Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Petzold, J.
PTEN and the PI3K/Akt Pathway in Biliary Tract Cancer
Humanmedizin; [ Diplomarbeit ] Medical University of Graz; 2014. pp. 147
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Haybäck Johannes
- Huppertz Berthold
- Altmetrics:
- Abstract:
- Introduction: Biliary tract cancer and its most frequent type, gallbladder cancer, are relatively seldom diseases with a very poor outcome. There are high risk areas, and the global incidence will increase notably in the future. The tumor suppressor PTEN and the proto-oncogenic PI3K/Akt pathway play an important role in many human cancer entities. This thesis investigates the influence of PTEN and the PI3K/Akt pathway on biliary tract cancer to understand the molecular mechanisms that are responsible for cancer formation. Material & Methods: Eight biliary tract cancer cell lines, eight frozen gallbladder cancer samples, and nine frozen tumor-free gallbladder specimens were investigated by qRT-PCR and Western blot. Furthermore, an immunohistochemical staining of 396 gallbladder cancer samples, 101 tumor-free gallbladder samples, and 3 mild chronic cholecystitis specimens was conducted. Results: PTEN was downregulated or upregulated and, in the latter case, simultaneously inactivated in all biliary tract cancer cell lines. The inactivation of PTEN led to mTOR activation in an Akt-independent manner. The transition from normal gallbladder epithelium to gallbladder cancer as well as loss of differentiation, invasion, and poor prognosis were characterized by the overexpression of PTEN. Decreasing levels of nuclear phospho-p70S6K and phospho-mTOR correlated with tumor progression and reduced survival. Discussion: The inactivation of PTEN due to phosphorylation apparently correlates with its overexpression and could be a promising objective for targeted therapies in the future. The alteration of the PI3K/PTEN ratio may lead to the activation of Akt, mTOR as well as p70S6K and may promote gallbladder carcinogenesis in chronic cholecystitis. Nuclear phospho-p70S6K and phospho-mTOR could be used to estimate the likelihood of metastasis by comparing the expression levels in cancer and tumor-free tissue of patients with gallbladder cancer. Additional studies are required that pursue these findings and thereby provide further insights into the PI3K/Akt pathway in gallbladder carcinogenesis.