect their differentiation, and intercellular adhesion. Further, loss of scrib is sufficient to cause reduced cell survival, activation of the JNK pathway and a mild reduction of cell adhesion. Our data show that for scrib cells to induce aggressive tumor growth characterized by loss of differentiation, cell adhesion, increased proliferation and invasion, cooperative interactions that derail signaling pathways play an essential role in the mechanisms leading to tumorigenesis. Thus, our study provides new insights on the effects of loss of scrib and the modification of these effects via cooperative interactions that enhance the overall tumorigenic potential of scrib deficient cells.
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Affiliation(s)
- Indrayani Waghmare
- Department of Biology, University of Dayton, Dayton, Ohio, United States of America
| | - Madhuri Kango-Singh
- Department of Biology, University of Dayton, Dayton, Ohio, United States of America
- Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, Ohio, United States of America
- Premedical Programs, University of Dayton, Dayton, Ohio, United States of America
- SupraMolecular Applied Research and Technology Center (SMART), University of Dayton, Dayton, Ohio, United States of America
- * E-mail:
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CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer 2016; 15:579-86. [DOI: 10.1007/s10689-016-9899-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Thakur R, Mishra DP. Pharmacological modulation of beta-catenin and its applications in cancer therapy. J Cell Mol Med 2013; 17:449-56. [PMID: 23490077 PMCID: PMC3822645 DOI: 10.1111/jcmm.12033] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 01/17/2013] [Indexed: 12/22/2022] Open
Abstract
Beta-catenin (β-catenin) is a multifunction protein with a central role in physiological homeostasis. Its abnormal expression leads to various diseases including cancer. In normal physiology, β-catenin either maintains integrity of epithelial tissues or controls transcription of various genes on extracellular instigations. In epithelial tissues, β-catenin functions as a component of the cadherin protein complex and regulates epithelial cell growth and intracellular adhesion. In Wnt signalling, β-catenin is a major transcriptional modulator and plays a crucial role in embryogenesis, stem cell renewal and organ regeneration. Aberrant expression of β-catenin can induce malignant pathways in normal cells and its abnormal activity is also exploited by existing malignant programmes. It acts as an oncogene and modulates transcription of genes to drive cancer initiation, progression, survival and relapse. Abnormal expression and function of β-catenin in cancer makes it a putative drug target. In the past decade, various attempts have been made to identify and characterize various pharmacological inhibitors of β-catenin. Many of these inhibitors are currently being investigated for their anticancer activities in a variety of cancers. The first half of this review will focus on the role of β-catenin in cancer initiation, maintenance, progression and relapse whereas the second half will briefly summarize the recent progress in development of agents for the pharmacological modulation of β-catenin activity in cancer therapeutics.
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Affiliation(s)
- Ravi Thakur
- Cell Death Research Laboratory, Division of Endocrinology, Central Drug Research Institute, Lucknow, India
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12
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Affiliation(s)
- Y Wallis
- DNA Laboratory, Regional Genetic Services, Birmingham Heartlands Hospital, Birmingham
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13
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Low membranous expression of beta-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary. Mod Pathol 2010; 23:113-22. [PMID: 19820688 DOI: 10.1038/modpathol.2009.141] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Mutations in the beta-catenin gene are common in ovarian endometrioid carcinoma. Few studies have addressed the association of beta-catenin expression with tumor characteristics and patient outcome, yielding controversial results. The purpose of this study was to retrospectively assess the expression of beta-catenin in ovarian endometrioid carcinoma and correlate its expression with the Gynecologic Oncology Group's (GOG) grading system, clinicopathological characteristics, and patient survival. A total of 49 patients with primary ovarian endometrioid carcinoma were included in this study. A four-tier score grading system was used for the membranous staining (negative, weak, moderate, and strong) and the percentage of positive cells for the nuclear staining of beta-catenin. The status of five morphometric parameters, nuclear morphology (uniform or pleomorphic), mitotic count, glandular pattern, degree of squamous differentiation, and status of papillary pattern, was assessed. We found that a low membranous expression of beta-catenin and a high mitotic count (>15 per 10 high-power fields) were significantly associated with poor prognosis and early recurrence of ovarian endometrioid carcinoma. In addition, cases with nuclear expression of beta-catenin showed an intermediate overall survival risk and late disease recurrence. Young age at the time of diagnosis, advanced disease stage, and suboptimal debulking were among the clinical factors predicting poor survival and early disease recurrence. The presence of squamous differentiation, a papillary pattern or nuclear pleomorphism did not show any correlation with overall survival or disease-free survival. Low membranous expression of beta-catenin and high mitotic count are poor prognostic indicators in patients with ovarian endometrioid carcinoma, whereas the GOG grading system showed no prognostic value. Our data suggest that there is a need to define a better grading system for ovarian endometrioid carcinoma. Molecular markers such as beta-catenin and mitotic count could aid in defining this grading system.
