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Zhang J, Li Q, Sun Q, Wang B, Cui Y, Lou C, Yao Y, Zhang Y. Epigenetic modifications inhibit the expression of MARVELD1 and in turn tumorigenesis by regulating the Wnt/β-catenin pathway in pan-cancer. J Cancer 2022; 13:225-242. [PMID: 34976185 PMCID: PMC8692698 DOI: 10.7150/jca.63608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 11/21/2021] [Indexed: 12/15/2022] Open
Abstract
MARVEL domain-containing 1 (MARVELD1) is one of the MARVEL domain-containing proteins. Expression of MARVELD1 in tumor and non-tumor tissues, the relationship between its expression and cancer prognosis, and upstream regulation of MARVELD1 were examined using pan-cancer data from The Cancer Genome Atlas. MARVELD1 expression was significantly downregulated in tissues used for pan-cancer analysis compared to that in normal tissues. Low expression of MARVELD1 was associated with poor disease outcomes in pan-cancer. Colon cancer patients with low expression of MARVELD1 had worse progression free survival and overall survival than those with high expression levels in our cohort. Hypermethylation and histone modification in the MARVELD1 promoter locus synergistically affected its expression in pan-cancer. The function of MARVELD1 in colon cancer remains to be studied. Gene Ontology enrichment analysis revealed that MARVELD1 may modulate processes associated with inhibition of tumorigenesis in colon cancer. Both upstream transcription factors and downstream functional enrichment of MARVELD1 were related to the Wnt/β-catenin signaling pathway. Overexpression of MARVELD1 inhibited the expression of β-catenin and its entry into the nucleus. MARVELD1 also inhibited the proliferation, migration, and invasion of colon cancer cells. With Wnt/β-catenin activator LiCl treatment, rescue experiments demonstrated that the role of MARVELD1 in colon cancer progression was dependent on the Wnt/β-catenin pathway. These results indicate that MARVELD1 acts as a tumor suppressor and inhibits tumorigenesis via the Wnt/β-catenin pathway.
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Affiliation(s)
- Jingchun Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Qingwei Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Qinliang Sun
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Ying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Changjie Lou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
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Perret C. Axel Kahn et la carcinogenèse digestive : de l’oncogenèse ciblée à l’aventure de la β-caténine. Med Sci (Paris) 2021; 37 Hors série n° 2:35-37. [PMID: 34895461 DOI: 10.1051/medsci/2021227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Kim CW, Lee SM, Ko EB, Go RE, Jeung EB, Kim MS, Choi KC. Inhibitory effects of cigarette smoke extracts on neural differentiation of mouse embryonic stem cells. Reprod Toxicol 2020; 95:75-85. [PMID: 32454085 DOI: 10.1016/j.reprotox.2020.05.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/13/2020] [Accepted: 05/18/2020] [Indexed: 12/24/2022]
Abstract
Maternal smoking during the perinatal period is linked to adverse neonatal outcomes such as low birth weight and birth defects. Numerous studies have shown that cigarette smoke or nicotine exposure has a widespread effect on fetal nerve development. However, there exists a lack of understanding of what specific changes occur at the cellular level on persistent exposure to cigarette smoke during the differentiation of embryonic stem cells (ESCs) into neural cells. We previously investigated the effects of cigarette smoke extract (CSE) and its major component, nicotine, on the neural differentiation of mouse embryonic stem cells (mESCs). Differentiation of mESCs into neural progenitor cells (NPCs) or neural crest cells (NCCs) was induced with chemically defined media, and the cells were continuously exposed to CSE or nicotine during neural differentiation and development. Disturbed balance of the pluripotency state was observed in the NPCs, with consequent inhibition of neurite outgrowth and glial fibrillary acidic protein (Gfap) expression. These inhibitions correlated with the altered expression of proteins involved in the Notch-1 signaling pathways. The migration ability of NCCs was significantly decreased by CSE or nicotine exposure, which was associated with reduced protein expression of migration-related proteins. Taken together, we concluded that CSE and nicotine inhibit differentiation of mESCs into NPCs or NCCs, and may disrupt functional development of neural cells. These results imply that cigarette smoking during the perinatal period potentially inhibits neural differentiation and development of ESCs cells, leading to neonatal abnormal brain development and behavioral abnormalities.
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Affiliation(s)
- Cho-Won Kim
- Laboratory of Biochemistry and Immunology, Republic of Korea
| | - Sung-Moo Lee
- Laboratory of Biochemistry and Immunology, Republic of Korea
| | - Eul-Bee Ko
- Laboratory of Biochemistry and Immunology, Republic of Korea
| | - Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, Republic of Korea
| | - Eui-Bae Jeung
- Laboratory of Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Min-Seok Kim
- Inhalation Toxicology Research Group, Jeonbuk Department of Inhalation Research, Jeongeup, Korea Institute of Toxicology, Jeonbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, Republic of Korea.
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Gong H, Chen W, Mi L, Wang D, Zhao Y, Yu C, Zhao A. Qici Sanling decoction suppresses bladder cancer growth by inhibiting the Wnt/Β-catenin pathway. PHARMACEUTICAL BIOLOGY 2019; 57:507-513. [PMID: 31401919 PMCID: PMC6713157 DOI: 10.1080/13880209.2019.1626449] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/23/2019] [Accepted: 05/28/2019] [Indexed: 06/10/2023]
Abstract
Context: Bladder cancer, which has high recurrence, is one of the most deadly cancers in the world. Astragalus propinquus Schischkin (Fabaceae) and Sagittaria sagittifolia L. (Alismataceae) are important herbs reported to be effective in cancer therapy. Objective: The efficacy of QCSL (Qici Sanling decoction) in bladder cancer treatment was examined. Materials and methods: T24 cells were injected into the flanks of nude mice and the mice were randomly divided into five groups: control; 20 mg/kg XAV-939 (an inhibitor of the WNT/β-catenin pathway); QCSL (100, 200, or 400 mg/kg). After 7 weeks, the mice were anaesthetised using isoflurane and the xenografts were excised to perform further experiments. Results: Both XAV-939 (tumour volume: 379.67 ± 159.92 mm3) and QCSL (796.18 ± 101.6 mm3) dramatically suppressed tumour growth comparing with control group (3612.12 ± 575.03 mm3). XAV-939 and QCSL treatments decreased cell proliferation from 56.3 ± 0.05% to 29.02 ± 0.07% and 37.51 ± 0.04%, respectively. In agreement, more infiltration of immune cells and pyknotic cells upon XAV-939 (apoptosis rates: 43.92 ± 0.03%) and QCSL (34.57 ± 0.04%) treatment comparing with control group (15.59 ± 0.03%) were observed. Furthermore, TUNEL staining of xenograft tumours illustrated more apoptotic cells upon XAV-939 and QCSL treatment. Mechanistically, XAV-939 and QCSL treatments significantly inhibited WNT/β-catenin pathway in T24 xenograft tumours. Discussion and conclusions: Our findings give new insights into the role of QCSL in bladder cancer and explore potential mechanisms contributing to the therapeutic effects of QCSL in bladder cancer.
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Affiliation(s)
- Hua Gong
- Department of Urology, Longhua Hospital, Shanghai, China
| | - Weihua Chen
- Department of Urology, Shanghai East Hospital, Shanghai, China
| | - Lanhua Mi
- Department of Urology, Longhua Hospital, Shanghai, China
| | - Dan Wang
- Department of Urology, Longhua Hospital, Shanghai, China
| | - Youkang Zhao
- Department of Urology, Longhua Hospital, Shanghai, China
| | - Chao Yu
- Department of Urology, Longhua Hospital, Shanghai, China
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai, China
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Di Domenico M, Giovane G, Kouidhi S, Iorio R, Romano M, De Francesco F, Feola A, Siciliano C, Califano L, Giordano A. HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers. Cancer Biol Ther 2018; 19:850-857. [PMID: 28362190 DOI: 10.1080/15384047.2017.1310349] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.
