Transgelin: Discovering its Role in Prostate Cancer Progression
Samalia, Priya Darshni
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Samalia, P. D. (2013). Transgelin: Discovering its Role in Prostate Cancer Progression (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/4477
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http://hdl.handle.net/10523/4477
Abstract:
Prostate cancer is the most commonly diagnosed cancer and the second highest cancer causing mortality amongst men in the Western world. The best possible prognosis for prostate cancer lies in early detection and therefore treatment of prostate cancer. Unfortunately, treatments are limited with significant associated morbidity. The need to develop better diagnostic and prognostic indicators and to identify new therapies are thus needed.
Cancer causes disruption of cytoskeletal actin filaments and associated actin-binding proteins. Actin-binding proteins thus provide a potential diagnostic and therapeutic target. Transgelin is a 22 kD transformation and shape-change sensitive actin-binding protein, that forms actin cross-links which increase filament rigidity and bundle filaments into stress fibres.
Using RT-PCR and Western blot analysis transgelin was shown to be expressed in non cancerous whole prostate tissue and in normal prostate epithelial cell isolates grown in culture conditions; transgelin was immunolocalised to both epithelial and stromal components of benign prostate tissue. Screening of cDNA libraries showed a significant downregulation of transgelin expression during prostate cancer progression. Transgelin expression was significantly downregulated in prostate cancer cell lines compared to normal prostate epithelial cells by real-time RT-PCR and Western blot. Transgelin expression was also reduced in clinical samples of prostate tissue compared to matched normal tissue by real-time RT-PCR. These results suggested a role of transgelin in the molecular regulation of prostate carcinogenesis and its potential role as a tumour suppressor.
In order to elucidate the role of transgelin downregulation in the initiation of prostate carcinogenesis RNAi technology was employed. Functional inactivation of transgelin in normal prostate epithelial cells was achieved by designing siRNA duplexes targeted to transgelin mRNA. Prostate epithelial cells with at least a two-fold reduction in transgelin mRNA expression did not gain a proliferative advantage, anchorage-independent growth, increased wound healing ability or increased expression of MMP9 compared to control cells; suggesting that transgelin was not a key initiator of carcinogenesis.
The TGF-β1 signaling pathway plays a tumour suppressive role in healthy prostate cells by the inhibition of cell proliferation and induction of apoptosis. As prostate cancer progresses prostate cancer cells become unresponsive to the tumour suppressive effects of TGF-β1. TGF-β1 therefore provides a putative anticancer target. Optimal TGF-β1 signaling requires an intact cytoskeleton for the recruitment of intracellular signal transduction of Smad proteins. Incubation of prostate epithelial cells with TGF-β1 induced transgelin expression. This response was attenuated in prostate cancer cell lines. These observations suggest that TGF-β1 maintains its own tumour suppressive properties by promoting a stable cytoskeleton. Additionally this response occurred independent of the Ras-MEK-ERK pathway.
In conclusion, the work presented here provides evidence that transgelin expression is downregulated during prostate cancer progression. Transgelin downregulation may be an early event in the carcinogenic process however its loss alone is insufficient to invoke the hallmarks of cancer. Expression of transgelin is induced by incubation with TGF-β1 and this response is attenuated in prostate cancer cell lines. Transgelin is involved in the structural maintenance of the cytoskeleton as well as in signal transduction.
Date:
2013
Advisor:
Stanton, Jo-Ann; Assinder, Stephen
Degree Name:
Doctor of Philosophy
Degree Discipline:
Anatomy
Publisher:
University of Otago
Keywords:
transgelin; prostate; cancer; TGF-beta; actin
Research Type:
Thesis
Languages:
English
Collections
- Anatomy [221]
- Thesis - Doctoral [3014]