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The Hippo effector TAZ in rhabdomyosarcomaMohamed, Abdalla Ahmed Diaai January 2015 (has links)
Persistent hyperactivity of the Hippo effector YAP in activated but not quiescent satellite cells (muscle stem cells) can give rise to embryonal rhabdomyosarcoma (ERMS). Taz is a paralogue of Yap and both have similar functions in most cell types. However, one report has suggested that Taz can, unlike Yap, promote the differentiation of myoblasts into myotubes. To further characterise the role of Taz in the muscle lineage and rhabdomyosarcoma TAZ abundance and localisation in rhabdomyosarcoma tissue arrays were assessed to test for association with clinical outcome. Additionally, wildtype TAZ and constitutively active TAZ S89A pMSCV retroviral vectors were created to stably transduce C2C12 myoblasts testing for Taz function. In addition, anchorage independent soft agarose assay has been performed in order to assess the tumourigenic property of Taz in C2C12 myoblasts. The presence of TAZ staining in ERMS was significantly associated with poorer survival. TAZ S89A expression in comparison to empty vector (negative control) significantly increased the proliferation of C2C12 myoblasts in reduced foetal calf serum (FCS). TAZ S89A- expressing myoblasts were able to grow and to form more colonies than empty vector myoblasts. In marked contradiction to the pro-tumourigenic role of TAZ in C2C12 myoblasts, ectopic TAZ expression enhanced the differentiation of C2C12 myoblasts. These findings point out the complex and obscure role of TAZ in the muscle lineage. Collectively, these results suggest that TAZ staining is associated with poorer survival in ERMS and that TAZ can transform C2C12 myoblasts indicating a contextual role for TAZ in the muscle lineage.
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Tumour-Suppressive Effects of Pannexin 1 and Its Mechanism of Action and Regulation in RhabdomyosarcomaXiang, Xiao 28 May 2021 (has links)
Rhabdomyosarcoma (RMS) is a paediatric neoplasm of skeletal muscle in dire need of novel therapeutic strategies. We explored the role of pannexin 1 (PANX1), an emerging regulator of skeletal muscle differentiation, in the two major histological subtypes of RMS: embryonal RMS (eRMS) and alveolar RMS (aRMS).
We found that PANX1 levels are down-regulated in eRMS and aRMS tissue specimens and patient-derived cell lines. While PANX1 transcripts were expressed in RMS, we showed that the majority lacked the putative 5’ untranslated region (5’UTR) and the first ATG start codon, which contributed to low PANX1 expression. Re-introduction of PANX1 in eRMS and aRMS patient-derived cell lines induced their partial differentiation and suppressed their malignant properties in vitro and in vivo. Notably, our data suggest that the PANX1-mediated tumour-inhibitory function in RMS does not depend on its canonical channel function.
Furthermore, our genome-wide transcriptomic study found that PANX1 over-expression in RMS cells induced changes in expression of genes in various cellular processes and signaling pathways involved in tumour-suppression including connexin 43 (Cx43), which was previously shown to induce RMS cell differentiation. At the protein level, we showed that the PANX1 interactome in RMS cells involved plasma membrane and cytoskeleton associated proteins including the neuroblast differentiation-associated protein AHNAK, also known as desmoyokin. We demonstrated that PANX1-mediated tumour-suppression in RMS cells depended on its interaction with AHNAK. We further constructed the first searchable PANX1 transcriptome and interactome databases and made them available for the scientific community.
We then searched for a means by which to increase PANX1 levels as a new therapeutic approach for RMS. We found quercetin, a clinical approved natural flavonoid, as a PANX1 up-regulator in RMS cells. This induction of PANX1 expression involved alternative transcription of a PANX1 mRNA variant containing a translationally active 5’UTR, which depended, in part, on binding of the transcription factor ETV4 (ETS Variant Transcription Factor 4) in the PANX1 promoter. Moreover, quercetin treatment induced RMS cell differentiation, inhibited tumour spheroid growth, and induced regression of established tumour spheroids.
