Abstract
Human papillomaviruses (HPV) cause malignant epithelial cancers including cervical carcinoma, non-melanoma skin and head and neck cancer. They drive tumor development through the expression of their oncoproteins E6 and E7. Designer nucleases were shown to be efficient to specifically destroy HPV16 and HPV18 oncogenes to induce cell cycle arrest and apoptosis. Here, we used high-capacity adenoviral vectors (HCAdVs) expressing the complete CRISPR/Cas9 machinery specific for HPV18-E6 or HPV16-E6. Cervical cancer cell lines SiHa and CaSki containing HPV16 and HeLa cells containing HPV18 genomes integrated into the cellular genome, as well as HPV-negative cancer cells were transduced with HPV-type-specific CRISPR-HCAdV. Upon adenoviral delivery, the expression of HPV-type-specific CRISPR/Cas9 resulted in decreased cell viability of HPV-positive cervical cancer cell lines, whereas HPV-negative cells were unaffected. Transduced cervical cancer cells showed increased apoptosis induction and decreased proliferation compared to untreated or HPV negative control cells. This suggests that HCAdV can serve as HPV-specific cancer gene therapeutic agents when armed with HPV-type-specific CRISPR/Cas9. Based on the versatility of the CRISPR/Cas9 system, we anticipate that our approach can contribute to personalized treatment options specific for the respective HPV type present in each individual tumor.
Highlights
Human papillomaviruses (HPV) are small non-enveloped epitheliotropic DNA viruses with a circular genome comprised of approximately 8000 base pairs
Transduced cervical cancer cells showed increased apoptosis induction and decreased proliferation compared to untreated or HPV negative control cells. This suggests that high-capacity adenoviral vectors (HCAdVs) can serve as HPV-specific cancer gene therapeutic agents when armed with HPV-type-specific CRISPR/Cas9
HPV are a cofactor in the development of dermatologic malignancies, such as Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin summarized as non-melanoma skin cancer (NMSC), and their precursor lesions, actinic keratosis (AK) [4]
Summary
Human papillomaviruses (HPV) are small non-enveloped epitheliotropic DNA viruses with a circular genome comprised of approximately 8000 base pairs (bp). Over 200 different HPV types are known. HPV DNA was found in oropharyngeal carcinomas summarized as head and neck cancer (HNC) and are regarded as important carcinogens [3]. HPV are a cofactor in the development of dermatologic malignancies, such as Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin summarized as non-melanoma skin cancer (NMSC), and their precursor lesions, actinic keratosis (AK) [4]. Despite the availability of a protective vaccination against high-risk HPV, not all girls and young women (as well as boys and young men) are vaccinated. It is likely, that HPV-associated tumors represent
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