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Affiliation(s)
- Marina Di Domenico
- a Department of Biochemistry , Biophysics and General Pathology, University of Campania "Luigi Vanvitelli" , Italy.,b IRCCS Institute of Women's Health Malzoni Clinic , Avellino , Italy.,c Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University , Philadelphia , PA , USA
| | - Giancarlo Giovane
- d Department of Experimental Medicine , Section of Hygiene, Occupational Medicine and Forensic Medicine, University of Campania "Luigi Vanvitelli" , Italy
| | - Soumaya Kouidhi
- e Laboratory BVBGR, LR11ES31, ISBST, Higher Institute of Biotechnology of Sidi Thabet, University of Manouba , Tunis , Tunisia.,f Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar , Tunis
| | - Rosamaria Iorio
- a Department of Biochemistry , Biophysics and General Pathology, University of Campania "Luigi Vanvitelli" , Italy
| | - Maurizio Romano
- g Hepatobiliary and Liver Transplantation Unit, Azienda Ospedaliera , Padova , Italy.,h Department of Surgical , Gastrointestinal and Oncological Sciences (DiSCOG), University of Padova , Padova ( PD ), Italy
| | - Francesco De Francesco
- h Department of Surgical , Gastrointestinal and Oncological Sciences (DiSCOG), University of Padova , Padova ( PD ), Italy
| | - Antonia Feola
- a Department of Biochemistry , Biophysics and General Pathology, University of Campania "Luigi Vanvitelli" , Italy
| | - Camilla Siciliano
- a Department of Biochemistry , Biophysics and General Pathology, University of Campania "Luigi Vanvitelli" , Italy
| | - Luigi Califano
- i Department of Maxillofacial Surgery , University of Naples "Federico II" , Naples , Italy
| | - Antonio Giordano
- c Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University , Philadelphia , PA , USA.,j Department of Medicine , Surgery and Neuroscience, University of Siena , Siena , Italy
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Abd-Rabou AA. Calcium, a Cell Cycle Commander, Drives Colon Cancer Cell Diffpoptosis. Indian J Clin Biochem 2016; 32:9-18. [PMID: 28149007 DOI: 10.1007/s12291-016-0562-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 03/15/2016] [Indexed: 01/08/2023]
Abstract
The story of the cell commonder, calcium, reaches into all corners of the cell and controls cell proliferation, differentiation, function, and even death. The calcium-driven eukaryotic revolution is one of the great turning points in the life history, happened about two billion years later when it was converted from a dangerous killer that had to be kept out of cell into the cell master which drives the cell. This review article will take the readers to a tour of tissues chosen to best show the calcium's many faces (proliferator, differentiator, and killer). The reader will first see calcium and its many helpers, such as the calcium-binding signaler protein calmodulin, directing the key events of the cell cycle. Then the tour will move onto the colon to show calcium driving the proliferation of progenitor cells, then the differentiation and ultimately the programmed death of their progeny. Moreover, the reader will learn of the striking disabling and bypassing of calcium-dependent control mechanisms during carcinogenesis. Finally, recommendations should be taken from the underlying mechanisms through which calcium masters the presistance, progression, and even apoptosis of colorectal cancer cells. Thus, this could be of great interest for designing of chemoprevention protocols.
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Affiliation(s)
- Ahmed A Abd-Rabou
- Hormones Department (Cancer Biology and Nano-Drug Delivery Group), Medical Research Division, National Research Center, Cairo, 12622 Egypt.,Center for Aging and Associated Diseases, Zewail City of Science and Technology, 6th of October, Egypt
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BMP and TGF-β pathway mediators are critical upstream regulators of Wnt signaling during midbrain dopamine differentiation in human pluripotent stem cells. Dev Biol 2013; 376:62-73. [PMID: 23352789 DOI: 10.1016/j.ydbio.2013.01.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 01/08/2013] [Accepted: 01/09/2013] [Indexed: 01/21/2023]
Abstract
Although many laboratories currently use small molecule inhibitors of the BMP (Dorsomorphin/DM) and TGF-β (SB431542/SB) signaling pathways in protocols to generate midbrain dopamine (mDA) neurons from hES and hiPS cells, until now, these substances have not been thought to play a role in the mDA differentiation process. We report here that the transient inhibition of constitutive BMP (pSMADs 1, 5, 8) signaling, either alone or in combination with TGF-β inhibition (pSMADs 2, 3), is critically important in the upstream regulation of Wnt1-Lmx1a signaling in mDA progenitors. We postulate that the mechanism via which DM or DM/SB mediates these effects involves the up-regulation in SMAD-interacting protein 1 (SIP1), which results in greater repression of the Wnt antagonist, secreted frizzled related protein 1 (Sfrp1) in stem cells. Accordingly, knockdown of SIP1 reverses the inductive effects of DM/SB on mDA differentiation while Sfrp1 knockdown/inhibition mimics DM/SB. The rise in Wnt1-Lmx1a levels in SMAD-inhibited cultures is, however, accompanied by a reciprocal down-regulation in SHH-Foxa2 levels leading to the generation of few TH+ neurons that co-express Foxa2. If however, exogenous SHH/FGF8 is added along with SMAD inhibitors, equilibrium in these two important pathways is achieved such that authentic (Lmx1a+Foxa2+TH+) mDA neuron differentiation is promoted while alternate cell fates are suppressed in stem cell cultures. These data indicate that activators/inhibitors of BMP and TGF-β signaling play a critical upstream regulatory role in the mDA differentiation process in human pluripotent stem cells.
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Silva RD, Marie SKN, Uno M, Matushita H, Wakamatsu A, Rosemberg S, Oba-Shinjo SM. CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants. Clinics (Sao Paulo) 2013; 68:167-72. [PMID: 23525311 PMCID: PMC3584274 DOI: 10.6061/clinics/2013(02)oa08] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 10/15/2012] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVES We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor. METHODS Sixty-one medulloblastoma cases were analyzed for β-catenin gene (CTNNB1) mutations, β-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information. RESULTS CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3β phosphorylation sites, which participate in β-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear β-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1) were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants. CONCLUSIONS A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of β-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.
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Affiliation(s)
- Roseli da Silva
- Laboratory of Molecular and Cellular Biology, Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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Tang FY, Pai MH, Kuo YH, Wang XD. Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer. Mol Nutr Food Res 2012; 56:1520-31. [PMID: 22961879 DOI: 10.1002/mnfr.201200098] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/02/2012] [Accepted: 07/24/2012] [Indexed: 12/26/2022]
Abstract
SCOPE Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. METHODS AND RESULTS To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help prevent tumor growth and progression in a mouse xenograft model of colon cancer. The inhibitory effects of lycopene and fish oil on tumor growth were verified by western blotting analysis, bioluminescent imaging, immunohistochemical (IHC) staining and ELISA. The results demonstrated that lycopene and fish oil synergistically inhibited the growth of colon cancer in tumor-bearing mice. The bioluminescent imaging, histopathological and IHC staining results indicated that lycopene and fish oil effectively suppressed tumor growth and progression of colon cancer in vivo. The chemopreventive effects of lycopene and fish oil were associated with augmented expression of the cell cycle inhibitors such as p21(CIP1/WAF1) and p27(Kip1) , and suppression of proliferating cell nuclear antigen, β-catenin, cyclin D1 and c-Myc proteins. Furthermore, lycopene and fish oil inhibited tumor progression through suppression of MMP-7, MMP-9, COX-2 and PGE2. CONCLUSION These results show that lycopene and fish oil act synergistically as chemopreventive agents against tumor growth and progression in a mouse xenograft model of colon cancer.
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Affiliation(s)
- Feng-Yao Tang
- Department of Nutrition, Biomedical Science Laboratory, China Medical University, Taichung, Taiwan.
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Edwards JM, Alsop S, Modesitt SC. Coexisting atypical polypoid adenomyoma and endometrioid endometrial carcinoma in a young woman with Cowden Syndrome: Case report and implications for screening and prevention. GYNECOLOGIC ONCOLOGY CASE REPORTS 2012; 2:29-31. [PMID: 24371612 DOI: 10.1016/j.gynor.2011.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 12/27/2011] [Indexed: 11/29/2022]
Abstract
► Cowden Syndrome is a rare hereditary cancer syndrome, which confers an increased risk of breast, thyroid, endometrial and colon cancer. ► Atypical polypoid adenomyoma does not generally represent a premalignant lesion, but must be carefully screened for foci of malignancy. ► Cancer screening must be intensified for patients who meet the diagnostic criteria for Cowden Syndrome.
