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Carbon-ion irradiation overcomes HPV-integration/E2 gene-disruption induced radioresistance of cervical keratinocytes.

ABSTRACT: To date, only few data exist on mechanisms underlying the human papillomavirus (HPV)-associated irradiation response. It has been suggested, that the viral E2 gene plays an important role in that context. The aim of the current study is to compare the effect of photon- and carbon-ion (12C)-radiation therapy (RT) on cells with different HPV and E2 gene status. We hypothesized that 12C-RT might overcome the radioresistance of E2 gene-disrupted cells. We analyzed four different cell lines that differed in HPV status or E2 gene status. Cells were irradiated with either photons or 12C. Clonogenic survival, cell cycle and expression of Rb and p53 were analyzed. Radiosensitivity seemed to be dependent on E2 gene status and type of RT. 12C-RT led to lower surviving fractions, indicating higher radiosensitivity even in cells with disrupted E2 gene. The observed relative biological effectiveness (RBE) of 12C-RT for C33a/Caski and W12/S12 was 1.3/4 and 2.7/2.5, respectively. Cell cycle regulation after both photon- and 12C-RT was dependent on HPV status and on E2 gene status. Furthermore, the effect of RT on expression of p53 and Rb seemed to be dependent on E2 gene status and type of RT. We showed that 12C-RT overcomes HPV-integration induced radioresistance. The effect of RT on cell cycle regulation as well as on expression of p53 and Rb seemed to be dependent on HPV status, E2 gene status and type of RT. Differences in Rb expression and cell cycle regulation may play a role for enhanced radiosensitivity to 12C-RT of cells with disrupted E2 gene.

SUBMITTER: Arians N

PROVIDER: S-EPMC6805985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs) are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240). We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular genes, by HPV integration remains an issue to be fully resolved.

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Carbon-ion irradiation overcomes HPV-integration/E2 gene-disruption induced radioresistance of cervical keratinocytes.

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