Collectively, we demonstrate down-regulation of PANX1 in RMS and the dramatic tumour-inhibitory effects of restoring PANX1 expression in this malignancy. We show that PANX1-induced tumour-suppression does not rely on its canonical channel function but rather by signaling transduction via interaction with AHNAK. We reveal that PANX1 expression can be regulated at the translational level by the 5’UTR of its mRNA via quercetin-induced alternative transcription. We further demonstrate quercetin as a potential therapeutic agent for RMS by showing its tumour-suppressive effects in RMS. These studies not only substantiate our current understanding of PANX1, but also establish PANX1 as a therapeutic target in RMS and provide potential therapeutic options for its treatment.
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AMORE (Ablative surgery, MOulage technique, brachytherapy and REconstruction) for childhood head and neck rhabdomyosarcoma /Buwalda, Joeri, January 1900 (has links)
Proefschrift Universiteit van Amsterdam. / Rugtitel: AMORE for childhood head and neck rhabdomyosarcoma. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.
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Mitochondrial biogenesis and apoptosis in human rhabdomyosarcoma cells /Leung, Lisa H. January 2005 (has links)
Thesis (M.Sc.)--York University, 2005. Graduate Programme in Biology. / Typescript. Includes bibliographical references. Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR19680
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Malignant tumors of the maxillofacial and oral region in children: A clinicopathologic studyMohamed, Ashraf January 1994 (has links)
Magister Chirurgiae Dentium - MChD / This is a retrospective study of malignant tumours of the maxillofacial and oral region in children that presented over a 20 year period (1973 to 1993) at the Red Cross War Memorial Children's Hospital and Groote Schuur Hospital, Cape Town. Of the 352 children that were treated for a malignant tumour arising from various anatomic sites in the head and neck region, 30 were found to have had maxillofacial and oral involvement. This represented an incidence of 8,5%. Histologically, the majority of the tumours were non-odontogenic and mesenchymal in
origin. The rhabdomyosarcoma was found to be the most common neoplasm, followed by the Burkitt's lymphoma. The age range was 6 months to 13.8 years (mean age 5.7 years). Males were more commonly affected than females, with a ratio of 1.3:1. There were 26 (86,7%) black patients and 4 (13,3%) white patients, representing a ratio of 6.5:1. Fifty percent of the cases were from the Eastern Cape. The mandible and the maxilla were the most common sites to be involved, followed by the soft tissues of the face. The most common presenting symptom was a painless swelling (73,3%) of the face. Twenty percent of the patients had "floating" or loose teeth. Radiographic features in the jaws were poorly circumscribed destructive lytic lesions with displacement of teeth. Histologic type was found to be the most significant
variable affecting the outcome, with the Burkitt's lymphomas having the best prognosis and the rhabdomysarcomas the worst. The most common cause of death was metastases to the lungs. It is concluded that although malignant tumours of the maxillofacial and oral region in children are rare, their prognosis is poor. Therefore, any child presenting with a facial swelling should be viewed with suspicion.
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The Role of Cytomegalovirus in Glioblastoma and RhabdomyosarcomaPrice, Richard Lee, III 27 August 2012 (has links)
No description available.