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Affiliation(s)
- James M Edwards
- Department of Obstetrics and Gynecology, Duke University Medical Center, DUMC Box 3616, Durham, NC, USA
| | - Skylar Alsop
- Department of Pathology, Maryview Medical Center, 3636 High Street, Portsmouth, VA 23707, USA
| | - Susan C Modesitt
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia, PO Box 800712, Charlottesville, VA 22908, USA
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Sun Z, Cao X, Jiang MM, Qiu Y, Zhou H, Chen L, Qin B, Wu H, Jiang F, Chen J, Liu J, Dai Y, Chen HF, Hu QY, Wu Z, Zeng JZ, Yao XS, Zhang XK. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene 2011; 31:2653-67. [PMID: 21986938 PMCID: PMC3257393 DOI: 10.1038/onc.2011.448] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including adenomatous polyposis coli (APC) and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, has a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is glycogen synthase kinase 3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA binding and transactivation, and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
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Affiliation(s)
- Z Sun
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
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Tang FY, Pai MH, Wang XD. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011; 59:9011-21. [PMID: 21744871 DOI: 10.1021/jf2017644] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene could prevent the growth and progression of colorectal tumor in a mouse xenograft model. Bioluminescence imaging, histopathological, immunofluorescence (IFC), and immunohistochemical (IHC) staining results indicated that lycopene could effectively suppress the growth and progression of colon cancer in tumor-bearing mice. The results demonstrated that lycopene significantly suppressed the nuclear expression of PCNA and β-catenin proteins in tumor tissues. Consumption of lycopene could also augment the E-cadherin adherent molecule and nuclear levels of cell cycle inhibitor p21(CIP1/WAF1) protein. The chemopreventive effects of lycopene were associated with suppression of COX-2, PGE(2), and phosphorylated ERK1/2 proteins. Furthermore, the inhibitory effects of lycopene were inversely correlated with the plasma levels of matrix metalloproteinase 9 (MMP-9) in tumor-bearing mice. These results suggested that lycopene could act as a chemopreventive agent against the growth and progression of colorectal cancer in a mouse xenograft model.
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Affiliation(s)
- Feng-Yao Tang
- Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan, Republic of China.
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Mimura M, Masuda A, Nishiumi S, Kawakami K, Fujishima Y, Yoshie T, Mizuno S, Miki I, Ohno H, Hase K, Minamoto T, Azuma T, Yoshida M. AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene. Int J Cancer 2011; 130:1011-20. [PMID: 21484796 DOI: 10.1002/ijc.26131] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Accepted: 03/29/2011] [Indexed: 11/12/2022]
Abstract
Recent evidence has suggested that carcinoma is accompanied by the loss of cell polarity. An epithelial cell-specific form of the AP-1 clathrin adaptor complex, AP1B, is involved in the polarized transport of membrane proteins to the basolateral surface of epithelial cells. In our study, we investigated whether AP1B is involved in intestinal tumorigenesis. The cellular polarity of intestinal tumor cells was examined using APC(Min/+) mice as an in vivo model and SW480 cells with a truncating mutation in the adenomatous polyposis coli (APC) gene as an in vitro model by confocal microscopy. Next, the expression of AP1B in intestinal tumor cells was examined by real-time polymerase chain reaction (PCR) and Western blotting. The localization of β-catenin and the expression of AP1B in the tumor tissue of patients with colorectal cancer were evaluated by confocal microscopy and real-time PCR, respectively, and the relationships among cell polarity, AP1B expression and intestinal tumorigenesis were examined. Cellular polarity was lost in intestinal tumor cells, and the expression of AP1B was downregulated. In addition, the reduction in the expression level of AP1B correlated with the nuclear localization of β-catenin in human colorectal cancer. Our study indicates the close associations between AP1B, intestinal tumorigenesis and mutations in the APC gene. This is the first report to reveal the relationships among AP1B, cellular polarity and intestinal tumorigenesis, and achieving a detailed understanding of AP1B will hopefully lead to discovery of therapeutic targets and novel biomarkers for intestinal cancer.
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Affiliation(s)
- Mitsuko Mimura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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Chen L, Hu L, Li L, Liu Y, Tu QQ, Chang YX, Yan HX, Wu MC, Wang HY. Dysregulation of β-catenin by hepatitis B virus X protein in HBV-infected human hepatocellular carcinomas. ACTA ACUST UNITED AC 2010; 4:399-411. [PMID: 21107751 DOI: 10.1007/s11684-010-0170-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 10/04/2010] [Indexed: 12/20/2022]
Abstract
β-catenin is a key molecule involved in both cell-cell adhesion and Wnt signaling pathway. In our study, we found that, in the development of hepatocellular carcinoma (HCC), β-catenin was correlated with hepatitis B virus (HBV) X gene encoded protein, which is essential for HBV infectivity and is a potential cofactor in viral carcinogenesis. The expression levels of wild-type β-catenin and E-cadherin were decreased in HepG2 cells expressing hepatitis B virus X protein (HBx), accompanied by destabilization of adherens junction. Reverse transcriptase PCR (RT-PCR), Northern and Western blot showed that reduction of wild-type β-catenin expression involved degradation of the protein. However, RNA interference (RNAi) and luciferase assay indicated that HBx enhanced β-catenin mediated signaling in HepG2 cells. In addition, immunohistochemical and Western blot analysis of β-catenin revealed that a decrease in the β-catenin protein level was found in 58.3% of HBV-related HCCs versus 19.2% of non-HBV-related tumors. Our data suggest that the expression of HBx contributed to the development of HCC, in part, by repressing the wild-type β-catenin expression and enforcing β-catenin-dependent signaling pathway, thus inducing cellular changes leading to acquisition of metastatic and/or proliferation properties.
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Affiliation(s)
- Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China
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16
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Ellis PE, Ghaem-Maghami S. Molecular Characteristics and Risk Factors in Endometrial Cancer. Int J Gynecol Cancer 2010; 20:1207-16. [DOI: 10.1111/igc.0b013e3181f1a400] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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17
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Ge X, Wang X. Role of Wnt canonical pathway in hematological malignancies. J Hematol Oncol 2010; 3:33. [PMID: 20843302 PMCID: PMC2954871 DOI: 10.1186/1756-8722-3-33] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Accepted: 09/15/2010] [Indexed: 12/13/2022] Open
Abstract
Wnt canonical signaling pathway plays a diverse role in embryonic development and maintenance of organs and tissues in adults. It has been observed that Wnt/β-catenin signaling pathway is involved in the pathogenesis of many carcinomas. Moreover, Wnt/β-catenin pathway has been revealed to be associated with angiogenesis. Wnt canonical pathway signaling has great potential as a therapeutic target. It has been disclosed that some hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, may occur partly due to the constitutive activation of Wnt canonical signaling pathway. This review will summarize the latest development in Wnt canonical signaling pathway and its roles in tumorigenesis and angiogenesis.
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Affiliation(s)
- Xueling Ge
- Department of Hematology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, China
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18
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Junxia W, Ping G, Yuan H, Lijun Z, Jihong R, Fang L, Min L, Xi W, Ting H, Ke D, Huizhong Z. Double strand RNA-guided endogeneous E-cadherin up-regulation induces the apoptosis and inhibits proliferation of breast carcinoma cells in vitro and in vivo. Cancer Sci 2010; 101:1790-6. [PMID: 20518789 PMCID: PMC11158458 DOI: 10.1111/j.1349-7006.2010.01594.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
E-cadherin plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Down-regulation of E-cadherin expression correlates with a strong invasive potential, resulting in poor prognosis in many human carcinomas, including breast cancer. Restoration of E-cadherin can inhibit cell invasion and metastasis in many types of tumors. It has been demonstrated that promoter hypermethylation causes transcriptional down-regulation of E-cadherin. Here, using an RNAa technique specifically activating the expression of E-cadherin through transcriptional regulation, we assessed the phenotype changes of a breast carcinoma cell line with transfection of small-activating RNAs (saRNAs). We observed cell apoptosis, proliferation inhibition and reduction in human breast cancer migration in vitro. Animal experiment results showed that saRNA could inhibit tumor growth in vivo compared with scramble double-small RNA (dsRNA).This study provides a new potential strategy for breast cancer therapy, and also demonstrates the potential for saRNA as a therapeutic option for enhancing tumor suppressor gene expression in breast cancer. (Cancer Sci 2010).
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Affiliation(s)
- Wei Junxia
- Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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19
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Wang C, Li Z, Yang Z, Zhao H, Yang Y, Chen K, Cai X, Wang L, Shi Y, Qiu S, Fan J, Zha X. The effect of receptor protein tyrosine phosphatase kappa on the change of cell adhesion and proliferation induced by N-acetylglucosaminyltransferase V. J Cell Biochem 2010; 109:113-23. [PMID: 19911372 DOI: 10.1002/jcb.22387] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
N-acetylglucosaminyltransferase V (GnT-V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT-V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPkappa) but also decreased its protein level. Moreover, GnT-V overexpression decreased cell calcium-independent adhesion and increased the tyrosine phosphorylation level of beta-catenin, in which RPTPkappa played an important role. Since RPTPkappa has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPkappa on the change of cell adhesion and beta-catenin signaling induced by GnT-V. Our results showed that preventing RPTPkappa cleavage rescued the above effects of GnT-V, suggesting that furin cleavage could be one of the factors for RPTPkappa to regulate cell adhesion and beta-catenin signaling in GnT-V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of beta-catenin was associated with the increased nuclear level of beta-catenin and downstream signaling molecules such as c-myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT-V could decrease human hepatoma SMMC-7721 cell adhesion and promote cell proliferation partially through RPTPkappa.
