Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins

Harden, Mallory E.; Münger, Karl

doi:10.1016/j.virol.2017.04.022

“…miR‐141 was found to be up‐regulated in cervical cancer compared to their normal counterparts in other studies (Gao et al ., ; Rao et al ., ). The up‐regulation of miR‐141 in cervical cancer was observed in association with the dysregulation of DROSHA, a critical enzyme in the miRNA biogenesis pathway, for which the expression is suggested to be modulated by HPV16 E6/E7 oncoproteins (Harden and Munger, ; Muralidhar et al ., ). miR‐210, is a well‐known hypoxia‐inducible miRNA, termed ‘master hypoxamiRs’.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer

Liu

¹

,

Chan

²

,

Chu

³

et al. 2018

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Cervical cancer is one of the leading causes of cancer death in women globally, despite the widespread use of cytology/human papillomavirus (HPV) screening. In the present study, we aimed to identify the potential role of microRNA (miRNA) as a diagnostic biomarker in the detection of cervical pre‐malignant lesions and cancer. In total, we recruited 582 patients with cervical diseases and 145 control individuals. The expression levels of six miRNAs (miR‐20a, miR‐92a, miR‐141, miR‐183*, miR‐210 and miR‐944) were found to be significantly up‐regulated in cervical cancer and pre‐malignant lesions compared to normal cervical samples, indicating that they are oncogenic miRNAs. Receiver operating characteristic curve analysis showed that these six miRNAs can be used to distinguish patients with cervical pre‐malignant lesions or cancer from normal individuals and they also had a good predictive performance, particularly in cervical lesions. Combined use of these six miRNAs further enhanced the diagnostic accuracy over any single miRNA marker, with an area under the curve of 0.998, 0.996 and 0.959, a diagnostic sensitivity of 97.9%, 97.2% and 91.4%, and a specificity of 98.6%, 96.6% and 87.6% for low‐grade lesions, high‐grade lesions and cancer, respectively. This six oncogenic miRNA signature may be suitable for use as diagnostic marker for cervical pre‐malignant lesions and cancer in the near future.

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“…These findings suggest that only low levels of E6 might be translated in this tumor. In addition to binding to TP53, E6 also interacts with a number of antiapoptotic proteins and PDZ domain‐containing proteins . It also activates the TERT promoter .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to binding to TP53, E6 also interacts with a number of antiapoptotic proteins and PDZ domain-containing proteins. 58,[71][72][73][74][75][76] It also activates the TERT promoter. [77][78][79][80] Perhaps TERT gene-containing chromosome 3q amplification in part compensated for the low levels of E6.…”

Section: Discussionmentioning

confidence: 99%

“…Of approximately 144 million reads, 97.8% passed filtering with >96% having Phred scores >30. Gene model annotation files were downloaded from the genome website browser (NCBI/UCSC/Ensembl) for (GRCh37/hg19) and in custom format from Papillomavirus Episteme for HPV70. Indexes of the custom reference genome were built, and paired‐end clean reads were aligned to the reference using STAR v2.5 .…”

Section: Methodsmentioning

confidence: 99%

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Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV‐negative cervical cancer

Arsdale

¹

,

Patterson

²

,

Maggi

³

et al. 2019

Genes Chromosomes & Cancer

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Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV‐negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR‐E6‐E7‐E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B‐cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70‐BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV‐associated tumorigenesis.

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“…These findings suggest that only low levels of E6 might be translated in this tumor. In addition to binding to TP53, E6 also interacts with a number of anti-apoptotic proteins and PDZ domain-containing proteins (55)(56)(57)(58)(59)(60)(61). It also activates the TERT promoter (62-65).…”

Section: Discussionmentioning

confidence: 99%

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

Arsdale

¹

,

Patterson

²

,

Maggi

³

et al. 2019

Preprint

0

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Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis. Statement of SignificanceMultiple HPV types have been defined as high risk for cancer causation. However, genomic analyses applied here detected a non-high risk HPV in a carcinoma that was HPV negative, and elucidated virally-associated tumorigenic genetic events. This stresses the importance of thorough genomic analyses for elucidating genetic processes in HPV-associated tumorigenesis. Author SummaryCervical cancer is the second leading cause of cancer death in women worldwide. Most cervical cancers are caused by one of 15 high risk types of human papilloma viruses (HPVs), although hundreds of types of HPVs exist. We used a series of contemporary genomics analyses to examine a cervical cancer that was clinically determined to be HPV-negative.These detected DNA of HPV70, an HPV type not considered to be high risk, in the tumor.Approximately half of the HPV70 DNA genome was present including the viral E6 and E7 oncogenes. Moreover, the viral DNA was inserted into the BCL11B gene in the human genome. BCL11B is known to be mutated in certain human cancers. The HPV70 DNA interacted with the human BCL11B gene to produce altered forms of RNA encoding unusual, truncated forms of the BCL11B protein. These results strongly implicate HPV70 as being oncogenic, suggest that this tumor was caused by a combination of viral oncogenes plus the virally-activated human BCL11B gene, demonstrate novel truncated BCL11B variants with oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate HPV tumorigenesis insights

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Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins

Cited by 23 publications

References 36 publications

Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer

Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV‐negative cervical cancer

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

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