AIB1 is a novel target of the high-risk HPV E6 protein and a biomarker of cervical cancer progression.
AIB1
E6
E7
P53
cervical cancer
oncoproteins
papillomavirus
Journal
Journal of medical virology
ISSN: 1096-9071
Titre abrégé: J Med Virol
Pays: United States
ID NLM: 7705876
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
13
04
2022
received:
23
03
2022
accepted:
17
04
2022
pubmed:
20
4
2022
medline:
16
6
2022
entrez:
19
4
2022
Statut:
ppublish
Résumé
The high-risk human papillomaviruses (HPV-16, -18) are critical etiologic agents in human malignancy, most importantly in cervical cancer. These oncogenic viruses encode the E6 and E7 proteins that are uniformly retained and expressed in cervical cancers and required for maintenance of the tumorigenic phenotype. The E6 and E7 proteins were first identified as targeting the p53 and pRB tumor suppressor pathways, respectively, in host cells, thereby leading to disruption of cell cycle controls. In addition to p53 degradation, a number of other functions and critical targets for E6 have been described, including telomerase, Myc, PDZ-containing proteins, Akt, Wnt, mTORC1, as well as others. In this study, we identified Amplified in Breast Cancer 1 (AIB1) as a new E6 target. We first found that E6 and hTERT altered similar profiling of gene expression in human foreskin keratinocytes (HFK), independent of telomerase activity. Importantly, AIB1 was a common transcriptional target of both E6 and hTERT. We then verified that high-risk E6 but not low-risk E6 expression led to increases in AIB1 transcript levels by real-time RT-PCR, suggesting that AIB1 upregulation may play an important role in cancer development. Western blots demonstrated that AIB1 expression increased in HPV-16 E6 and E7 expressing (E6E7) immortalized foreskin and cervical keratinocytes, and in three of four common cervical cancer cell lines as well. Then, we evaluated the expression of AIB1 in human cervical lesions and invasive carcinoma using immunohistochemical staining. Strikingly, AIB1 showed positivity in the nucleus of cells in the immediate suprabasal epithelium, while nuclei of the basal epithelium were negative, as evident in the Cervical Intraepithelial Neoplasia 1 (CIN1) samples. As the pathological grading of cervical lesions increased from CIN1, CIN2, CIN3 carcinoma in situ and invasive carcinoma, AIB1 staining increased progressively, suggesting that AIB1 may serve as a novel histological biomarker for cervical cancer development. For cases of invasive cervical carcinoma, AIB1 staining was specific to cancerous lesions. Increased expression of AIB1 was also observed in transgenic mouse cervical neoplasia and cancer models induced by E6E7 and estrogen. Knockdown of AIB1 expression in E6E7 immortalized human cervical cells significantly abolished cell proliferation. Taken together, these data support AIB1 as a novel target of HPV E6 and a biomarker of cervical cancer progression.
Identifiants
pubmed: 35437795
doi: 10.1002/jmv.27795
pmc: PMC9199254
mid: NIHMS1799623
doi:
Substances chimiques
Biomarkers
0
Oncogene Proteins, Viral
0
Papillomavirus E7 Proteins
0
Transcription Factors
0
Tumor Suppressor Protein p53
0
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3962-3977Subventions
Organisme : NIAID NIH HHS
ID : R56 AI157872
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA226542
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA258016
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA180524
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222148
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205632
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Informations de copyright
© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.
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