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Affiliation(s)
- Can Wang
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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20
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Barnes EA, Kenerson HL, Mak BC, Yeung RS. The loss of tuberin promotes cell invasion through the ß-catenin pathway. Am J Respir Cell Mol Biol 2009; 43:617-27. [PMID: 20042714 DOI: 10.1165/rcmb.2008-0335oc] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mutations in the tumor suppressor tuberin (TSC2) are a common factor in the development of lymphangioleiomyomatosis (LAM). LAM is a cystic lung disease that is characterized by the infiltration of smooth muscle-like cells into the pulmonary parenchyma. The mechanism by which the loss of tuberin promotes the development of LAM has yet to be elucidated, although several lines of evidence suggest it is due to the metastasis of tuberin-deficient cells. Here we show that tuberin-null cells become nonadherent and invasive. These nonadherent cells express cleaved forms of β-catenin. In reporter assays, the β-catenin products are transcriptionally active and promote MMP7 expression. Invasion by the tuberin-null cells is mediated by MMP7. Examination of LAM tissues shows the expression of cleaved β-catenin products and MMP7 consistent with a model that tuberin-deficient cells acquire invasive properties through a β-catenin-dependent mechanism, which may underlie the development of LAM.
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Affiliation(s)
- Elizabeth A Barnes
- University of Washington, Department of Surgery, Seattle, Washington 98195, USA
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21
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Hoenerhoff MJ, Hong HH, Ton TV, Lahousse SA, Sills RC. A review of the molecular mechanisms of chemically induced neoplasia in rat and mouse models in National Toxicology Program bioassays and their relevance to human cancer. Toxicol Pathol 2009; 37:835-48. [PMID: 19846892 PMCID: PMC3524969 DOI: 10.1177/0192623309351726] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds.
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Affiliation(s)
- Mark J Hoenerhoff
- Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27519, USA.
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22
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Kirkland SC. Type I collagen inhibits differentiation and promotes a stem cell-like phenotype in human colorectal carcinoma cells. Br J Cancer 2009; 101:320-6. [PMID: 19568234 PMCID: PMC2720218 DOI: 10.1038/sj.bjc.6605143] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: Human colorectal cancer is caused by mutations and is thought to be maintained by a population of cancer stem cells. Further phenotypic changes occurring at the invasive edge suggest that colon cancer cells are also regulated by their microenvironment. Type I collagen, a promoter of the malignant phenotype in pancreatic carcinoma cells, is highly expressed at the invasive front of human colorectal cancer. Methods: This study investigates the role of type I collagen in specifying the colorectal cancer cell phenotype. The effect of type I collagen on morphology, localisation of cell–cell adhesion proteins, differentiation and stem cell-like characteristics was examined in a panel of human colorectal carcinoma cell lines. Results: Human colorectal carcinoma cells grown on type I collagen in serum-free medium show an epithelial–mesenchymal-like transition (EMT-like), assuming a more flattened less cohesive morphology. Type I collagen downregulates E-cadherin and β-catenin at cell–cell junctions. Furthermore, type I collagen inhibits differentiation, increases clonogenicity and promotes expression of stem cell markers CD133 and Bmi1. Type I collagen effects were partially abrogated by a function-blocking antibody to α2 integrin. Conclusion: Together, these results indicate that type I collagen promotes expression of a stem cell-like phenotype in human colorectal cancer cells likely through α2β1 integrin.
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Affiliation(s)
- S C Kirkland
- Department of Histopathology, Imperial College London, DuCane Road, London W12 ONN, UK.
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23
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Kam Y, Quaranta V. Cadherin-bound beta-catenin feeds into the Wnt pathway upon adherens junctions dissociation: evidence for an intersection between beta-catenin pools. PLoS One 2009; 4:e4580. [PMID: 19238201 PMCID: PMC2640460 DOI: 10.1371/journal.pone.0004580] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2008] [Accepted: 01/09/2009] [Indexed: 01/07/2023] Open
Abstract
β-catenin is an essential component of two cellular systems: cadherin-based adherens junctions (AJ) and the Wnt signaling pathway. A functional or physical connection between these β-catenin pools has been suggested in previous studies, but not conclusively demonstrated to date. To further examine this intersection, we treated A431 cell colonies with lysophosphatidic acid (LPA), which forces rapid and synchronized dissociation of AJ. A combination of immunostaining, time-lapse microscopy using photoactivatable-GFP-tagged β-catenin, and image analyses indicate that the cadherin-bound pool of β-catenin, internalized together with E-cadherin, accumulates at the perinuclear endocytic recycling compartment (ERC) upon AJ dissociation, and can be translocated into the cell nucleus upon Wnt pathway activation. These results suggest that the ERC may be a site of residence for β-catenin destined to enter the nucleus, and that dissociation of AJ may influence β-catenin levels in the ERC, effectively affecting β-catenin substrate levels available downstream for the Wnt pathway. This intersection provides a mechanism for integrating cell-cell adhesion with Wnt signaling and could be critical in developmental and cancer processes that rely on β-catenin-dependent gene expression.
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Affiliation(s)
- Yoonseok Kam
- Cancer Biology Department, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Vito Quaranta
- Cancer Biology Department, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- * E-mail:
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24
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de Jesus Perez VA, Alastalo TP, Wu JC, Axelrod JD, Cooke JP, Amieva M, Rabinovitch M. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. ACTA ACUST UNITED AC 2009; 184:83-99. [PMID: 19139264 PMCID: PMC2615088 DOI: 10.1083/jcb.200806049] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mutations in bone morphogenetic protein (BMP) receptor II (BMPRII) are associated with pulmonary artery endothelial cell (PAEC) apoptosis and the loss of small vessels seen in idiopathic pulmonary arterial hypertension. Given the low penetrance of BMPRII mutations, abnormalities in other converging signaling pathways may be necessary for disease development. We hypothesized that BMPRII supports normal PAEC function by recruiting Wingless (Wnt) signaling pathways to promote proliferation, survival, and motility. In this study, we report that BMP-2, via BMPRII-mediated inhibition of GSK3-beta, induces beta-catenin (beta-C) accumulation and transcriptional activity necessary for PAEC survival and proliferation. At the same time, BMP-2 mediates phosphorylated Smad1 (pSmad1) or, with loss of BMPRII, pSmad3-dependent recruitment of Disheveled (Dvl) to promote RhoA-Rac1 signaling necessary for motility. Finally, using an angiogenesis assay in severe combined immunodeficient mice, we demonstrate that both beta-C- and Dvl-mediated RhoA-Rac1 activation are necessary for vascular growth in vivo. These findings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2-mediated angiogenesis.
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25
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Bourguignon LYW, Xia W, Wong G. Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem 2009; 284:2657-2671. [PMID: 19047049 PMCID: PMC2631959 DOI: 10.1074/jbc.m806708200] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2008] [Revised: 11/10/2008] [Indexed: 12/18/2022] Open
Abstract
In this study we have investigated hyaluronan (HA)-mediated CD44 (an HA receptor) interactions with p300 (a histone acetyltransferase) and SIRT1 (a histone deacetylase) in human breast tumor cells (MCF-7 cells). Specifically, our results indicate that HA binding to CD44 up-regulates p300 expression and its acetyltransferase activity that, in turn, promotes acetylation of beta-catenin and NFkappaB-p65 leading to activation of beta-catenin-associated T-cell factor/lymphocyte enhancer factor transcriptional co-activation and NFkappaB-specific transcriptional up-regulation, respectively. These changes then cause the expression of the MDR1 (P-glycoprotein/P-gp) gene and the anti-apoptotic gene Bcl-x(L) resulting in chemoresistance in MCF-7 cells. Our data also show that down-regulation of p300, beta-catenin, or NFkappaB-p65 in MCF-7 cells (by transfecting cells with p300-, beta-catenin-, or NFkappaB-p65-specific small interfering RNA) inhibits the HA/CD44-mediated beta-catenin/NFkappaB-p65 acetylation and abrogates the aforementioned transcriptional activities. Subsequently, there is a significant decrease in both MDR1 and Bcl-x(L) gene expression and an enhancement in caspase-3 activity and chemosensitivity in the breast tumor cells. Further analyses indicate that activation of SIRT1 (deacetylase) by resveratrol (a natural antioxidant) induces SIRT1-p300 association and acetyltransferase inactivation, leading to deacetylation of HA/CD44-induced beta-catenin and NFkappaB-p65, inhibition of beta-catenin-T-cell factor/lymphocyte enhancer factor and NFkappaB-specific transcriptional activation, and the impairment of MDR1 and Bcl-x(L) gene expression. All these multiple effects lead to an activation of caspase-3 and a reduction of chemoresistance. Together, these findings suggest that the interactions between HA/CD44-stimulated p300 (acetyltransferase) and resveratrol-activated SIRT1 (deacetylase) play pivotal roles in regulating the balance between cell survival versus apoptosis, and multidrug resistance versus sensitivity in breast tumor cells.
