Zelluläre Rolle des Valosin-containing Protein (VCP) im kolorektalen Karzinom

Kolonkarzinome sind weltweit die dritthäufigste und zweittödlichste Krebserkrankung. Dabei sind Menschen, die sich nur geringfügig körperlich betätigen, viel Salz und rotes Fleisch konsumieren, aktiv oder passiv rauchen, übergewichtig oder familiär prädispositioniert sind, besonders gefährdet für di...

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Bibliographic Details
Main Author: Schmitt, Lisa-Maria
Contributors: Buchholz, Malte (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2023
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Colorectal cancer is the third most common and second most lethal cancer worldwide. Risk factors for developing CRC are low physical activity, high consumption of red meat and salt, smoking, adiposity and familiar predisposition. The development from a small polyp to an invasive metastatic carcinoma takes years and presumes losses and mutations of various genes. The prognosis of about 3,2 million new diagnosed CRC cases in 2040 reveals the urgency for new therapy and diagnostic possibilities. In a previous project a shRNA library screening in pancreatic cancer cell lines identified VCP as a potential new target for targeted therapies. VCP, the valosine-containing protein, is a chaperon, which takes part in different cellular processes, e.g. the proteasomal degradation of mis- and unfolded proteins or ubiquitination. A few publications already showed an overexpression of VCP in various tumor entities. This overexpression was shown to correlate with a poor prognosis. Databank analysis of CRC patient tissue samples also revealed VCP overexpression. The role of this overexpression in CRC and how it affects its viability, proliferation and progression remains unclear. Therefore, further analysis about the cellular functions of VCP in CRC represent an interesting starting point. The aim of this dissertation was to determine the cellular effects of a VCP knockdown on various processes. On the basis of this, statements should be made about the functions of VCP in CRC, about the effect of a VCP overexpression in CRC and if VCP could also serve as a diagnostic and prognostic biomarker in CRC cells. For this, viability and proliferation assays were performed. This showed that VCP seems to be essential for and CRC cell viability and proliferation. Further, it could be demonstrated that a VCP knockdown also seems to induce DNA damage, apoptosis, cell cycle arrest, senescence and partly UPR. An induction of autophagy could not be shown. These data reveal a new, until now unclear perspective on potential new therapy approaches and VCP as prognostic marker in CRC. It was shown that VCP takes part in various cellular processes and that VCP is significantly involved in the maintenance of viability and proliferation of CRC cells. In conclusion, these results could be a first evidence for VCP as therapeutic and prognostic biomarker and could also be a promising basis for further analysis.