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Kashibuchi K, Tomita K, Schalken JA, Kume H, Takeuchi T, Kitamura T. The prognostic value of E-cadherin, alpha-, beta- and gamma-catenin in bladder cancer patients who underwent radical cystectomy. Int J Urol 2007; 14:789-94. [PMID: 17760743 DOI: 10.1111/j.1442-2042.2007.01830.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVES To determine the value of the loss of expression of E-cadherin and cadherin associated molecules as useful markers for both prognosis and chemosensitivity in bladder cancer patients who have undergone radical cystectomy. PATIENTS AND METHODS In 55 paraffin embedded specimens of radical cystectomy at our hospital from 1982 to 2000, the expression of E-cadherin, alpha-, beta- and gamma-catenin was examined by immunohistochemical staining. To evaluate the prognostic significance of these molecules, Kaplan-Meier survival curves were constructed and a statistical analysis was calculated by a log-rank test. A multivariate test (tumor stage, tumor grade, lymph node metastasis, configuration, the expression of E-cadherin, alpha-, beta- and gamma-catenin) was performed to detect prognostic markers. RESULTS Normal expression was found in 33 cases (60.0%) for E-cadherin, 29 (52.7%) for alpha-catenin, 31 cases (56.4%) for beta-catenin, and 31 cases (56.4%) for gamma-catenin. The expression patterns for E-cadherin, alpha-, beta- and gamma-catenin were significantly correlated with each other (P < 0.01). Survival analysis showed a significant difference between normal and aberrant expression in each staining. A multivariate analysis revealed that the expression of alpha- catenin was an independent prognostic factor (P = 0.0191). In 23 patients that received adjuvant chemotherapy, there was a significant difference in survival between the normal and aberrant expression of alpha-catenin, but not other molecules. CONCLUSION Alpha-catenin may not only be a good prognostic marker, but also one of key molecules that determine the chemosensitivities in patients with invasive bladder cancer.
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Affiliation(s)
- Keishi Kashibuchi
- Department of Urology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan
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Pantel K, Schlimok G, Angstwurm M, Passlick B, Izbicki JR, Johnson JP, Riethmüller G. Early metastasis of human solid tumours: expression of cell adhesion molecules. CIBA FOUNDATION SYMPOSIUM 2007; 189:157-70; discussion 170-3, 174-6. [PMID: 7587630 DOI: 10.1002/9780470514719.ch12] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Loss and gain of cell surface molecules determines the mobilization, emigration and invasiveness of epithelial cancer cells. As a first approach to gain further insight into these processes, we have followed two strategies: (1) to identify tumour cells which have disseminated early from primary carcinomas and to obtain information about the phenotype and prognostic significance of these cells; and (2) to identify molecular changes occurring in primary tumour cells at the time they develop their metastatic potential. Our analyses indicate that changes in the adhesive properties of solid tumour cells, such as down-regulation of desmosomal proteins (e.g. plakoglobin) and neo-expression of ICAM-1 or MUC18, are important determinants of the metastatic capability of individual malignant cells. The expression pattern of these cell adhesion molecules during tumour progression appears to reflect a disturbance at the level of the molecular elements normally responsible for controlling their expression. The outlined current strategies for detection, characterization and antibody therapy of cancer micrometastasis can be applied to the secondary prevention of metastatic disease in patients with minimal residual cancer.
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Affiliation(s)
- K Pantel
- Institut für Immunologie, Ludwig-Maximilians-Universität, München, Germany
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Senda T, Iizuka-Kogo A, Onouchi T, Shimomura A. Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Med Mol Morphol 2007; 40:68-81. [PMID: 17572842 DOI: 10.1007/s00795-006-0352-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2006] [Accepted: 12/19/2006] [Indexed: 01/17/2023]
Abstract
The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in most sporadic colorectal tumors. During both embryonic and postnatal periods, APC is widely expressed in a variety of tissues, including the brain and gastrointestinal tract. The APC gene product (APC) is a large multidomain protein consisting of 2843 amino acids. APC downregulates the Wnt signaling pathway through its binding to beta-catenin and Axin. Most mutated APC proteins in colorectal tumors lack the beta-catenin-binding regions and fail to inhibit Wnt signaling, leading to the overproliferation of tumor cells. Several mouse models (APC580D, APCDelta716, APC1309, APCMin, APC1638T) have been established to investigate carcinogenesis caused by APC mutations. APC also binds to APC-stimulated guanine nucleotide exchange factor, the kinesin superfamily-associated protein 3, IQGAP1, microtubules, EB1, and discs large (DLG). APC has both nuclear localization signals and nuclear export signals in its molecule, suggesting its occasional nuclear localization and export of beta-catenin from the nucleus. APC is highly expressed in the intestinal and colorectal epithelia and may be involved in homeostasis of the enterocyte renewal phenomena, in which proliferation, migration, differentiation, and apoptosis are highly regulated both temporally and spatially. Through the many binding proteins mentioned, APC can exert multiple functions involved in epithelial homeostasis.
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Affiliation(s)
- Takao Senda
- Department of Anatomy I, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.
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17
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Haj M, Rappaport A, Hiat A, Loberant N, Cohen I. The Loss of Intercellular Adhesion Molecules in Breast Cancer: Does it Predict a Poor Prognosis? Breast Care (Basel) 2007. [DOI: 10.1159/000110745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Winer IS, Bommer GT, Gonik N, Fearon ER. Lysine residues Lys-19 and Lys-49 of beta-catenin regulate its levels and function in T cell factor transcriptional activation and neoplastic transformation. J Biol Chem 2006; 281:26181-7. [PMID: 16849322 DOI: 10.1074/jbc.m604217200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Wnt signaling regulates cell fate determination, proliferation, and survival, among other processes. Certain Wnt ligands stabilize the beta-catenin protein, leading to the ability of beta-catenin to activate T cell factor-regulated genes. In the absence of Wnts, beta-catenin is phosphorylated at defined serine and threonine residues in its amino (N) terminus. The phosphorylated beta-catenin is recognized by a beta-transducin repeat-containing protein (betaTrCP) and associated ubiquitin ligase components. The serine/threonine residues and betaTrCP-binding site in the N-terminal region of beta-catenin constitute a key regulatory motif targeted by somatic mutations in human cancers, resulting in constitutive stabilization of the mutant beta-catenin proteins. Structural studies have implicated beta-catenin lysine 19 as the major target for betaTrCP-dependent ubiquitination, but Lys-19 mutations in cancer have not been reported. We studied the consequences of single amino acid substitutions of the only 2 lysine residues in the N-terminal 130 amino acids of beta-catenin. Mutation of Lys-19 minimally affected beta-catenin levels and functional activity, and mutation of Lys-49 led to reduced beta-catenin levels and function. In contrast, beta-catenin proteins with substitutions at both Lys-19 and Lys-49 positions were present at elevated levels and had the ability to potently activate T cell factor-dependent transcription and promote neoplastic transformation. We furthermore demonstrate that the K19/K49 double mutant forms of beta-catenin are stabilized as a result of reduced betaTrCP-dependent ubiquitination. Our findings suggest that Lys-19 is a primary in vivo site of betaTrCP-dependent ubiquitination and Lys-49 may be a secondary or cryptic site. Moreover, our results inform understanding of why single amino acid substitutions at lysine 19 or 49 have not been reported in human cancer.
