Bedeutung des Tumorstammzellfaktors CD44v6 für die Wirkung von Photonen und 12C-Ionen bei Kopf-Hals-Tumorzellen

Neuere klinische Studien zeigen, dass beim HNSCC eine hohe Expression des Stammzellfaktors CD44v6 mit einer schlechten Prognose assoziiert ist. Ziel dieser Arbeit war es, die dafür verantwortlichen molekularen und zellulären Mechanismen aufzuklären. Die Untersuchungen wurden an zwei HNSCC-Zelllinien...

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Bibliographic Details
Main Author: Al-Bazaz, Maximilian
Contributors: Engenhart-Cabillic, Rita (Prof. Dr. med) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2022
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Recent clinical trials indicate that for HNSCC an elevated expression of the stem cell factor CD44v6 is associated with poor prognosis. The aim of this study was to unravel the underlying molecular and cellular mechanisms. The investigation was performed with two HNSCC cell lines characterized either by a high (UPCI:SCC040) or low (UPCI:SCC131) expression of CD44v6. In cell line with high level of CD44v6 expression was knocked-down by specific siRNA, while in cell line with low level the expression was enhanced by stable transfection with respective cDNA. Using these cell lines the following observations were made: 1. CD44v6 shows a strong effect on cell growth. KD of CD44v6 causes a reduction and, vice versa, an over-expression of CD44v6 a stimulation of cell growth. This effect is valid for all cell cycle phases. 2. After photon-irradiation, CD44v6 also affects cell cycle regulation. KD of CD44v6 was found to enhance the radiation-induced G2-arrest. 3. CD44v6 shows a strong effect on cellular radiosensitivity. However, this effect was only observed when cells were exposed to photons but not to 12C-ions. KD of CD44v6 led to an enhanced radiosensitivity, while overexpression resulted in a strongly enhanced radioresistance. The effect of CD44v6 on radiosensitivity was only apparent when cells were irradiated in S- but not for G1-phase. The enhanced radiosensitivity observed after KD of CD44v6 as especially seen for S-phase cells, which also coincides with a stronger radiation-induced G2 arrest, indicates that CD44v6 might be involved in DSB repair via homologous recombination. 4. This assumption was further confirmed by the observation, that in cells depleted in CD44v6, radiosensitivity is strongly enhanced when treated by the PARP1-inhibitor Olaparib. 5. For HNSCC showing an elevated expression of CD44v6 treatment with 12C-ions might be the optimal therapy, because it is demonstrated by this report for the first time, that the poor prognosis of HNSCC seen in clinical studies when expression of CD44v6 was high, might result from an enhanced cellular radioresistance. However, this resistance is apparent only when treated by photons but not after 12C-irradiation.