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Affiliation(s)
- Lilly Y W Bourguignon
- Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121.
| | - Weiliang Xia
- Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121
| | - Gabriel Wong
- Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121
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26
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Wang L, Li Z, Wang C, Yang Y, Sun L, Yao W, Cai X, Wu G, Zhou F, Zha X. E-cadherin decreased human breast cancer cells sensitivity to staurosporine by up-regulating Bcl-2 expression. Arch Biochem Biophys 2009; 481:116-22. [DOI: 10.1016/j.abb.2008.10.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2008] [Revised: 10/08/2008] [Accepted: 10/09/2008] [Indexed: 01/30/2023]
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27
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Fujisawa T, Sugiyama M, Tomimoto A, Wada K, Endo H, Takahashi H, Yoneda K, Yoneda M, Inamori M, Saito S, Terauchi Y, Kadowaki T, Tsuchiya N, Nakagama H, Nakajima A. Inhibition of peroxisome proliferator-activated receptor gamma promotes tumorigenesis through activation of the beta-catenin / T cell factor (TCF) pathway in the mouse intestine. J Pharmacol Sci 2008; 108:535-44. [PMID: 19075513 DOI: 10.1254/jphs.08193fp] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Although peroxisome proliferator-activated receptor gamma (PPARgamma) is strongly expressed in the intestinal epithelium, the role of PPARgamma in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARgamma inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated Apc(Min/+) mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and beta-catenin protein in the colon epithelium. To investigate its mechanism, the changes of beta-catenin/TCF (T cell factor) transcriptional activity and location of beta-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of Apc(Min/+) mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARgamma inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the beta-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased beta-catenin/TCF transcriptional activity and beta-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARgamma antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. beta-Catenin contributes to the promotion of tumorigenesis by PPARgamma antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.
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Affiliation(s)
- Toshio Fujisawa
- Division of Gastroenterology, Yokohama City University School of Medicine, Japan
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28
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Chen RS, Song YM, Zhou ZY, Tong T, Li Y, Fu M, Guo XL, Dong LJ, He X, Qiao HX, Zhan QM, Li W. Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway. Oncogene 2008; 28:599-609. [DOI: 10.1038/onc.2008.414] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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29
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Hong Y, Yang J, Wu W, Wang W, Kong X, Wang Y, Yun X, Zong H, Wei Y, Zhang S, Gu J. Knockdown of BCL2L12 leads to cisplatin resistance in MDA-MB-231 breast cancer cells. Biochim Biophys Acta Mol Basis Dis 2008; 1782:649-57. [PMID: 18930135 DOI: 10.1016/j.bbadis.2008.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2008] [Revised: 09/07/2008] [Accepted: 09/08/2008] [Indexed: 11/18/2022]
Abstract
BCL2L12, a newly identified member of Bcl-2 family, contains a BH2 domain and a putative BH3 domain. It was found to be highly expressed in normal breast tissues, and was associated with favorable prognosis in breast cancer patients. Here, we reported that the mRNA levels of BCL2L12 and its transcript variant BCL2L12A could be upregulated upon cisplatin treatment in MDA-MB-231 breast cancer cells. Knockdown of BCL2L12 and BCL2L12A dramatically inhibited cisplatin-induced apoptosis. In contrast, ectopic expressions of each of the proteins promoted cisplatin-induced apoptosis. These results indicated that decreased expressions or loss of BCL2L12 and BCL2L12A may contribute to the cisplatin resistance in breast cancer patients. Furthermore, we found that cisplatin-induced downregulation of beta-catenin was partially suppressed in BCL2L12- and BCL2L12A-knocked down MDA-MB-231 cells, which indicated that knockdown of these two proteins may stabilize beta-catenin in cisplatin-induced apoptosis. In short, we proposed that BCL2L12 and BCL2L12A may play an important role in cisplatin-induced apoptosis in MDA-MB-231 breast cancer cells.
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Affiliation(s)
- Yi Hong
- Gene Research Center, Institutes of Biomedical Science, Shanghai Medical College of Fudan University, Box 103, No. 138 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
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Tang FY, Shih CJ, Cheng LH, Ho HJ, Chen HJ. Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res 2008; 52:646-54. [PMID: 18537129 DOI: 10.1002/mnfr.200700272] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The aberrant regulation of the phosphoinositide 3-kinase/Akt survival signaling pathway in cancer has prompted significant interest in suppression of this pathway to treat cancer. Previous studies identified an important role for phosphoinositide 3-kinase/Akt in colon cancer progression. Lycopene, a major component in tomato, exhibited potential anti-carcinogenic activity. Consumption of tomato has been associated with reduced risk of several types of human cancer. However, the inhibitory mechanisms of lycopene on the proliferation of human colon cancer have not been studied well yet. Thus we investigated the inhibitory effects of lycopene on the Akt signaling pathway in human colon cancer HT-29 cells. Lycopene inhibited cell proliferation in human colon cancer HT-29 cells with a IC(50) value of 10 microM. Lycopene treatment suppressed Akt activation and non-phosphorylated beta-catenin protein level in human colon cancer cells. Immunocytochemical results indicated that lycopene increased the phosphorylated form of beta-catenin proteins. These effects were also associated with reduced promoter activity and protein expression of cyclin D1. Furthermore, lycopene significantly increased nuclear cyclin-dependent kinase inhibitor p27(kip)abundance and inhibited phosphorylation of the retinoblastoma tumor suppressor protein in human colon cancer cells. In conclusion, lycopene inhibited cell proliferation of human colon cancer cells via suppression of the Akt signaling pathway and downstream targeted molecules.
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Affiliation(s)
- Feng-Yao Tang
- Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan.
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31
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Anti-sense morpholino oligonucleotide assay shows critical involvement for NF-kappaB activation in the production of Wnt-1 protein by HepG2 cells: oncology implications. J Biomed Sci 2008; 15:633-43. [PMID: 18461473 DOI: 10.1007/s11373-008-9251-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2007] [Accepted: 04/08/2008] [Indexed: 02/07/2023] Open
Abstract
The link of proto-oncogenic protein Wnt-1 production with NF-kappaB activation has been functionally demonstrated in PC12 cells, a rat pheochromocytoma cell line of neural crest lineage, while it is not yet verified in human cells. The link can be indirectly supported in our previous report that functional proteomics identifies enhanced expression of NF-kappaB-associated Wnt-1 production in human hepatocellular carcinoma tissues. This study aimed to further validate this link in human cells using anti-sense strategy. The effects of sequence-specific anti-sense morpholino oligonucleotides (ONs) targeting against pre-mRNA sequences of human p50 and p65 subunits of NF-kappaB as well as Wnt-1 genes were investigated. It revealed that all the three morpholino ONs inhibited NF-kappaB activation in human hepatoblastoma cell line HepG2 cells along with decreased Wnt-1 production. Chromatin immunoprecipitation assay ascertained the direct binding of NF-kappaB-p50 to the Wnt-1 promoter. Additionally, anti-P50 and anti-P65 morpholino ONs also repressed the phosphorylation of Ikappa Balpha which temporarily correlated with the inhibition of NF-kappaB activation accompanied by decreased Wnt-1 production by HepG2 cells. In summary, NF-kappaB activation is critically involved in the production of Wnt-1 by HepG2 cells. These results may have important oncology implications in treating patients with NF-kappaB-associated Wnt-1-producing cancers.