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Affiliation(s)
- Ira S Winer
- Cell and Molecular Biology Graduate Program, Division of Molecular Medicine and Genetics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA
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Kashibuchi K, Tomita K, Schalken JA, Kume H, Yamaguchi T, Muto S, Horie S, Kitamura T. The Prognostic Value of E-Cadherin, α-, β-, and γ-Catenin in Urothelial Cancer of the Upper Urinary Tract. Eur Urol 2006; 49:839-45; discussion 845. [PMID: 16426728 DOI: 10.1016/j.eururo.2005.12.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2005] [Revised: 12/05/2005] [Accepted: 12/12/2005] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To determine the value of loss of the expression of E-cadherin and cadherin-associated molecules as useful markers for both prognosis and bladder recurrence in patients with upper urinary tract cancer. MATERIALS AND METHODS In 61 paraffin-embedded nephroureterectomy specimens, the expression of E-cadherin and alpha-, beta-, and gamma-catenin was examined by immunohistochemical staining. To evaluate the prognostic significance, Kaplan-Meier survival curves were calculated and compared by the log-rank test. A multivariate test was performed to detect prognostic markers. RESULTS Normal expression was found in 32 cases (52.5%) for E-cadherin, 41 cases (67.2%) for alpha-catenin, 42 cases (68.9%) for beta-catenin, and 31 cases (50.8%) for gamma-catenin. The expression patterns of E-cadherin and alpha-, beta- and gamma-catenin were significantly correlated with each other. Survival analysis showed a significant difference between normal and aberrant expression in each staining. Multivariate analysis revealed that tumor stage and the expression of E-cadherin were independent prognostic factors for cause-specific survival. In contrast, there was no significant correlation between the expression of E-cadherin and alpha-, beta-, and gamma-catenin and bladder recurrence. CONCLUSION Our data suggest E-cadherin may be a good prognostic marker for patients with upper urinary tract cancer.
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Affiliation(s)
- Keishi Kashibuchi
- Department of Urology, Faculty of Medicine, University of Tokyo, Japan
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20
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Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer 2006; 1765:189-222. [PMID: 16487661 DOI: 10.1016/j.bbcan.2006.01.002] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2005] [Revised: 12/30/2005] [Accepted: 01/03/2006] [Indexed: 12/31/2022]
Abstract
Mucins are large multifunctional glycoproteins whose primary functions are to protect and lubricate the surfaces of epithelial tissues lining ducts and lumens within the human body. Several lines of evidence also support the involvement of mucins in more complex biological processes such as epithelial cell renewal and differentiation, cell signaling, and cell adhesion. Recent studies have uncovered the role of select mucins in the pathogenesis of cancer, underscoring the importance of a detailed knowledge about mucin biology. Under normal physiological conditions, the production of mucins is optimally maintained by a host of elaborate and coordinated regulatory mechanisms, thereby affording a well-defined pattern of tissue-, time-, and developmental state-specific distribution. However, mucin homeostasis may be disrupted by the action of environmental and/or intrinsic factors that affect cellular integrity. This results in an altered cell behavior that often culminates into a variety of pathological conditions. Deregulated mucin production has indeed been associated with numerous types of cancers and inflammatory disorders. It is, therefore, crucial to comprehend the underlying basis of molecular mechanisms controlling mucin production in order to design and implement adequate therapeutic strategies for combating these diseases. Herein, we discuss some physiologically relevant regulatory aspects of mucin production, with a particular emphasis on aberrations that pertain to pathological situations. Our views of the achievements, the conceptual and technical limitations, as well as the future challenges associated with studies of mucin regulation are exposed.
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Affiliation(s)
- Mahefatiana Andrianifahanana
- Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, 68198-5870, USA
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Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 2003; 129:199-221. [PMID: 12707770 DOI: 10.1007/s00432-003-0431-0] [Citation(s) in RCA: 391] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2003] [Accepted: 02/27/2003] [Indexed: 01/23/2023]
Abstract
Cancer development depends on the aberrant activation of signal transduction pathways that control cell growth and survival and play important roles in normal embryonic development. This review will focus on one of the most powerful pathways, the canonical Wnt signal transduction cascade, which has been originally described in vertebrate and non-vertebrate embryogenesis and subsequently associated with the development of a multitude of different tumor types, mainly of gastrointestinal origin. In recent years, a variety of novel interacting components and functions have been identified in the Wnt pathway revealing not only the complexity of Wnt signaling but also its potency. Here we will concentrate on the role of the Wnt pathway in cancer development with emphasis placed on the molecular defects known to promote neoplastic transformation in humans and in animal models.
