PMID- 27390927 OWN - NLM STAT- MEDLINE DCOM- 20171002 LR - 20181202 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 16 DP - 2016 Jul 8 TI - Coalition of Oct4A and beta1 integrins in facilitating metastasis in ovarian cancer. PG - 432 LID - 10.1186/s12885-016-2458-z [doi] LID - 432 AB - BACKGROUND: Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. METHODS: The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. RESULTS: We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin beta1 expression and associated alpha5 and alpha2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34 and CD31 compared to vector control cell-derived xenografts. CONCLUSION: The expression of Oct4A may be crucial to promote and sustain integrin-mediated extracellular matrix (ECM) remodeling requisite for tumor metastasis in ovarian cancer patients. FAU - Samardzija, Chantel AU - Samardzija C AD - Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. FAU - Luwor, Rodney B AU - Luwor RB AD - Department of Surgery, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. FAU - Quinn, Michael A AU - Quinn MA AD - Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. FAU - Kannourakis, George AU - Kannourakis G AD - Fiona Elsey Cancer Research Institute, Suites 23-26, 106-110 Lydiard Street South, Ballarat Technology Central Park, Ballarat, 3353, Australia. AD - Federation University Australia, Ballarat, VIC, 3010, Australia. FAU - Findlay, Jock K AU - Findlay JK AD - Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. AD - The Hudson Institute of Medical Research, Clayton, Melbourne, VIC, 3168, Australia. FAU - Ahmed, Nuzhat AU - Ahmed N AD - Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. nuzhata@unimelb.edu.au. AD - Fiona Elsey Cancer Research Institute, Suites 23-26, 106-110 Lydiard Street South, Ballarat Technology Central Park, Ballarat, 3353, Australia. nuzhata@unimelb.edu.au. AD - Federation University Australia, Ballarat, VIC, 3010, Australia. nuzhata@unimelb.edu.au. AD - The Hudson Institute of Medical Research, Clayton, Melbourne, VIC, 3168, Australia. nuzhata@unimelb.edu.au. LA - eng PT - Journal Article DEP - 20160708 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Integrin alpha Chains) RN - 0 (Integrin beta1) RN - 0 (Octamer Transcription Factor-3) RN - 0 (POU5F1 protein, human) RN - 0 (Protein Isoforms) RN - EC 3.4.24.24 (MMP2 protein, human) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (MMP9 protein, human) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Cell Adhesion MH - Cell Line, Tumor MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Integrin alpha Chains/metabolism MH - Integrin beta1/*metabolism MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice, Inbred BALB C MH - Mice, Nude MH - Neoplasm Transplantation MH - Neoplasms, Cystic, Mucinous, and Serous/*metabolism/secondary MH - Octamer Transcription Factor-3/*metabolism MH - Ovarian Neoplasms/*metabolism/pathology MH - Protein Isoforms/metabolism MH - Spheroids, Cellular/metabolism MH - Tumor Burden PMC - PMC4939035 OTO - NOTNLM OT - Cancer stem cells OT - Chemoresistance OT - Integrins OT - Metastasis OT - Oct4A OT - Ovarian carcinoma OT - Recurrence EDAT- 2016/07/09 06:00 MHDA- 2017/10/03 06:00 PMCR- 2016/07/08 CRDT- 2016/07/09 06:00 PHST- 2015/11/08 00:00 [received] PHST- 2016/06/24 00:00 [accepted] PHST- 2016/07/09 06:00 [entrez] PHST- 2016/07/09 06:00 [pubmed] PHST- 2017/10/03 06:00 [medline] PHST- 2016/07/08 00:00 [pmc-release] AID - 10.1186/s12885-016-2458-z [pii] AID - 2458 [pii] AID - 10.1186/s12885-016-2458-z [doi] PST - epublish SO - BMC Cancer. 2016 Jul 8;16:432. doi: 10.1186/s12885-016-2458-z.