Malignancy Associated with Low-Risk HPV6 and HPV11: A Systematic Review and Implications for Cancer Prevention.

High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0-5.5% for penile and 0-87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV.

Study on the antineoplastic and toxicological effects of pomegranate (Punica granatum L.) leaf infusion using the K14-HPV16 transgenic mouse model.

Punica granatum L. (pomegranate) has been used in functional foods due to its various health benefits. However, the in vivo biological potential of its leaf remains little known. This study has aimed to characterize the antineoplastic and toxicological properties of using pomegranate leaf infusion (PLI) on transgenic mice carrying human papillomavirus (HPV) type 16 oncogenes. Thirty-eight mice were divided into 3 wild-type (WT) and 3 transgenic (HPV) groups, with exposure to 0.5% PLI, 1.0% PLI, and water. The animals' body weight, drink and food consumption were recorded. Internal organs, skin samples and intracardiac blood were collected to evaluate toxicological parameters, neoplastic lesions and oxidative stress. The results indicated that PLI was safe as no mortality, no behavioural disorders and no significant differences in the levels of microhematocrit, serum biochemical markers, internal organ histology, and oxidative stress was found among the WT groups. Histological analysis revealed that HPV animals that consumed PLI exhibited reduced hepatic, renal and cutaneous lesions compared with the HPV control group. Low-dose PLI consumption significantly diminished renal hydronephrosis lesions and relieved dysplasia and carcinoma lesions in the chest skin. Oxidative stress analysis showed that low-dose PLI consumption may have more benefits than high-dose PLI. These results suggest that oral administration of PLI has the potential to alleviate non-neoplastic and neoplastic lesions against HPV16-induced organ and skin injuries, though this requires further scientific research studies.

Decoding the role of inflammation-related microRNAs in cancer cachexia: a study using HPV16-transgenic mice and in silico approaches

Cachexia is associated with poor prognosis in cancer patients, and inflammation is one of its main drive factors. MicroRNAs have recently emerged as important players in cancer cachexia and are involved in reciprocal regulation networks with pro-inflammatory signaling pathways. We hypothesize that inflammation-driven cancer cachexia is regulated by specific microRNAs. The aim of this study is to explore the expression and role of inflammation-related microRNAs in muscle wasting. HPV16-transgenic mice develop systemic inflammation and muscle wasting and are a model for cancer cachexia. We employed gastrocnemius muscle samples from these mice to study the expression of microRNAs. Bioinformatic tools were then used to explore their potential role in muscle wasting. Among the microRNAs studied, miR-223-3p (p = 0.004), let-7b-5p (p = 0.034), miR-21a-5p (p = 0.034), miR-150-5p (p = 0.027), and miR-155-5p (p = 0.011) were significantly upregulated in muscles from cachectic mice. In silico analysis showed that these microRNAs participate in several processes related to muscle wasting, including muscle structure development and regulation of the MAPK pathway. When analyzing protein–protein interactions (PPI)-networks, two major clusters and the top 10 hubs were obtained. From the top 10, Kras (p = 0.050) and Ccdn1 (p = 0.009) were downregulated in cachectic muscles, as well as Map2k3 (p = 0.007). These results show that miR-223-3p, let-7b-5p, miR-21a-5p, miR-150-5p, and miR-155-5p, play a role in muscle wasting in HPV16 transgenic mice, possible through regulating the MAPK cascades. Future experimental studies are required to validate our in silico analysis, and to explore the usefulness of these microRNAs and MAPK signaling as new potential biomarkers or therapy targets for cancer cachexia. (AU)