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Affiliation(s)
- B Lustig
- Klinik für Abdominal- Endokrine- und Thoraxchirurgie, Klinikum Nürnberg, Nürnberg, Germany
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Kleeff J, Friess H, Liao Q, Büchler MW. Immunohistochemical presentation in non-malignant and malignant Barrett's epithelium. Dis Esophagus 2002; 15:10-5. [PMID: 12060037 DOI: 10.1046/j.1442-2050.2002.00211.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus, which is histologically characterized by metaplastic columnar epithelium, is a common condition observed in approximately 10-20% of patients with gastroesophageal reflux disease. These lesions can typically progress from metaplasia with atypia to low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. It is of great clinical importance to correctly grade these lesions and to identify changes with a high risk of malignant transformation, inasmuch as high-grade dysplasias and early adenocarcinomas in patients with Barrett's esophagus have a high chance for cure. The identification of high-risk lesions in Barrett's esophagus by histologic evaluation has drawbacks, especially regarding sampling errors and frequent intra- and interobserver discrepancies in the histopathologic grading/staging of these lesions. Immunostaining with a variety of antibodies provides a better understanding of the process of malignant transformation and helps to identify early markers of malignant transformation in Barrett's esophagus lesions. In this review, we will summarize the current knowledge about the value of immunostaining in the diagnosis of malignant and non-malignant Barrett's epithelium and its role to better define lesions with high risk for malignancy in this disorder.
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Affiliation(s)
- J Kleeff
- Department of Visceral and Transplantation Surgery, University of Bern, Switzerland
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Rojas AI, Ahmed AR. Adhesion receptors in health and disease. CRITICAL REVIEWS IN ORAL BIOLOGY AND MEDICINE : AN OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION OF ORAL BIOLOGISTS 2000; 10:337-58. [PMID: 10759413 DOI: 10.1177/10454411990100030601] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cell adhesion molecules have been recognized to play a major role in a variety of physiological and pathological phenomena. They determine the specificity of cell-cell binding and the interactions between cells and extracellular matrix proteins. Some of them may also function as receptors that trigger intracellular pathways and participate in cellular processes like migration, proliferation, differentiation, and cell death. The receptors that mediate adhesion between epithelial cells that are discussed in this review include integrins, selectins, the immunoglobulin superfamily members, and cadherins. The intent of this review is to inform the reader about recent advances in cellular and molecular functions of certain receptors, specifically those that are considered important in cell adhesion. We have deliberately not provided all-inclusive detailed information on every molecule, but instead, have presented a generalized overview in order to give the reader a global perspective. This information will be useful in enhancing the reader's understanding of the molecular pathology of diseases and recognizing the potential role of these receptors and ligands as therapeutic agents.
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Affiliation(s)
- A I Rojas
- Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, Massachusettes 02115, USA
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Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C, Birchmeier W. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 2000; 148:567-78. [PMID: 10662781 PMCID: PMC2174807 DOI: 10.1083/jcb.148.3.567] [Citation(s) in RCA: 499] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The anterior-posterior axis of the mouse embryo is defined before formation of the primitive streak, and axis specification and subsequent anterior development involves signaling from both embryonic ectoderm and visceral endoderm. Tauhe Wnt signaling pathway is essential for various developmental processes, but a role in anterior-posterior axis formation in the mouse has not been previously established. Beta-catenin is a central player in the Wnt pathway and in cadherin-mediated cell adhesion. We generated beta-catenin-deficient mouse embryos and observed a defect in anterior-posterior axis formation at embryonic day 5.5, as visualized by the absence of Hex and Hesx1 and the mislocation of cerberus-like and Lim1 expression. Subsequently, no mesoderm and head structures are generated. Intercellular adhesion is maintained since plakoglobin substitutes for beta-catenin. Our data demonstrate that beta-catenin function is essential in anterior-posterior axis formation in the mouse, and experiments with chimeric embryos show that this function is required in the embryonic ectoderm.
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Affiliation(s)
- Joerg Huelsken
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Regina Vogel
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Volker Brinkmann
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Bettina Erdmann
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
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Abstract
Cells from cancers show aberrant behaviour such as unrestrained growth, invasion into adjacent tissue and metastasis. All these features of cancer cell behaviour can be explained in terms of genetic changes and the functional impact of these changes. In this review, colorectal cancer (CRC) is examined as a classical example of multistep carcinogenesis. First there is an overview which shows that cancers develop by a process of somatic evolution. This gives rise to preferred genetic pathways of tumorigenesis. The factors which may influence the development and ultimate choice of genetic pathways are then examined. Next, CRC is studied as a specific disease and the putative genetic pathways are described. The mutations that comprise these pathways and the possible functional sequelae of these are explored. The review concludes with a look at those avenues which may further elucidate the natural history of CRC and lead to improved therapy.
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Affiliation(s)
- M Ilyas
- Cancer and Immunogenetics Laboratory, Imperial Cancer Research Fund, John Radcliffe Hospital, Headington, Oxford, U.K.
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Abstract
Although the advancement of molecular oncology in gastric cancer lags behind that of colorectal cancer, the rapid developments witnessed in recent years have improved our understanding of the carcinogenesis, aetiology, progression and metastasis of gastric cancer. The different molecular genetic alterations in intestinal and diffuse types of gastric cancer have further supported the concept that these two pathological types are different disease entities. The association of telomerase and cadherin changes with Helicobacter pylori infection reinforces its aetiological role. The mutated cadherin gene identified in familial gastric cancer has shone light onto the pathogenesis. Adhesion molecules have already been applied to daily clinical practice as prognostic markers. Future molecular studies will contribute to the screening, classification, disease monitoring and therapeutics of gastric cancer.
