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A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer

Samardzija, Chantel, Luwor, Rodney B., Volchek, Mila, Quinn, Michael A., Findlay, Jock K. and Ahmed, Nuzhat 2015, A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer, Molecular cancer, vol. 14, no. 152, pp. 1-19, doi: 10.1186/s12943-015-0417-y.

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Title A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer
Author(s) Samardzija, ChantelORCID iD for Samardzija, Chantel orcid.org/0000-0002-3000-6273
Luwor, Rodney B.
Volchek, Mila
Quinn, Michael A.
Findlay, Jock K.
Ahmed, Nuzhat
Journal name Molecular cancer
Volume number 14
Issue number 152
Start page 1
End page 19
Total pages 19
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2015-12
ISSN 1476-4598
Keyword(s) Ovarian carcinoma
Cancer stem cells
Metastasis
Ascites
Chemoresistance
Recurrence
Oct4A
Summary Background
High grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance.

Methods
To investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice.

Results
We demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells.

Conclusions
This data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.
Language eng
DOI 10.1186/s12943-015-0417-y
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
1112 Oncology And Carcinogenesis
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30093727

Document type: Journal Article
Collections: School of Exercise and Nutrition Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.