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32
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Kim DS, Kim MJ, Lee JY, Kim YZ, Kim EJ, Park JY. Aberrant methylation ofE-cadherinandH-cadheringenes in nonsmall cell lung cancer and its relation to clinicopathologic features. Cancer 2007; 110:2785-92. [DOI: 10.1002/cncr.23113] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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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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Bourguignon LYW, Peyrollier K, Gilad E, Brightman A. Hyaluronan-CD44 Interaction with Neural Wiskott-Aldrich Syndrome Protein (N-WASP) Promotes Actin Polymerization and ErbB2 Activation Leading to β-Catenin Nuclear Translocation, Transcriptional Up-regulation, and Cell Migration in Ovarian Tumor Cells. J Biol Chem 2007; 282:1265-80. [PMID: 17092940 DOI: 10.1074/jbc.m604672200] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In this study we have investigated the interaction of hyaluronan (HA) and CD44 with the neuronal Wiskott-Aldrich syndrome protein (N-WASP) in regulating actin polymerization and ErbB2/beta-catenin signaling in human ovarian tumor cells (SK-OV-3.ipl cells). Biochemical and immunological analyses indicate that N-WASP is expressed in SK-OV-3.ipl cells and that the binding of HA stimulates N-WASP association with CD44 and Arp2/Arp3 leading to filamentous actin formation and ovarian tumor cell migration. In addition, HA binding promotes CD44-N-WASP association with ErbB2 and activates ErbB2 kinase activity that in turn increases phosphorylation of the cytoskeletal protein, beta-catenin. Subsequently, phosphorylated beta-catenin is transported into the nucleus leading to beta-catenin-mediated TCF/LEF-transcriptional co-activation. Because HA-induced beta-catenin phosphorylation, nuclear translocation, and TCF/LEF transcriptional activation is effectively blocked by the ErbB2 inhibitor, AG825, we conclude that HA/CD44-N-WASP-associated ErbB2 activation is required for beta-catenin-mediated signaling events. Transfection of SK-OV-3.ipl cells with N-WASP-VCA (verpolin homology, cofilin homology, and acidic domain) fragment cDNA not only blocks HA/CD44-induced N-WASP-Arp2/3 complex formation but also inhibits actin polymerization/F-actin assembly and tumor cell migration. Overexpression of the N-WASP-VCA domain also significantly reduces HA-induced ErbB2 recruitment to CD44, diminishes beta-catenin phosphorylation/nuclear translocation, and abrogates TCF/LEF-specific transcriptional co-activation by beta-catenin. Taken together, our findings strongly suggest that N-WASP plays a pivotal role in regulating HA-mediated CD44-ErbB2 interaction, beta-catenin signaling, and actin cytoskeleton functions that are required for tumor-specific behaviors and ovarian cancer progression.
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Affiliation(s)
- Lilly Y W Bourguignon
- Department of Medicine, University of California, Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
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Asp J, Persson F, Kost-Alimova M, Stenman G. CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer 2006; 45:820-8. [PMID: 16736500 DOI: 10.1002/gcc.20346] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Pleomorphic salivary gland adenomas are characterized by recurrent chromosome rearrangements of 8q12, leading to activation of the PLAG1 oncogene. Here we demonstrate that CHCHD7-PLAG1 is a novel and recurrent gene fusion generated by a cytogenetically cryptic rearrangement in pleomorphic adenomas. CHCHD7 is a newly identified member of a multifamily of proteins containing a conserved (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2) domain. Northern blot analysis revealed that the gene is ubiquitously expressed. Its biological function is unknown and the gene has hitherto not been associated with neoplasia. CHCHD7 and PLAG1 are located head-to-head about 500 bp apart in 8q12. Molecular analyses of 27 tumors revealed CHCHD7-PLAG1 fusions in three tumors, two of which had t(6;8) and t(8;15) translocations as the sole anomalies and one a normal karyotype. FISH analyses of interphase nuclei and nuclear chromatin fibers of a fourth adenoma with a normal karyotype revealed that a second fusion partner gene, TCEA1, located about 2 Mb centromeric to PLAG1, also is fused to PLAG1 as a result of a cryptic 8q rearrangement. The breakpoints in both fusions occur in the 5'-noncoding regions of the genes, leading to activation of PLAG1 by promoter swapping/substitution. Western blot and immunohistochemical analyses demonstrated that the PLAG1 protein was overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with both fusions. Our findings further emphasize the significance of PLAG1 activation in pleomorphic adenomas and demonstrate that the gene is more frequently activated than previously anticipated.
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Affiliation(s)
- Julia Asp
- Lundberg Laboratory for Cancer Research, Department of Pathology, The Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden
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Liu J, Wang H, Zuo Y, Farmer SR. Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin. Mol Cell Biol 2006; 26:5827-37. [PMID: 16847334 PMCID: PMC1592783 DOI: 10.1128/mcb.00441-06] [Citation(s) in RCA: 202] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Studies have demonstrated cross talk between beta-catenin and peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathways. Specifically, activation of PPARgamma induces the proteasomal degradation of beta-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic beta-catenin is resistant to such degradation and inhibits the expression of PPARgamma target genes. In the present studies, we demonstrate a functional interaction between beta-catenin and PPARgamma that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of beta-catenin and a catenin binding domain (CBD) within PPARgamma. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic beta-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPARgamma. Furthermore, these mutations render S37A beta-catenin susceptible to proteasomal degradation in response to activation of PPARgamma. Mutation of F372 within the CBD (helices 7 and 8) of PPARgamma disrupts its binding to beta-catenin and significantly reduces the ability of PPARgamma to induce the proteasomal degradation of beta-catenin. We suggest that in normal cells, PPARgamma can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated beta-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain.
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Affiliation(s)
- Jiajian Liu
- Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118.
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Megy S, Bertho G, Gharbi-Benarous J, Baleux F, Benarous R, Girault JP. STD and TRNOESY NMR studies for the epitope mapping of the phosphorylation motif of the oncogenic protein beta-catenin recognized by a selective monoclonal antibody. FEBS Lett 2006; 580:5411-22. [PMID: 16996060 DOI: 10.1016/j.febslet.2006.08.084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Revised: 06/30/2006] [Accepted: 08/09/2006] [Indexed: 10/24/2022]
Abstract
The interaction of the P-beta-Cat(19-44) peptide, a 26 amino acid peptide (K(19)AAVSHWQQQSYLDpSGIHpSGATTTAP(44)) that mimics the phosphorylated beta-Catenin antigen, has been studied with its monoclonal antibody BC-22, by transferred nuclear Overhauser effect NMR spectroscopy (TRNOESY) and saturation transfer difference NMR (STD NMR) spectroscopy. This antibody is specific to diphosphorylated beta-Catenin and does not react with the non-phosphorylated protein. Phosphorylation of beta-Catenin at sites Ser33 and Ser37 on the DSGXXS motif is required for the interaction of beta-Catenin with the ubiquitin ligase SCF(beta-TrCP). beta-TrCP is involved in the ubiquitination and proteasome targeting of the oncogenic protein beta-Catenin, the accumulation of which has been implicated in various human cancers. The three-dimensional structure of the P-beta-Cat(19-44) in the bound conformation was determined by TRNOESY NMR experiments; the peptide adopts a compact structure in the presence of mAb with formation of turns around Trp25 and Gln26, with a tight bend created by the DpS(33)GIHpS(37) motif; the peptide residues (D32-pS37) forming this bend are recognized by the antibody as demonstrated by STD NMR experiments. STD NMR studies provide evidence for the existence of a conformational epitope containing tandem repeats of phosphoserine motifs. The peptide's epitope is predominantly located in the large bend and in the N-terminal segment, implicating bidentate association. These findings are in excellent agreement with a recently published NMR structure required for the interaction of beta-Catenin with the SCF(beta-TrCP) protein.
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Affiliation(s)
- Simon Megy
- Université Paris V-René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, 45 Rue des Saint-Pères, 75270 Paris Cedex 06, France
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Stenman G. Fusion oncogenes and tumor type specificity--insights from salivary gland tumors. Semin Cancer Biol 2006; 15:224-35. [PMID: 15826837 DOI: 10.1016/j.semcancer.2005.01.002] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Salivary gland tumors are frequently characterized by recurrent chromosome translocations, which have recently been shown to result in pathogenetically relevant fusion oncogenes. These genes encode novel fusion proteins as well as ectopically expressed normal or truncated proteins, and are found in both benign and malignant salivary gland tumors. The major targets of the translocations are DNA-binding transcription factors (PLAG1 and HMGA2) involved in growth factor signaling and cell cycle regulation, and coactivators of the Notch (MAML2) and cAMP (TORC1) signaling pathways. Identification of these fusion oncogenes has contributed to our knowledge of molecular pathways leading to epithelial tumors in general, and to salivary gland tumors in particular. Interestingly, the fusions in salivary gland tumors do not seem to be as tumor type specific as those in leukemias and sarcomas. Instead, they may function by activating basic transformation pathways that can function in multiple cell types. The downstream gene products of these fusions will be important targets for development of new intracellular therapeutic strategies.