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Affiliation(s)
- A O Chan
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Abstract
Cells from cancers show aberrant behaviour such as unrestrained growth, invasion into adjacent tissue and metastasis. All these features of cancer cell behaviour can be explained in terms of genetic changes and the functional impact of these changes. In this review, colorectal cancer (CRC) is examined as a classical example of multistep carcinogenesis. First there is an overview which shows that cancers develop by a process of somatic evolution. This gives rise to preferred genetic pathways of tumorigenesis. The factors which may influence the development and ultimate choice of genetic pathways are then examined. Next, CRC is studied as a specific disease and the putative genetic pathways are described. The mutations that comprise these pathways and the possible functional sequelae of these are explored. The review concludes with a look at those avenues which may further elucidate the natural history of CRC and lead to improved therapy.
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Affiliation(s)
- M Ilyas
- Cancer and Immunogenetics Laboratory, John Radcliffe Hospital, Headington, Oxford, U.K.
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SYRIGOS K, HARRINGTON K, WAXMAN J, KRAUSZ T, PIGNATELLI M. ALTERED gamma-CATENIN EXPRESSION CORRELATES WITH POOR SURVIVAL IN PATIENTS WITH BLADDER CANCER. J Urol 1998. [DOI: 10.1016/s0022-5347(01)62438-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- K.N. SYRIGOS
- From the Departments of Clinical Oncology and Histopathology, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London, United Kingdom
| | - K. HARRINGTON
- From the Departments of Clinical Oncology and Histopathology, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London, United Kingdom
| | - J. WAXMAN
- From the Departments of Clinical Oncology and Histopathology, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London, United Kingdom
| | - T. KRAUSZ
- From the Departments of Clinical Oncology and Histopathology, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London, United Kingdom
| | - M. PIGNATELLI
- From the Departments of Clinical Oncology and Histopathology, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London, United Kingdom
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Roesler J, Srivatsan E, Moatamed F, Peters J, Livingston EH. Tumor suppressor activity of neural cell adhesion molecule in colon carcinoma. Am J Surg 1997; 174:251-7. [PMID: 9324132 DOI: 10.1016/s0002-9610(97)00142-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Neural Cell Adhesion Molecule (NCAM) is a well-characterized member of the immunoglobin superfamily. The structure of NCAM is similar to the tumor suppressor Deleted in Colon Carcinoma (DCC). NCAM has been found in some epithelial tissues and plays a role in tumorigenesis of some cancers. The purpose of the present study was to determine if NCAM is present in normal human colon. Once its presence was established, its function as a tumor suppressor was investigated. METHODS Colon tumors and normal proximal margins were processed for reverse transcription-polymerase chain reaction (RT-PCR) of the NCAM-180 message. Immunohistochemistry of the tissue was performed to determine the distribution of NCAM. RESULTS RT-PCR analysis demonstrated the presence of the NCAM-180 kD isoform in normal colonic epithelia. Immunohistochemistry showed NCAM on the basolateral surface of colonic epithelial cells of the villous tips. Tumors from 15 patients followed up for 4 years were studied. All seven tumors expressing NCAM-180 were from patients having a benign clinical course. Seven of eight tumors that lacked NCAM-180 were associated with aggressive clinical behaviors (presenting with obstruction, perforation or metastatic disease, or patient death within 18 months of presentation). The sole exception was in a villous adenoma excised from a patient who has had multiply recurrent polyps on follow-up. CONCLUSION We conclude that like DCC, NCAM is an important colonic adhesion molecule that functions as a tumor suppressor.
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Affiliation(s)
- J Roesler
- Surgical, Pathology and Research Services, West Los Angeles VAMC, and the University of California, Los Angeles, School of Medicine, 90095-6904, USA
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Jankowski JA, Bedford FK, Kim YS. Changes in gene structure and regulation of E-cadherin during epithelial development, differentiation, and disease. PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY 1997; 57:187-215. [PMID: 9175434 DOI: 10.1016/s0079-6603(08)60281-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- J A Jankowski
- Department of Medicine, University of Birmingham, England
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Christ AD, Blumberg RS. The intestinal epithelial cell: immunological aspects. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 1997; 18:449-61. [PMID: 9144864 DOI: 10.1007/bf00824052] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
IECs likely play an important role in immunological defense mechanism. Apart from being a passive barrier against luminal bacteria, IECs secrete protective and microbiocidal products such as ITF, complement components and cryptdins into the lumen. Moreover, IECs produce secretory component that is essential for the transport of IgA from the lamina propria into the lumen. IECs also have regulatory functions. They express adhesion molecules important in the homing of T cells and other leukocytes, and likely modulate T cell functions in a paracrine way. Furthermore, IECs secrete cytokines, either constitutively or after bacterial challenge, and they express cytokine receptors. Lastly, IECs may play an important role as non-professional antigen-presenting cells by expressing classical MHC class I and class II and nonclassical MHC class I molecules on the cell surface. This aspect is particularly intriguing in that IECs also express a FcR that may have a function in luminal antigen sampling.
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Affiliation(s)
- A D Christ
- Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Abstract
There is a general consensus that cell-cell and cell-matrix interactions determine, at least in part, the behaviour of colon cancer. The biological mediators responsible for these interactions are cell adhesion molecules belonging to several major receptor families called integrins, cadherins, the immunoglobulin superfamily, hyaluronate receptors and mucins. Emerging data indicate that certain patterns of adhesion receptor expression are associated with more aggressive disease. The present review examines the role of each of the receptor families in the development and progression of large bowel cancer.
