Human Papillomavirus 58 E7 T20I/G63S Variant Isolated from an East Asian Population Possesses High Oncogenicity

Abstract

Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that HPV58 carrying an E7 natural variant, T20I/G63S (designated V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalize and transform primary cells, as well as degrading pRB more effectively, than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of the AKT and K-Ras/extracellular signal-regulated kinase (ERK) signaling pathways, V1 consistently showed greater oncogenicity than the prototype and other variants, as demonstrated by increased cell proliferation, migration, and invasion, as well as induction of larger tumors in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 than that of the prototype and all other common variants. Since V1 is more commonly found in eastern Asia, our report provides insight into the design of HPV screening assays and selection of components for HPV vaccines in this region. IMPORTANCE Epidemiological studies have revealed that a wild-type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of the virus’s greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of the AKT and K-Ras/ERK signaling pathways, thereby explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumors, all to a greater extent than the prototype HPV58 and other common variants.

Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5

“…Increased ERK phosphorylation was found in neural progenitor cells [ 50 ] and the rat fibroblast cell line 3Y1 [ 51 ], and human keratinocytes expressing HPV oncogene E7 or inhibitors of ERK signaling can reduce oncogene expression and inhibit a neoplastic phenotype through EGFR/MEK/ERK signaling [ 52 ] or K-Ras/ERK signaling [ 53 , 54 ]. In a skin carcinogenesis mouse model, papilloma formation was found in mice lacking DUSP5 and its regulation of nuclear ERK activity also served DUSP5 as tumor suppressor in epidermis Ras modulation [ 55 ].…”

Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China

“…Moreover, these mutations were also found to be unique to lineage C (Supplementary Table S5). For HPV58, both epidemiological and experimental evidence indicated that linked mutations of C632T (E7:T20I) and G760A (E7:G63S), mostly found in sublineage A3, were positively associated with high oncogenicity [22,33,42]. While C632T uniquely occurred in 100% (n=19) of the Changsha sublineage A3 strains, G760A was found in all strains of sublineage A3 (n=19) and B1 (n=4) (Supplementary Table S6).…”

Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia

“…We then decided to provide further experimental evidence to explain their relative contribution to cancer risk. Indeed, when comparing these HPV58 E7 variants, V1 showed a greater ability to induce the immortalization and transformation of primary cells [ 259 ], promoting cell proliferation, migration, invasion, and increased tumour burden in athymic nude mice [ 260 ]. We also provided a molecular explanation for this.…”

“…We also provided a molecular explanation for this. V1 can degrade pRb, as well as activate AKT and K-Ras/extracellular signal-regulated kinase (ERK) signalling pathways, more effectively than its prototype and other variants [ 259 , 260 ]. This can potentially explain the high prevalence of HPV58 in cervical lesions and its increased association with cervical cancer risks.…”