Knockdown of stem cell regulator Oct4A in ovarian cancer reveals cellular reprogramming associated with key regulators of cytoskeleton-extracellular matrix remodelling
journal contributionposted on 05.08.2021, 07:57 by Chantel Samardzija, David GreeningDavid Greening, Ruth Escalona, Maoshan Chen, Maree Bilandzic, Rodney Luwor, George Kannourakis, Jock K Findlay, Nuzhat Ahmed
Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas.
C.S. and R.E. are recipients of the Australian Postgraduate Award. N.A. is supported by June Wilson Will Trust, BJT Legal, Fiona Elsey Cancer Research Institute, Ballarat, Australia. D.G. is supported by the LIMS Molecular Biology Stone Fellowship, La Trobe University Research Focus Area Leadership Grant, and La Trobe University Start-up Fund. MC is supported by a La Trobe University Postgraduate Scholarship. This work was made possible through the Victorian State Government Operational Infrastructure Support to the Hudson Institute of Medical Research. We acknowledge the La Trobe University-Comprehensive Proteomics Platform for providing infrastructure and expertise for Protein Identification & Quantification. This work was supported by the funds received from Ovarian Cancer Research Foundation, Australia to N. A.
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PROSTATE-CANCERTUMOR BURDENMOUSE MODELIN-VIVOMETASTASISEXOSOMESPLECTINCell Line, TumorExtracellular MatrixCytoskeletonAnimalsHumansMiceOvarian NeoplasmsDisease Models, AnimalProteomeXenograft Model Antitumor AssaysProteomicsComputational BiologySignal TransductionFemaleOctamer Transcription Factor-3Neoplastic Stem CellsGene Knockdown TechniquesCellular ReprogrammingBiomarkers