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Affiliation(s)
- M V Agrez
- Faculty of Medicine and Health Sciences, University of Newcastle, Callaghan, New South Wales, Australia
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Weitzman JB, Hemler ME, Brodt P. Reduction of tumorigenicity by alpha 3 integrin in a rhabdomyosarcoma cell line. CELL ADHESION AND COMMUNICATION 1996; 4:41-52. [PMID: 8870972 DOI: 10.3109/15419069609010762] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The expression levels of integrin adhesion receptors have often been correlated with neoplastic transformation and invasiveness. To investigate more definitively the role of the integrin VLA-3 (alpha 3 beta 1) in tumor cell behavior, we transfected alpha 3 subunit cDNA into human rhabdomyosarcoma (RD) cells. Transfectants expressing high levels of alpha 3 beta 1 on their cell surface displayed an altered morphology and decreased anchorage-dependent growth in vitro. Cells expressing alpha 3 also displayed marked reduction in anchorage-independent growth in soft agar and in their ability to form tumors when injected subcutaneously into athymic nude mice. Thus, VLA-3 can repress the transformed phenotype of rhabdomyosarcoma tumor cells. Similar changes in morphology and growth characteristics were observed in cells expressing a chimeric molecule X3C4 in which the alpha 3 cytoplasmic domain had been exchanged with that of the alpha 4 integrin subunit. Therefore, alpha 3 inhibitory effects in RD cells appear not to require specific signalling through the alpha 3 cytoplasmic domain.
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Affiliation(s)
- J B Weitzman
- Division of Tumor Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol 1996; 16:2128-34. [PMID: 8628279 PMCID: PMC231200 DOI: 10.1128/mcb.16.5.2128] [Citation(s) in RCA: 269] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins. Here we have investigated the effects of Wnt-1 expression on the tumor suppressor protein APC, which also associates with catenins. Expression of Wnt-1 in two different cell lines greatly increased the stability of APC-catenin complexes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associated with APC were also markedly increased. The stabilization of catenins by Wnt-1 was primarily the result of a selective increase in the amount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of cell extracts. Exogenous expression of beta-catenin was possible in cells already responding to Wnt-1 but not in the parental cells, suggesting that Wnt-1 inhibits an essential regulatory mechanism for beta-catenin turnover. APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accumulation of monomeric catenins and stabilization of catenin complex formation with both APC and cadherins.
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Affiliation(s)
- J Papkoff
- SUGEN, Inc., Redwood City, California 94063, USA
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Abstract
E-cadherin is a cell-cell adhesion molecule which is anchored to the cytoskeleton via catenins. There is increasing evidence which suggests that E-cadherin also acts as a suppressor of tumour invasion and metastasis. Both in vitro and in vivo studies have revealed that expression of E-cadherin correlates inversely with the motile and invasive behaviour of a tumour cell; it also correlates inversely with metastasis in patients with cancer. The function of E-cadherin is highly dependent on the functional activity of catenins. This review summarizes progress, from both basic and clinical research, in our understanding of the roles of E-cadherin and catenins, and discusses the clinical relevance of the discoveries.
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Affiliation(s)
- W G Jiang
- University Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff, UK
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Sulekova Z, Reina-Sanchez J, Ballhausen WG. Multiple APC messenger RNA isoforms encoding exon 15 short open reading frames are expressed in the context of a novel exon 10A-derived sequence. Int J Cancer 1995; 63:435-41. [PMID: 7591245 DOI: 10.1002/ijc.2910630323] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Intragenic splice mechanisms affecting the coding exons 8 to 15 of the human adenomatous polyposis coli (APC) gene have been analyzed. Three mechanisms within this gene area were found to contribute to mRNA heterogeneity: (i) facultative expression of exon 9-encoded sequences; (ii) in-frame insertion of a 54-nucleotide sequence encoded by a novel exon located 1.6 kb down-stream from exon 10, provisionally designated APC exon 10A; (iii) skipping of exon 14, resulting in a novel exon 13/15 connection. Interestingly the latter event provided the mRNA with a novel open reading frame, which was terminated after 19 codons of exon 15-derived sequences. Combinatorial joining of these segments yielded 7 different transcripts in addition to an mRNA species resulting from an exon 10/15 connection, as determined by cloning and sequence analysis. RT-PCR expression analyses were carried out to demonstrate that this complexity of splice variants is indeed synthesized in cell lines derived from various tissues. Furthermore, in accordance with our findings at the transcript level, we provide Western blot analyses demonstrating that moderate steady-state levels of genuine APC-specific low m.w. polypeptide chains exist. These APC "light chains", however, are not identical with polypeptide chains, which have been reported to accompany apoptosis and necrosis, since the molecules described here are definitively co-expressed with p300apc at the transcript and protein levels.
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Affiliation(s)
- Z Sulekova
- Institute for Human Genetics, The University, Erlangen, Germany
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41
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Koenig SH. Classes of hydration sites at protein-water interfaces: the source of contrast in magnetic resonance imaging. Biophys J 1995; 69:593-603. [PMID: 8527674 PMCID: PMC1236285 DOI: 10.1016/s0006-3495(95)79933-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Immobilized protein solute, approximately 20 wt %, alters the longitudinal and transverse nuclear magnetic relaxation rates 1/T1 and 1/T2 of solvent water protons in a manner that makes their values indistinguishable from those of a typical human tissue. There is now a quantitative theory at the molecular level (S.H. Koenig and R. D. Brown III (1993) Magn. Reson. Med. 30:685-695) that accounts for this, as a function of magnetic field strength, in terms of several distinguishable classes of water-binding sites at the protein-water interface at which significant relaxation and solute-solvent transfer of proton Zeeman energy occur. We review the arguments that these several classes of sites, characterized by widely disparate values of the resident lifetimes tau M of the bound waters, are associated with different numbers of hydrogen bonds that stabilize the particular protein-water complex. The sites that dominate relaxation-and produce contrast in magnetic resonance imaging (MRI), which derives from 1/T1 and 1/T2 of tissue water protons-have tau M approximately 10(-6)s. These, which involve four hydrogen bonds, occupy < or = 1% of the protein-water interface. Sites that involve three bonds, although more numerous, have < or = 20% smaller intrinsic effect on relaxation. The greater part of the "traditional" hydration monolayer, with even shorter-lived hydrogen-bonded waters, has little influence on solvent relaxation and is relatively unimportant in MRI. Finally, we argue, from the data, that most of the protein of tissue (a typical tissue is mostly protein) must be rotationally immobile (with Brownian rotational relaxation times slower than that of a 5 x 10(7) Da (very heavy) globular protein). We propose a functional basis for this immobilization ("cytoplasmic order"), and then indicate a way in which this order can break down ("cytoplasmic chaos") as a result of neoplastic transformation (cancer) and alter water-proton rates of pathological tissue and, hence, image contrast in MRI.
