Integration of high-risk human papillomavirus (HPV) into the host genome is a crucial
event for the development of cervical cancer, however, the underlying mechanism of
HPV integration-driven carcinogenesis remains unknown. Here, we performed long-read
RNA sequencing on 12 high-grade squamous intraepithelial lesions (HSIL) and cervical
cancer patients, including 3 pairs of cervical cancer and corresponding para-cancerous
tissue samples to investigate the full-length landscape of cross-species genome integrations.
In addition to massive unannotated isoforms, transcriptional regulatory events, and
gene chimerism, more importantly, we found that HPV-human fusion events were prevalent
in HPV-associated cervical cancers. Combined with the genome data, we revealed the
existence of a universal transcription pattern in these fusion events, whereby structurally
similar fusion transcripts were generated by specific splicing in E6 and a canonical
splicing donor site in E1 linking to various human splicing acceptors. Highly expressed
HPV-human fusion transcripts, eg, HPV16 E6*I-E7-E1SD880-human gene, were the key driver of cervical carcinogenesis, which could trigger overexpression
of E6*I and E7, and destroy the transcription of tumor suppressor genes CMAHP, TP63 and P3H2. Finally, evidence from in vitro and in vivo experiments demonstrates that the novel read-through fusion gene mRNA, E1-CMAHP (E1C,
formed by the integration of HPV58 E1 with CMAHP), existed in the fusion transcript
can promote malignant transformation of cervical epithelial cells via regulating downstream oncogenes to participate in various biological processes. Taken
together, we reveal a previously unknown mechanism of HPV integration-driven carcinogenesis
and provide a novel target for the diagnosis and treatment of cervical cancer.
Abbreviations:
APA (Alternative polyadenylation positions sites), AS (Alternative splicing), ATSS (Alternative transcription start sites), DEGs (Differentially expressed genes), E1C (E1-CMAHP), Ect1_E1C (The stable Ect1/E6E7 cell line overexpressing E1-CMAHP), Ect1_NC (The stable Ect1/E6E7 cell line with control plasmid), EMT (Epithelial-to-mesenchymal transition), HR-HPV (High-risk human papillomavirus), HSIL (High-grade squamous intraepithelial lesions), PacBio Iso-Seq (Pacific Biosciences Isoform sequencing), RNA-seq (RNA sequencing), SCC (Squamous cell carcinoma), TCGA (The Cancer Genome Atlas)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: October 09, 2022
Accepted:
September 26,
2022
Received in revised form:
September 18,
2022
Received:
August 6,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
