E6/E7 Functional Differences among Two Natural Human Papillomavirus 18 Variants in Human Keratinocytes

Abstract

It is suggested that HPV-18 variants from the A lineage have higher oncogenic potential compared to B variants. Some studies show uneven distribution of HPV-18 variants in cervical adenocarcinomas and squamous cell carcinomas. Regarding HPV-18 variants’ functions, the few studies reported focus on E6, and none were performed using natural host cells. Here, we immortalized primary human keratinocytes (PHKs) with E6/E7 of HPV-18 A1 and B1 sublineages and functionally characterized these cells. PHK18A1 reached immortalization significantly faster than PHK18B1 and formed a higher number of colonies in monolayer and 3D cultures. Moreover, PHK18A1 showed greater invasion ability and higher resistance to apoptosis induced by actinomycin-D. Nevertheless, no differences were observed regarding morphology, proliferation after immortalization, migration, or epithelial development in raft cultures. Noteworthy, our study highlights qualitative differences among HPV-18 A1 and B1 immortalized PHKs: in contrast to PHK18A1, which formed more compact colonies and spheroids of firmly grouped cells and tended to invade and migrate as clustered cells, morphologically, PHK18B1 colonies and spheroids were looser, and migration and invasion of single cells were observed. Although these observations may be relevant for the association of these variants with cervical cancer of different histological subtypes, further studies are warranted to elucidate the mechanisms behind these findings.

In Silico Analysis of the Apoptotic and HPV Inhibitory Roles of Some Selected Phytochemicals Detected from the Rhizomes of Greater Cardamom

“…Human papilloma-virus (HPV) proteins E6 and E7 play a crucial role in the molecular pathogenesis of cervical cancer. Literature indicated that these proteins interact with various cell cycle regulatory proteins to establish cervical cancer prognosis [ 46 – 48 ]. BCL2 is considered one of the most critical anti-apoptotic proteins related to lymphoma development [ 49 ].…”

Virus-host interaction: investigating novel transcription factors involved in coupling HPV life cycle and epithelial differentiation

“…Thus, we speculated whether HPV-18 E6 and E7 oncoproteins influence PAX6, HMGB1, NFE2, and FOXI expression and localization. Interestingly, in the background of raft cultures obtained from HPV-18 E6 and E7 immortalized cells [44], we observed, in general, the high levels of all TFs evaluated throughout the entire thickness of the epithelia ( Fig 6 ), in contrast to the normal epithelial where expression of these proteins is mostly limited to basal layers cells ( Fig 3 ). While the data presented here is preliminary and further studies are warranted, it suggests a potential relevance of PAX6, HMGB1, NFE2, and FOXIl in this scenario where epithelial differentiation is disturbed and proliferation must be maintained, such as observed in HPV immortalized cells.…”

“…To evaluate the association of PAX6, HMGB1, NFE2, and FOXI1 expression with the epithelial differentiation program, we analyzed the levels of these proteins in raft cultures grown from HFKs [44]. Overall, we observed that all four TFs levels are higher in undifferentiated basal layer cells compared to differentiated cells of the upper layers ( Fig 3 and S4 Table ).…”

E7 Oncogene HPV58 Variants Detected in Northeast Brazil: Genetic and Functional Analysis

“…It is widely known that the E7 protein interacts with various biological pathways and plays an important role in oncogenesis [ 63 , 64 , 65 ]. Therefore, genetic variants of E7 may impact these pathways by altering protein–protein interaction rather than affecting their stability [ 66 , 67 ]. Some studies demonstrated that E7 oncogene variants suppressed the activity of the NF-kB pathway [ 68 , 69 ].…”