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Affiliation(s)
- S H Koenig
- Relaxometry Inc., Mahopac, New York 10541, USA
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42
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Cui Y, Brown JD, Moon RT, Christian JL. Xwnt-8b: a maternally expressed Xenopus Wnt gene with a potential role in establishing the dorsoventral axis. Development 1995; 121:2177-86. [PMID: 7635061 DOI: 10.1242/dev.121.7.2177] [Citation(s) in RCA: 103] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In amphibian embryos, establishment of dorsal-ventral asymmetry is believed to involve dorsal-ventral differences in vegetally derived mesoderm-inducing signals and/or differences in the competence of animal hemisphere (ectodermal) cells to respond to these signals. Previous studies have shown that certain Wnt proteins can generate an ectopic dorsal axis when misexpressed, and that they do so by modifying the response of ectodermal cells to inducers. None of these Wnt proteins are expressed at an appropriate time to do so in vivo. In this study, we describe the isolation and characterization of a full length cDNA for the Xenopus Wnt gene, Xwnt-8b, whose biological activity and expression pattern suggest that it may be involved in establishment of the dorsoventral axis. Both maternal and zygotic Xwnt-8b transcripts undergo alternative splicing to generate mRNAs which encode two different forms of Xwnt-8b protein. During early cleavage stages Xwnt-8b transcripts are confined primarily to animal hemisphere blastomeres, while zygotically derived Xwnt-8b transcripts are restricted almost exclusively to a band of cells in the prospective forebrain of neurula and tailbud stage embryos. Ectopically expressed Xwnt-8b can completely rescue dorsal development of embryos ventralized by exposure to ultraviolet light, and can induce a complete secondary axis in wild-type embryos. Axis induction is observed only if Xwnt-8b is supplied prior to the onset of zygotic gene transcription. This biological activity, together with the presence of maternal Xwnt-8b transcripts in cells that will be induced to form the dorsal mesoderm, is consistent with the possibility that Xwnt-8b may be the endogenous agent that establishes asymmetry in the response of ectodermal cells to mesoderm-inducing signals, thereby initiating dorsal development.
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Affiliation(s)
- Y Cui
- Department of Cell Biology and Anatomy, Oregon Health Sciences University, School of Medicine, Portland 97201, USA
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Abstract
Gastric cancer involves changes in multiple oncogenes and multiple suppressor genes, and it causes genetic instability. Aberrant expression and amplification of the c-met gene, inactivation of the p53 gene, and CD44 abnormal transcripts are common events of both well differentiated and poorly differentiated gastric cancers. Amplification of the cyclin E gene is also observed in gastric cancer regardless of histologic type. Decreased expression of the pic1 (p21) gene occurs independent of the p53 mutations. In addition, K-ras mutations, c-erbB-2 gene amplification, loss of heterozygosity (LOH) and mutations of the APC gene, LOH of the bcl-2 gene, and LOH at the DCC locus are preferentially associated with well differentiated gastric cancer. Moreover, LOH on chromosome 1q is involved in the progression of well differentiated cancer. Precancerous lesions, including hyperplastic polyp, intestinal metaplasia, and adenoma, share genetic changes found in well differentiated cancers. Conversely, genetic instability may be involved in the first step of stomach carcinogenesis of the poorly differentiated type. Reduction or loss of cadherin and catenins, K-sam gene amplification, and c-met gene amplification are necessary for the development and progression of poorly differentiated or scirrhous carcinoma. Interaction between cell-adhesion molecules in the c-met expressed tumor cells and hepatocyte growth factor from stromal cells is implicated in the morphogenesis of two types of gastric cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- E Tahara
- Department of Pathology, Hiroshima University School of Medicine, Japan
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44
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Waddell WR, Miesfeld RL. Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase: the effect of sulindac. J Surg Oncol 1995; 58:252-6. [PMID: 7723369 DOI: 10.1002/jso.2930580411] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
A putative explanation of the effect of sulindac on adenomatous colon and duodenal polyps from clinical observations and related in vitro experiments is presented. In cells with mutant APC genes, persistent high prostaglandin content of polyps leads to desensitization, downregulation of adenylate cyclase, uncoupling of cAMP synthesis from prostaglandin, and inactivation of protein kinase A (PKA). It is suggested that in normal cells, (APC) protein binds to catenins and microtubules to maintain structure and contribute to cell-cell communication, adherence, and the dephosphorylated state, a necessary condition for such functions. Cells with mutant APC product become isolated, deprived of communication and adhesion to other epithelial cells, overphosphorylated, and without corrective capability. The latter is largely due to downregulation of cAMP synthesis and protein kinase A activity secondary to high prostaglandin. Three main biochemical defects ensue: (1) the restrictive influence of PKA catalyzed phosphorylation of Raf-1 kinase and resultant effects on the MAP kinase cascade and transcription is lost, (2) the transcription of immediate early genes, including cyclooxygenase is stimulated, and (3) the stimulation of protein tyrosine phosphatase (PTPase) by PKA is in abeyance. These putative abnormalities are reversed by inhibition of cyclooxygenase-1 by sulindac. cAMP synthesis and PKA activity return to normal. PKA catalyzed phosphorylations block Raf-1 kinase at the confluence of the Ras and protein kinase C pathways. The MAP kinase cascade is inhibited as is transcription of immediate early genes. At the same time PKA stimulates PTPase, which dephosphorylates the cytoskeleton and restores cell-cell communication, adherence, and structure. The transformed phenotype is circumvented by adjustment of the phosphorylation state and mutant cells rejoin the epithelial community. The redox state of cytoplasm in mutant cells may be shifted toward reduction.
