CUL2 overexpression driven by CUL2/E2F1/miR-424 regulatory loop promotes HPV16 E7 induced cervical carcinogenesis

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.

The lysine acetyltransferase GCN5 contributes to human papillomavirus oncoprotein E7‐induced cell proliferation via up‐regulating E2F1

“…62 E2F1 overexpression has been reported to promote cervical carcinogenesis. 63 HPV E7 can bind and promote the degradation of retinoblastoma protein (pRb), resulting in the release of E2F1 from the pRb-E2F complex and thereby promote malignant transformation of cervical epithelium. 64,65 pRb is an established target of E7, and E2F1 is an important regulator of Rb.…”

miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer

“…RNA extraction and real-time quantitative reverse transcriptase-PCR (RT-qPCR) was performed as described previously. 9 Briefly, RNA was extracted from primary colorectal tissues or cultured cells using Trizol reagent (Thermo Fisher Scientific, Waltham, MA, USA). For miR-424, stem-loop RT-PCR was performed.…”

HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

“…A large number of ubiquitin ligases have been reported to be HPV E7 interactors, a principal one being cullin 2 (CUL2), a core component of the cullin-RING-based ESC (ElonginBC-Cullin-SOCS-box) E3 ubiquitin-protein ligase complex [126,127]. This interaction occurs via the E7 CR1 domain, as well as through its C-terminal sequences, and drives cell cycle progression by degradation of pRb and upregulation of CDK2 and cyclins A and E [58,128]. In fact, interactions between E7 and CUL2 complex were validated for 17 different HPV types from both the α- (HPV-16, -18, -31, -33, -45, -6b, -55, -74, -2a, and -57) and β-genus (HPV-8, -25, -98, -17a, -38, -76, and -92) HPV types.…”