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Affiliation(s)
- Göran Stenman
- Lundberg Laboratory for Cancer Research, Department of Pathology, Göteborg University, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
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Hörkkö TT, Klintrup K, Mäkinen JM, Näpänkangas JB, Tuominen HJ, Mäkelä J, Karttunen TJ, Mäkinen MJ. Budding invasive margin and prognosis in colorectal cancer – no direct association with β-catenin expression. Eur J Cancer 2006; 42:964-71. [PMID: 16563744 DOI: 10.1016/j.ejca.2006.01.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2005] [Revised: 12/16/2005] [Accepted: 01/03/2006] [Indexed: 11/19/2022]
Abstract
Cancer cell budding at the invasive margin has been associated with poor prognosis in rectal cancer. beta-Catenin is an adhesion protein involved in the nuclear Wnt/beta-catenin pathway, and mesenchymal transition of colorectal cancer cells. Hence, we investigated the relationship between cancer cell budding at the invasive margin, beta-catenin expression, and 5-year-survival in colorectal cancer. Four hundred and sixty six colorectal cancer specimens were analysed for budding margin, and 108 specimens from the same set for beta-catenin by immunohistochemistry. A budding margin was present in 24.0% of the cases and predicted a poor 5-year-survival (15.4%, P < 0.00001). Nuclear beta-catenin expression increased from the central area towards the invasive margin (P < 0.001), but did not predict budding. Budding margin is an independent factor associated with poor prognosis in colorectal cancer, and could be utilised in diagnostic pathology. Nuclear beta-catenin was often found at the invasive margin, but is unlikely to be the sole cause of budding.
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Affiliation(s)
- Tuomo T Hörkkö
- Department of Pathology, Oulu University Hospital, University of Oulu, Aapistie 5, POB 5000, FIN-90014, Oulu, Finland
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40
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Yan HX, Yang W, Zhang R, Chen L, Tang L, Zhai B, Liu SQ, Cao HF, Man XB, Wu HP, Wu MC, Wang HY. Protein-tyrosine phosphatase PCP-2 inhibits beta-catenin signaling and increases E-cadherin-dependent cell adhesion. J Biol Chem 2006; 281:15423-33. [PMID: 16574648 DOI: 10.1074/jbc.m602607200] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
beta-Catenin is a key molecule involved in both cell adhesion and Wnt signaling pathway. However, the exact relationship between these two roles has not been clearly elucidated. Tyrosine phosphorylation of beta-catenin was shown to decrease its binding to E-cadherin, leading to decreased cell adhesion and increased beta-catenin signaling. We have previously shown that receptor-like protein-tyrosine phosphatase PCP-2 localizes to the adherens junctions and directly binds and dephosphorylates beta-catenin, suggesting that PCP-2 might regulate the balance between signaling and adhesive beta-catenin. Here we demonstrate that PCP-2 can inhibit both the wild-type and constitutively active forms of beta-catenin in activating target genes such as c-myc. The phosphatase activity of PCP-2 is required for this effect since loss of catalytic activity attenuates its inhibitory effect on beta-catenin activation. Expression of PCP-2 in SW480 colon cancer cells can lead to stabilization of cytosolic pools of beta-catenin perhaps, by virtue of their physical interaction. PCP-2 expression also leads to increased membrane-bound E-cadherin and greater stabilization of adherens junctions by dephosphorylation of beta-catenin, which could further sequester cytosolic beta-catenin and thus inhibit beta-catenin mediated nuclear signaling. Furthermore, SW480 cells stably expressing PCP-2 have a reduced ability to proliferate and migrate. Thus, PCP-2 may play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may be an alternative mechanism for activating beta-catenin signaling.
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Affiliation(s)
- He-Xin Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438
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Tzeng SL, Cheng YW, Li CH, Lin YS, Hsu HC, Kang JJ. Physiological and functional interactions between Tcf4 and Daxx in colon cancer cells. J Biol Chem 2006; 281:15405-11. [PMID: 16569639 DOI: 10.1074/jbc.m601807200] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Daxx, a human cell death-associated protein, was isolated as a Tcf4-interacting protein, using a yeast two-hybrid screen. Co-immunoprecipitation in HEK-293T cells and yeast two-hybrid screen in Y190 cells were performed to identify the interaction between Tcf4 with Daxx and to map the binding regions of Tcf4. In the nucleus, Daxx reduced DNA binding activity of Tcf4 and repressed Tcf4 transcriptional activity. Overexpression of Daxx altered the expression of genes downstream of Tcf4, including cyclin D1 and Hath-1, and induced G1 phase arrest in colon cancer cells. A reduction in Daxx protein expression was also observed in colon adenocarcinoma tissue when compared with normal colon tissue. This evidence suggests a possible physiological function of Daxx, via interaction with Tcf4, to regulate proliferation and differentiation of colon cells.
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Affiliation(s)
- Shu-Ling Tzeng
- Institute of Toxicology, Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Nong CZ, Pan LL, He WS, Zha XL, Ye HH, Huang HY. P120ctn overexpression enhances β-catenin-E-cadherin binding and down regulates expression of survivin and cyclin D1 in BEL-7404 hepatoma cells. World J Gastroenterol 2006; 12:1187-91. [PMID: 16534869 PMCID: PMC4124427 DOI: 10.3748/wjg.v12.i8.1187] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To understand the role of P120ctn in E-cadherin-mediated cell-cell adhesion and signaling as well as in hepatoma cell biological function.
METHODS: We stably overexpressed p120ctn isoform 3A in BEL-7404 human hepatoma cells and studied the effect of p120ctn on β-catenin and E-cadherin binding as well as p120ctn and β-catenin subcellular localization using immunoprecipitation, Western blotting and confocal microscopy. We also investigated the inhibitory effect of p120ctn transfection on the expression of apoptotic protein survivin survivin and cell cycle regulator cyclin D1 in the cells.
RERULTS: Western blotting indicated that p120ctn expression increased after cells were transfected with p120ctn isoform 3A. The protein was located mainly at membrane under immunofluorescent microscope. β-catenin nuclear expression was reduced after overexpression of p120ctn isoform 3A. The p120ctn-E-cadherin binding increased after transfection of p120ctn isoform 3A. Furthermore, overexpression of p120ctn down regulated the expression of apoptotic protein survivin and cell cycle regulator cyclin D1. These effects led to reduction of cell proliferation.
CONCLUSION: Our results indicate that p120ctn plays an important role in regulating the formation of E-cadherin and -catenin complex, cell apoptosis, cell cycle and cancer cell biological function.
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Affiliation(s)
- Chao-Zan Nong
- Department of Experimental Center, Guangxi Hospital for Nationalities, Nanning, Guangxi Zhuang Autonomous Region, China
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Dalal KM, Moraitis D, Iwamoto C, Shaha AR, Patel SG, Ghossein RA. Clinical curiosity: Cribriform-morular variant of papillary thyroid carcinoma. Head Neck 2006; 28:471-6. [PMID: 16477606 DOI: 10.1002/hed.20383] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND There is an increasing awareness of the association of papillary thyroid carcinoma and familial adenomatous polyposis (FAP). Although the incidence is rare, most tend to occur in women. Several authors have described a distinctive histologic variant of papillary thyroid carcinoma, the cribriform-morular variant, which is associated with FAP but also may be encountered in patients with non-FAP. This diagnosis may precede the symptoms of colorectal polyposis. METHODS A healthy 36-year-old woman was seen with a left thyroid nodule, and a 34-year-old woman with FAP was seen with a right thyroid nodule; both masses were suspicious for papillary thyroid carcinoma. Both patients underwent total thyroidectomy. RESULTS Pathologic examination of both specimens revealed papillary thyroid carcinoma, cribriform-morular variant. The first patient subsequently underwent colonoscopy, which was negative for polyposis. CONCLUSIONS Patients diagnosed with the cribriform-morular variant of papillary thyroid cancer should be screened for the presence of FAP.
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Affiliation(s)
- Kimberly M Dalal
- Division of Head and Neck Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
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Ghogomu SM, van Venrooy S, Ritthaler M, Wedlich D, Gradl D. HIC-5 is a novel repressor of lymphoid enhancer factor/T-cell factor-driven transcription. J Biol Chem 2005; 281:1755-64. [PMID: 16291758 DOI: 10.1074/jbc.m505869200] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Activation of Wnt/beta-catenin target genes is regulated by a heterodimer of beta-catenin and the high mobility group box transcription factors of the lymphoid enhancer factor (LEF)/T-cell factor (TCF) family. In vertebrates, four LEF/TCF family members have been identified. They all contain a conserved beta-catenin-binding motif at the N terminus and a highly conserved high mobility group box for DNA binding. The core sequence between these motifs is less conserved and contributes to the specific properties of the individual family members. To identify interacting proteins that allocate specific functions to the individual LEF/TCF transcription factors, we performed a yeast two-hybrid screen using the less conserved core sequence as bait. We isolated the murine LIM protein HIC-5 (hydrogen peroxide-induced clone 5; also termed ARA-55 (androgen receptor activator of 55 kDa)) and cloned the highly conserved Xenopus homolog. In addition, we report that the LIM domain-containing C-terminal half of HIC-5 binds to a conserved alternatively spliced exon in LEF/TCF transcription factors. Our functional analyses revealed that HIC-5 acts as negative regulator of a subset of LEF/TCF family members, which have been characterized as activators in reporter gene analyses and in the Xenopus axis induction assay. In addition, we observed a repressive interference of LEF/TCF family members with HIC-5-mediated activation of glucocorticoid-driven transcription, which again could be allocated to specific LEF/TCF subtypes. With the characterization of HIC-5 as a binding partner of the alternatively spliced exon in LEF/TCF transcription factors, we identified a novel molecular mechanism in the dialog of steroid and canonical Wnt signaling that is LEF/TCF subtype-dependent.
