Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use

Abstract

Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers. Human papillomaviruses have been applied clinically to different facets of human papillomavirus-related cancers, including prevention, screening, diagnosis, treatment, and prognosis. Several types of prophylactic vaccines have been publicly utilized worldwide and have greatly decreased the occurrence of human papillomavirus-related cancers, which have benefited numerous people. Although various therapeutic vaccines have been developed and tested clinically, none of them have been officially approved to date. Enhancing the efficacy of vaccines and searching for innovative technologies targeting human papillomaviruses remain critical challenges that warrant continuous research and attention in the future.

Fig. 1

A timeline of HPV research. Since the presence was identified in 1956, study on HPV has continued to date. Apart from oncogenic mechanisms, vaccines targeting HPV have been developed. Moreover, WHO has launched strategies for worldwide CC elimination. This figure was created with BioRender (www.bioender.com)

Fig. 2

Global HPV vaccine availability and the association between hr-HPVs and cancers. a Percentage of HPV vaccine availability among different regions. b The association between hr-HPVs and cancers. Cervical cancer, oropharyngeal squamous cell carcinoma, anal cancer, vaginal cancer, vulvar cancer, and penile cancer are well recognized as closely associated with hr-HPVs. c Number of cancer cases caused by hr-HPV per year. This figure was created with BioRender (www.bioender.com)

Fig. 3

The life cycle of hr-HPVs. HPVs enter the basal layer of the epithelium and undergo different stages: infection, replication, capsid synthesis, virion assembly, and virion release. Early proteins are of great significance during HPV infection. Persistent infection results in hyperplasia and dysplasia. Without intervention, dysplasia has a great possibility to evolve into cancers. This figure was created with BioRender (www.bioender.com)

Fig. 4

Oncogenic mechanisms of hr-HPVs and therapeutic strategies for hr-HPV-related cancers. hr-HPVs contribute to the oncogenesis through various ways, including evading immune responses, promoting cell proliferation, resisting apoptosis, inducing cell immortality, fostering angiogenesis, and promoting cell invasion. Different types of therapies treating hr-HPV-related cancers have been widely applied in clinic, aiming to gain better efficacy and prognosis. This figure was created with BioRender (www.bioender.com)

Fig. 5

Oncogenic signaling pathways of hr-HPVs. a Oncogenic signaling pathways of E5. E5 can activate epidermal growth factor receptor (EGFR) signaling. Through EGFR, E5 activates the PI3K/AKT and MAPK/ERK pathways to promote uncontrolled cell proliferation. Moreover, E5 facilitates cell migration and inhibits apoptosis and immune responses, which ultimately leads to the generation of cancers. b Oncogenic signaling pathways of E6. E6 is well-known for binding with and degrading p53 in a ubiquitin–proteasome way. Degradation of p53 promotes cell proliferation and inhibits apoptosis. E6 is able to inhibit autophagy and immune responses and facilitate cell immortalization and invasion independent of p53 degradation as well. In addition, E6 promotes glycolysis and lipid synthesis to support cell growth. c Oncogenic signaling pathways of E7. E7 binds with pRb to release E2F, promoting cells entering the S-phase. E7 can increase the expression of cyclins to enable cells to alter from the G1-phase to S-phase unrestrictedly, resulting in uncontrolled cell proliferation. Moreover, E7 boosts cell migration and hinders immune responses to further stimulate the occurrence of cancers. This figure was created with BioRender (www.bioender.com)