High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors

Abstract

Cervical cancer is the fourth most common cause of cancer in women worldwide in terms of both incidence and mortality. Persistent infection with high-risk types of human papillomavirus (HPV), namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, constitute a necessary cause for the development of cervical cancer. Viral oncoproteins E6 and E7 play central roles in the carcinogenic process by virtue of their interactions with cell master proteins such as p53, retinoblastoma (Rb), mammalian target of rapamycin (mTOR), and c-MYC. For the synthesis of E6 and E7, HPVs use a bicistronic messenger RNA (mRNA) that has been studied in cultured cells. Here, we report that in cervical tumors, HPV-18, -39, and -45 transcribe E6/E7 mRNAs with extremely short 5′ untranslated regions (UTRs) or even lacking a 5′ UTR (i.e., zero to three nucleotides long) to express E6. We show that the translation of HPV-18 E6 cistron is regulated by the motif ACCaugGCGCG(C/A)UUU surrounding the AUG start codon, which we term Translation Initiation of Leaderless mRNAs (TILM). This motif is conserved in all HPV types of the phylogenetically coherent group forming genus alpha, species 7, which infect mucosal epithelia. We further show that the translation of HPV-18 E6 largely relies on the cap structure and eIF4E and eIF4AI, two key translation initiation factors linking translation and cancer but does not involve scanning. Our results support the notion that E6 forms the center of the positive oncogenic feedback loop node involving eIF4E, the mTOR cascade, and p53.

Factors affecting HPV infection in U.S. and Beijing females: A modeling study

“…While the high-risk HPVs (e.g., HPV 16 and 18) may lead to various cancers (e.g., nearly all cervical cancers, and most vulvar, vaginal, oropharyngeal, anal, and penile cancers ( 5 )). The oncoproteins E6 and E7 of high-risk HPVs are responsible for HPV oncogenesis ( 6 , 7 ). The cervical transition zone is extremely vulnerable to HPV infections, and it is the predominant site of origin of cervical cancer ( 8 ).…”

Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells

“…A different cis -element surrounding the AUG codon mediates translation initiation on leaderless mRNAs (TILM) that are capped and have very short or no 5′ UTRs. HPV E6 oncoprotein expression uses TILM-directed initiation, which requires the cap structure, eIF4E, and eIF4A1 and could drive E6 production by cancer cells ( García et al 2021 ).…”

Hsa-miR-194-5p and hsa-miR-195-5p are down-regulated expressed in high dysplasia HPV-positive Pap smear samples compared to normal cytology HPV-positive Pap smear samples

“…In numerous human cases, high-risk (HR) HPV infections [including HPV16 and HPV18] have been identified as substantial risk factors for CC development [ 8 ]. Long-term misexpression of HR HPV E6 and E7 oncogenes contributes to CC development [ 9 ]. These oncogenes trigger neoplastic cell transformation primarily because of genetic and epigenetic instability.…”