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Affiliation(s)
- Stephen Mbigha Ghogomu
- Zoologisches Institut II, Universität Karlsruhe (Technische Hochschule), Kaiserstrasse 12, 76131 Karlsruhe, Germany
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Kato N, Shibuya H, Fukase M, Tamura G, Motoyama T. Involvement of adenomatous polyposis coli (APC) gene in testicular yolk sac tumor of infants. Hum Pathol 2005; 37:48-53. [PMID: 16360415 DOI: 10.1016/j.humpath.2005.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Accepted: 09/13/2005] [Indexed: 11/20/2022]
Abstract
The pathogenesis of testicular yolk sac tumor (YST) of infants is still unclear. Infantile YSTs rarely show isochromosome 12p or aneuploidy, which are common in adult germ cell tumors. On the other hand, recent epigenetic studies suggest the involvement of some tumor suppressor genes, including the adenomatous polyposis coli (APC) gene. In the present study, we examined 10 infantile pure YSTs for mutation, allelic loss, promoter methylation, and protein expression status of the APC gene to evaluate whether the APC gene plays a significant role in the pathogenesis of infantile YSTs. Loss of heterozygosity at 5q21, where the APC gene is localized, was detected in at least 3 (30%) of the 9 YSTs examined. None of the 10 YSTs showed mutations. Promoter methylation was detected in 7 (70%) of the 10 YSTs; among 7 YSTs showing methylation, 3 YSTs also harbored loss of heterozygosity at 5q21. Immunohistochemically, 8 infantile YSTs did not express the APC protein, whereas 2 YSTs without showing APC methylation, as well as germ cells of normal infantile testes, expressed this protein in the cytoplasm. These data indicate that inactivation of the APC gene, by allelic loss and/or promoter methylation, is related to the occurrence of infantile YSTs.
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Affiliation(s)
- Noriko Kato
- Department of Pathology, Yamagata University School of Medicine, 990-9585, Japan.
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Elmileik H, Paterson AC, Kew MC. Beta-catenin mutations and expression, 249serine p53 tumor suppressor gene mutation, and hepatitis B virus infection in southern African Blacks with hepatocellular carcinoma. J Surg Oncol 2005; 91:258-63. [PMID: 16121349 DOI: 10.1002/jso.20304] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES To ascertain the prevalence of deregulating mutations of beta-catenin gene, and to correlate this with the occurrence of 249(serine) p53 gene mutation and hepatitis B virus infection in southern African Blacks with hepatocellular carcinoma. METHODS Paired cancer/non-cancerous liver tissues from 21 and cancer tissues alone from 20 Black Africans with hepatocellular carcinoma were studied. RT-PCR-SSCP and sequencing were used to detect mutations in exon 3 of the beta-catenin gene, and PCR, restriction endonuclease analysis, and sequencing to detect the p53 gene mutation. Immunostaining was used to identify beta-catenin protein expression in hepatocytes. RESULTS No mutations in exon 3 of the beta-catenin gene were found in tumor or non-tumorous tissues. Immunohistochemical staining showed beta-catenin protein expression in membranes and cytoplasm of hepatocytes but not in the nuclei. The 249serine p53 gene mutation was detected in 27.2% of the hepatocellular carcinoma tissues but not in non-cancerous tissues. No correlation was found between beta-catenin mutation and over-expression and 249serine p53 gene mutations or hepatitis B virus surface antigenemia. CONCLUSIONS Unlike hepatocellular carcinomas in China, Japan, and Europe, deregulating beta-catenin gene mutations do not appear to occur in southern African Blacks with this tumor and do not therefore interact with either the 249serine p53 gene mutation or hepatitis B virus infection in its pathogenesis.
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Affiliation(s)
- Hashim Elmileik
- MRC/University Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Rieger-Christ KM, Ng L, Hanley RS, Durrani O, Ma H, Yee AS, Libertino JA, Summerhayes IC. Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 2005; 92:2153-9. [PMID: 15942628 PMCID: PMC2361803 DOI: 10.1038/sj.bjc.6602651] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with <1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression.
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Affiliation(s)
- K M Rieger-Christ
- Cell and Molecular Biology Laboratory, Robert E Wise MD Research and Education Institute, 31 Mall Road, Burlington, MA 01805, USA
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
| | - L Ng
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
| | - R S Hanley
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
| | - O Durrani
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
| | - H Ma
- Tufts University School of Medicine, 136 Harrison Avenue, Boston, USA
| | - A S Yee
- Tufts University School of Medicine, 136 Harrison Avenue, Boston, USA
| | - J A Libertino
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
| | - I C Summerhayes
- Cell and Molecular Biology Laboratory, Robert E Wise MD Research and Education Institute, 31 Mall Road, Burlington, MA 01805, USA
- Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
- Cell and Molecular Biology Laboratory, Robert E Wise MD Research and Education Institute, 31 Mall Road, Burlington, MA 01805, USA. E-mail:
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48
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Senda T, Shimomura A, Iizuka-Kogo A. Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. Anat Sci Int 2005; 80:121-31. [PMID: 16158975 DOI: 10.1111/j.1447-073x.2005.00106.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The adenomatous polyposis coli (Apc) gene is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. The Apc gene product (APC), basically a cytoplasmic protein, blocks cell cycle progression and plays crucial roles in development. The APC binds to beta-catenin, axin and glycogen synthase kinase 3beta to form a large protein complex, in which beta-catenin is phosphorylated and broken down, resulting in negative regulation of the Wnt signaling pathway. Most of the mutated Apc genes in colorectal tumors lack beta-catenin-binding regions and fail to inhibit Wnt signaling, leading to overproliferation of tumor cells. The APC, having some nuclear localizing signals in its molecule, can also be localized in the nucleus. The nuclear APC exports excess beta-catenin to the cytoplasm. Through its C-terminus, APC binds to post-synaptic density discs large zonula occludens domain-containing proteins, such as discs large (DLG) and post-synaptic density (PSD)-95, and may play important roles in epithelial morphogenesis, brain development and neuronal functions. In addition, APC is involved in cell motility through its association with microtubules and APC-stimulated guanine nucleotide exchange factor. Colocalization of APC and DLG is dependent on microtubules. The Apc gene is highly expressed in the embryonic and postnatal developing brain. Recently, we found that APC is required for the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by facilitating the clustering of PSD-95 and these receptors at the postsynapse. In addition, APC is present in astrocytes, although its role in astrocytes is, as yet, unknown.
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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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Zhao X, Ren W, Yang W, Wang Y, Kong H, Wang L, Yan L, Xu G, Fei J, Fu J, Zhang C, Wang Z. Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice. Int J Cancer 2005; 118:643-8. [PMID: 16108035 DOI: 10.1002/ijc.21400] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin-like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that beta-catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of beta-catenin as well as c-myc, downstream of beta-catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human beta-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse beta-catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice.
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Affiliation(s)
- Xudong Zhao
- Laboratory of Genetic Engineering, Department of Medical Genetics, Institute of Health Science, Shanghai Institutes for Biologic Sciences of Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai, China
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50
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McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer. Int Immunopharmacol 2005; 5:1113-30. [PMID: 15914317 DOI: 10.1016/j.intimp.2004.11.017] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Revised: 11/19/2004] [Accepted: 11/29/2004] [Indexed: 01/12/2023]
Abstract
Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis. When these processes loose integration such as cancer, then uncontrolled cell growth occurs. Cancer of the oesophagus ranks as the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Prognosis of this disease is poor, with an overall 5-year survival rate of less than 10%. Unraveling the mechanisms or developing animal models for oesophageal carcinoma have thus far not been successful. It is believed that oesophageal cancer has an intricate molecular mechanism of evading apoptosis by the down-regulation of Bax, up-regulation of Bcl-2, Bcl-xl and Survivin, mutation of p53 and alteration in Fas expression. A great deal of research has been performed in order to determine the key genes that initiate and promote the growth of oesophageal cancer. This review focuses on apoptosis and candidate genes linked to the development of oesophageal cancer, which it is hoped may provide diagnostic and therapeutic tools, and potential therapeutic strategies for the management of this carcinoma.
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Affiliation(s)
- M L McCabe
- School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, P/Bag 3, Johannesburg, 2050, South Africa
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