TY  - GEN
AV  - public
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/28639/
N2  - Persistent infections with oncogenic human papillomaviruses (HPVs) represent a major risk factor for the development of cervical cancer. The viral E6 and E7 proteins are the central driving forces for cervical carcinogenesis by inhibiting important tumor-suppressor pathways in the host cell and by generating genomic instability. Cervical cancer cells are dependent on the continuous expression of E6/E7 in order to maintain their malignant phenotype (?oncogene addiction?). Therefore, the identification and characterization of so far unknown, E6/E7-regulated factors should enable a better understanding of the mechanisms behind HPV-linked tumorigenesis and could possibly reveal new therapeutic starting points.
The present study shows that the expression of the cellular growth differentiation factor 15 (GDF15) gene, a pro-apoptotic stress response gene, is downregulated by E6 in HPV-positive cervical cancer cells as well as in HPV-immortalized keratinocytes. This GDF15 repression is observed both at the mRNA and protein level, and mechanistically caused by the interference of E6 with the p53-dependent transcriptional activation of the GDF15 gene. The C/EBP homologous protein (CHOP) was identified as a second major activator of GDF15 expression in HPV-positive cancer cells. While p53 is the key determinant of basal GDF15 levels, it was found that both p53 and CHOP can differentially contribute to the stress-induced upregulation of GDF15 expression, dependently on the type of stress. On the phenotypic level, GDF15 overexpression blocked the capacity of cervical cancer cells to form colonies. Moreover, three anti-proliferative drugs, the ER stressor tunicamycin, the nonsteroidal anti-inflammatory drug sulindac sulfide, and the chemotherapeutic drug cisplatin, increased GDF15 levels in HPV-positive cancer cells. This was linked to the induction of apoptosis, as determined by the detection of apoptosis markers, TUNEL assays, and live cell imaging experiments visualizing Caspase activation. Both GDF15 knockout by the CRISPR/Cas9 technology and transient downregulation of GDF15 expression by RNA interference counteracted the pro-apoptotic stress response of HPV-positive cervical cancer cells towards those three agents.
In summary, these results identify GDF15 as a novel cellular target gene of oncogenic HPVs, which is repressed by the E6 oncoprotein. The findings of the functional studies indicate that the downregulation of GDF15 provides HPV-positive cells with a survival advantage, by increasing their resistance against different forms of cellular stress. From a clinical point of view, it is interesting that GDF15 also plays a role in the induction of apoptosis by cisplatin, the major cytostatic agent used for treating cervical carcinomas. This latter observation points out that the E6-mediated GDF15 repression could contribute to the chemotherapy resistance of HPV-positive cancer cells.
CY  - Heidelberg
A1  - Mändl, Julia
ID  - heidok28639
TI  - The Growth Differentiation Factor 15 ? 
a Novel Cellular Target Gene for Oncogenic Human Papillomaviruses
Y1  - 2021///
ER  -