Table of Contents
Ongoing projects deal with basic and translational aspects of the following topics:
1.) Targeted inhibition of the HPV E6 oncoprotein.
We have identified a small peptide that specifically blocks E6 in HPV-positive cancer cells, leading to apoptotic cell death (Dymalla et al., 2009). This peptide is currently used for structure-/function analyses of the HPV E6 oncoprotein. In addition, we aim to use the peptide to generate therapeutically useful agents (“small molecules” or therapeutic peptides) which also can specifically kill HPV-positive tumor cells.
Apoptotic cell death in HPV-positive cancer cells (SiHa) induced by
an E6-binding peptide (pep11) . Green: pep11-expressing cells. Red: Apoptotic cell death measured by TUNEL assay.
2.) Identification of cellular targets for oncogenic HPVs
We have identified novel cellular genes (e.g. BTG2, EZH2) which are deregulated by the HPV oncoproteins. Current work analyzes the role of these genes during viral carcinogenesis and their significance for cancers that are not known to be associated with viruses (e.g. colon, bladder, renal cancer). A major focus of our future work is the investigation of how HPVs can block cellular senescence, thereby inactivating a most critical tumorsuppressive defense mechanism of cells.
Induction of cellular senescence in HPV-positive HeLa cells upon inhibition of viral E6/E7 oncogene expression by RNA interference. HeLa cells were transfected by control siRNA (left panel) or E6/E7 silencing siRNA (right panel) and cellular senescence was detected 96 h post transfection by staining for the senescene marker SA beta-Galactosidase (blue). (Fig. from: Honegger et al., Int. J. Cancer, doi: 10.1002/ijc.28164, 2013).
3) Tumor viruses and exosomes.
The intercellular communication of tumor cells is increasingly recognized as a major determinant for carcinogenesis. Exosomes are small vesicles secreted by many cells, including tumor cells. They can serve as intercellular shuttles, transporting functionally active proteins, mRNAs, and miRNAs from tumor cells into recipient cells. We recently found that the viral oncogenes strongly modulate both the amounts and the contents of exosomes released from HPV-positive cells (Honegger et al., 2013). The further investigation of this issue could provide important new insights into the cell-to-cell communication of HPV-positive cancer cells.
Exosomes are small extracellular vesicles of endosomal origin. They can transport bioactive molecules (proteins, mRNAs, noncoding RNAs) from tumor cells into recipient cells. Electron microscopy, bar = 100 nm. (Fig. from: Honegger et al., Int. J. Cancer, doi: 10.1002/ijc.28164, 2013).