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Affiliation(s)
- W R Waddell
- Department of Surgery, University of Arizona, Tucson, USA
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Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A 1995; 92:3046-50. [PMID: 7708772 PMCID: PMC42356 DOI: 10.1073/pnas.92.7.3046] [Citation(s) in RCA: 819] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The APC tumor-suppressor protein associates with beta-catenin, a cell adhesion protein that is upregulated by the WNT1 oncogene. We examined the effects of exogenous APC expression on the distribution and amount of beta-catenin in a colorectal cancer cell containing only mutant APC. Expression of wild-type APC caused a pronounced reduction in total beta-catenin levels by eliminating an excessive supply of cytoplasmic beta-catenin indigenous to the SW480 colorectal cancer cell line. This reduction was due to an enhanced rate of beta-catenin protein degradation. Truncated mutant APC proteins, characteristic of those associated with cancer, lacked this activity. Mutational analysis revealed that the central region of the APC protein, which is typically deleted or severely truncated in tumors, was responsible for the down-regulation of beta-catenin. These results suggest that the tumor-suppressor activity of mutant APC may be compromised due to a defect in its ability to regulate beta-catenin.
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Affiliation(s)
- S Munemitsu
- Onyx Pharmaceuticals, Richmond, CA 94806, USA
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46
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Abstract
Gastrointestinal cancers involve genetic alterations in multiple oncogenes, multiple tumor suppressor genes, and multiple DNA repair genes. However, common and different genetic changes are observed in esophageal, gastric, and colorectal carcinomas, respectively. Inactivation of the p53 gene and expression of CD44 abnormal transcripts are common events that serve as a powerful tool for cancer diagnosis. Gene amplification of cyclin D is found preferentially in esophageal cancer, whereas gene amplification of cyclin E and c-met is frequently associated with gastric cancer. Mutations of the cyclin-dependent kinase inhibitor genes also occur in esophageal and gastric cancers. However, the scenario of multiple gene changes differs depending on the two histologic types of gastric cancer, because they may have different genetic pathways. Interestingly, the frequency of genetic instability is also quite different between the two types of gastric cancer. A new strategy of molecular diagnosis for gastrointestinal cancers, which started as routine work at Hiroshima City Medical Association Clinical Laboratory last August, may provide a new approach to cancer diagnosis for the next decade.
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Affiliation(s)
- E Tahara
- First Department of Pathology, Hiroshima University School of Medicine, Japan
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47
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Rubinfeld B, Souza B, Albert I, Munemitsu S, Polakis P. The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin. J Biol Chem 1995; 270:5549-55. [PMID: 7890674 DOI: 10.1074/jbc.270.10.5549] [Citation(s) in RCA: 229] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The tumor suppressor APC protein associates with the cadherin-binding proteins alpha- and beta-catenin. To examine the relationship between cadherin, catenins, and APC, we have tested combinatorial protein-protein interactions in vivo, using a yeast two-hybrid system, and in vitro, using purified proteins. beta-Catenin directly binds to APC at high and low affinity sites. alpha-Catenin cannot directly bind APC but associates with it by binding to beta-catenin. Plakoglobin, also known as gamma-catenin, directly binds to both APC and alpha-catenin and also to the APC-beta-catenin complex, but not directly to beta-catenin. beta-Catenin binds to multiple independent regions of APC, some of which include a previously identified consensus motif and others which contain the centrally located 20 amino acid repeat sequences. The APC binding site on beta-catenin may be discontinuous since neither the carboxyl- nor amino-terminal halves of beta-catenin will independently associate with APC, although the amino-terminal half independently binds alpha-catenin. The catenins bind to APC and E-cadherin in a similar fashion, but APC and E-cadherin do not associate with each other either in the presence or absence of catenins. Thus, APC forms distinct heteromeric complexes containing combinations of alpha-catenin, beta-catenin, and plakoglobin which are independent from the cadherin-catenin complexes.
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Affiliation(s)
- B Rubinfeld
- Onyx Pharmaceuticals, Richmond, California 94806
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48
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Abstract
An enormous number of germline and somatic mutations have been identified in the APC tumor suppressor gene. Nearly all of these mutations result in premature polypeptide chain termination, but the consequences to APC protein function are unknown. Recent advances, including the identification of an oligomerization domain, the localization of several beta-catenin binding sites, some of which down-regulate beta-catenin in vivo, and the identification of a microtubule-binding domain in the carboxy-terminal region of APC, are beginning to provide some clues.
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Affiliation(s)
- P Polakis
- Onyx Pharmaceuticals, Richmond, California 94806, USA
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49
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Augenlicht L, Velcich A, Heerdt BG. Short-chain fatty acids and molecular and cellular mechanisms of colonic cell differentiation and transformation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1995; 375:137-48. [PMID: 7645424 DOI: 10.1007/978-1-4899-0949-7_12] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- L Augenlicht
- Albert Einstein Cancer Center, Department of Oncology, Bronx, New York 10467 USA
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50
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