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MOLECULAR INSIGHTS INTO TCEA3 AND TCEAL7-MEDIATED DIFFERENTIATION AND APOPTOSIS IN RHABDOMYOSARCOMAKazim, Noor Ali 01 December 2018 (has links)
Rhabdomyosarcoma (RMS) is a highly malignant form of pediatric cancer that originates from skeletal muscle cells. While the normal skeletal muscle cells are generated via a highly regulated process called myogenesis that depends on myogenic regulatory factors (MRFs), the RMS cells fail to differentiate as a result of impaired myogenesis due to abnormal MRF activity. We found that TCEA3 regulates myogenin (an essential MRF member) activity at the gene expression level. Our work showed that depletion of TCEA3 in normal myoblast cells results in an inhibition of differentiation and downregulation of MRFs. TCEA3 confers myogenic activity and results in differential recruitment of RNAPII to target promoters. While its role in ovarian cancer is well understood, its role in RMS is yet unclear. Thus, our work focused on investigating the role of TCEA3 in both the RMS subtypes, ARMS and ERMS. The results revealed that TCEA3 is downregulated in both the RMS subtypes, and further, its overexpression resulted in a decrease in migration and inhibition of anchorage-independent growth. It also is shown to induce apoptosis through intrinsic and extrinsic pathways. Additionally, we found that over expressing TCEA3 in RMS cells could sensitize these cells to chemotherapeutic drugs. Similar to TCEA3, TCEAL7 is downregulated in various types of cancers, including over 90% of ovarian epithelial cancers, and has shown tumor suppressing properties in ovarian cancers. Our work on RMS showed that TCEAL7 is highly deregulated in both of the immortal cell lines representing ARMS and ERMS, and highly expressed in the normal myoblast cells. Further, deletion of Tceal7 inhibits the proliferation of myoblasts suggesting that TCEAL7 is involved in promoting cell cycle progression in myoblast cells. Deletion of TCEAL7 also revealed a loss of MyHC expression upon differentiation and overexpression of TCEAL7 in RMS promotes differentiation in RMS cells. Additionally, the overexpression of TCEAL7 has led to a decrease in expression of the oncogene, Cyclin D1. Overall, the overexpression of TCEAL7 in RMS cell induces apoptosis and sensitizes cells to TRAIL induced cell apoptosis.
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Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cellsCen, Ling. January 2007 (has links)
Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 89-108).
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Analysis of Myogenin Function in Rhabdomyosarcoma CellsFeldmann, Jamie Marie 01 January 2009 (has links)
Rhabdomyosarcomas (RMS) are the most common soft tissue cancer among children and are characterized by their expression of the myogenic regulatory factors MyoD and myogenin. Yet RMS cells cannot undergo normal myogenesis and are caught between the proliferation program and the terminal differentiation program. Many questions still remain about the defects present in rhabdomyosarcoma cells. In this work, we set out to understand the role of myogenin in these cells. To begin, we found that myogenin and its co-factors were present in rhabdomyosarcoma cells at levels that should support terminal differentiation. We examined the expression profile of several myogenin target genes in rhabdomyosarcoma cells and then assayed for myogenin activity using luciferase reporter constructs that contain myogenin dependent promoters to test for myogenin function. Many myogenin target genes were down regulated in RMS cells but that the target promoters on the luciferase constructs were activated. Terminal differentiation is a complicated process that involves many proteins. In cancer cells, it is important to compare the levels proteins with known functions to those levels in wild-type cells at the protein and RNA levels. Establishing the defect of rhabdomyosarcoma cells can lead to further insights into normal myogenesis, and may also lead to new therapeutic approaches in the treatment of this childhood cancer.
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Chromatin-Modifying Factors in Zebrafish Models of Rhabdomyosarcoma and HematopoiesisAlbacker, Colleen Elizabeth 20 December 2012 (has links)
Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses modifications on both the DNA and histones and is as important as the DNA sequence itself. Gene transcription, DNA repair, DNA replication, and the cell cycle are each impacted by the chromatin structure. A variety of enzymes modulate these modifications, and a suite of factors interacts with them to aid in promoting or inhibiting cellular functions. Many of these chromatin-modifying factors are deregulated in cancer, making them novel therapeutic targets. This dissertation describes the identification of an H3K9 histone methyltransferase, SUV39H1, as a suppressor of rhabdomyosarcoma formation in zebrafish. This suppressor is dependent on the methyltransferase domain of the enzyme, ruling out any scaffold effects since this enzyme is a part of a multiprotein complex. SUV39H1-overexpressing and control tumors share many of the same characteristics, including proliferation rate, muscle differentiation state, and tumor growth rate. The tumor suppressive phenotype cannot be rescued by alterations in the downstream muscle program alone. However, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. This initiation defect occurs between 5 and 7 days of life in the zebrafish, likely by impacting cyclin B1 expression. This dissertation also describes the development of a novel F1 transgenic screening strategy in the zebrafish. This approach was utilized to screen a variety of chromatin-modifying factors for their effects on hematopoietic development. The developed strategy will have future applications as a zebrafish screening tool. Our data suggest that chromatin-modifying factors play an important role in rhabdomyosarcoma and illustrate the use of the zebrafish in discovering genes involved in tumorigenesis and hematopoiesis.
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