Abstract
It has been shown that HPV16 E7, but not other genotypes, can bind to scaffold protein CUL2 during inducing cervical carcinogenesis, but the expression level, associated regulating mechanism, and potential carcinogenicity of CUL2 itself is still unknown as yet. Here, we demonstrated that CUL2 was specifically overexpressed in HPV16 positive cervical cancer cells and tissues, and CUL2 expression was significantly increased along with the cervical lesion progression and positively correlated with HPV16 E7. CUL2 knockdown slowed the growth of xenograft tumors in mouse models. Importantly, CUL2 specifically bound to HPV16 E7, but not HPV18 E7. Moreover, CUL2 acted as a direct target of miR-424, and reversely suppressed miR-424; E2F transcription factor 1 (E2F1) suppressed miR-424 expression; CUL2 bound to E2F1 and promoted E2F1 expression. Our results indicate the existence of a regulatory loop among CUL2, E2F1, and miR-424 in HPV16 positive cervical cancer cells. Our results suggest that E7 recruited CUL2, driven by CUL2/E2F1/miR-424 regulatory loop, is overexpressed and accelerates HPV16-induced cervical carcinogenesis. Our findings may serve as one of the explanations for a clinical phenomenon that HPV16 possesses the strongest cervical carcinogenicity among high-risk HPV genotypes.
Highlights
Cervical cancer is still one of the most common malignancies, ranking as the fourth most common in women worldwide and the second in less developed countries [1] Persistent infection with high-risk human papillomavirus (HR-HPV) is the casual factor for both cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN) [2,3,4]
Our findings suggest that Cullin 2 (CUL2) overexpression may participate in the early stage of HPV16 E7 induced carcinogenesis
We found that E2F transcription factor 1 (E2F1) mRNA level was increased in CIN 2-3 and cervical cancer tissues compared to normal tissues (Figure 6B), though there was no significant difference of E2F1 expression between normal cervix with and without HPV infection, indicating that aberrant E2F1 level might occur after the morphology change
Summary
Cervical cancer is still one of the most common malignancies, ranking as the fourth most common in women worldwide and the second in less developed countries [1] Persistent infection with high-risk human papillomavirus (HR-HPV) is the casual factor for both cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN) [2,3,4]. E6 and E7, two primary viral early oncoproteins, play key roles in the initiation and progression of cervical cancer by influencing the pathways related to the cellular transformation [7, 8]. HPV16 is a genotype that represents the most infection frequency and possesses the most powerful carcinogenic potential. Just based on those clinical evidences, American Society for Colposcopy and Cervical Pathology and other authoritative institutes recommend that HPV16+/ cytology- women can be referred to colposcopy directly [10, 11], it has been still unclear yet why HPV16 possesses the strongest carcinogenic capacity
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