Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Broutian, Tatevik; Jiang, Bo; Li, Jing‐Feng; Akagi, Keiko; Gui, Shanying; Zhou, Zhengqiu; Xiao, Weihong; Symer, David E.; Gillison, Maura L.

doi:10.1016/j.canlet.2020.01.012

Cited by 14 publications

(22 citation statements)

References 59 publications

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“…Broutian et al observed HPV insertions flanking a 16-fold somatic amplification of the gene PIM1 (Proviral insertion site for Moloney murine leukemia virus MuLV) in the HNSCC cell line UPCI:SCC090, in which more integration sites have been identified [8,22]. This amplification was accompanied by an increase of PIM1 transcripts [81]. PIM1 overexpression has been identified in HNSCCs and has been associated with poor survival [82][83][84].…”

Section: Deregulated Expression Of the Targeted Gene By Hpv Integrationmentioning

confidence: 99%

Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art

Balaji

Demers

Wuerdemann

et al. 2021

Cancers

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A constantly increasing incidence in high-risk Human Papillomaviruses (HPV)s driven head and neck squamous cell carcinomas (HNSCC)s, especially of oropharyngeal origin, is being observed. During persistent infections, viral DNA integration into the host genome may occur. Studies are examining if the physical status of the virus (episomal vs. integration) affects carcinogenesis and eventually has further-reaching consequences on disease progression and outcome. Here, we review the literature of the most recent five years focusing on the impact of HPV integration in HNSCCs, covering aspects of detection techniques used (from PCR up to NGS approaches), integration loci identified, and associations with genomic and clinical data. The consequences of HPV integration in the human genome, including the methylation status and deregulation of genes involved in cell signaling pathways, immune evasion, and response to therapy, are also summarized.

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Section: Deregulated Expression Of the Targeted Gene By Hpv Integrationmentioning

confidence: 99%

Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art

Balaji

Demers

Wuerdemann

et al. 2021

Cancers

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“…Documented cooperative interactions between HPV E6 and MYC in inducing telomerase ( hTERT ) expression and keratinocyte immortalization further support the pathophysiological significance of viral integration at this hotspot (Zhang et al 2017). Moreover, we have shown that genetic knockdown or small molecule inhibition of PIM1 induces cell death in UPCI:SCC090, a head and neck cancer cell line in which HPV integrants directly flank a 16-fold amplification of PIM1 (Broutian et al 2020). These archetypal, experimentally tractable examples each illustrate the contributions of HPV integrant-mediated transcriptional alterations to cellular transformation and the malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Akagi

et al. 2021

Preprint

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Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes, but the impacts of integration in tumorigenesis remain unclear. Analysis of 105 HPV-positive oropharyngeal cancers by whole genome sequencing detects viral integration in 77%, revealing five statistically significant integration hotspots near genes that regulate epithelial stem cell maintenance (i.e. SOX2, TP63, FGFR, MYC) and immune evasion (i.e. CD274). Somatic hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with local density of HPV integrants. Genes expressed at extreme outlier levels are increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking and/or de novo expression of noncoding or imprinted genes. We conclude that HPV integration contributes substantively to cancer development by causing extensive disruption of host genome structure and gene expression.

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“…Our results prove that PIM-1 may function as an oncogene in CC, and PIM-1 may exert its carcinogenic effects through activating the EGFR signaling via increasing the proliferation and decreasing the apoptosis of CC cells. The PIM kinases were first reported as most significantly up-regulated genes during the process of embryonic development 9,15 ; however, in recent years, PIMs were also found to be over-expressed in several cancers. The role of PIM-1 as an oncogene has been investigated in different studies.…”

Section: Discussionmentioning

confidence: 99%

“…The PIM kinases were first reported as most significantly up-regulated genes during the process of embryonic development 9 , 15 ; however, in recent years, PIMs were also found to be over-expressed in several cancers. The role of PIM-1 as an oncogene has been investigated in different studies.…”

Section: Discussionmentioning

confidence: 99%

“…7 , 18 In contrast, the correlation between PIM kinases and EGFR has been reported previously. 14 , 15 Siu et al 14 suggested that PIM-1 can regulate the EGFR signaling in prostate cancer cells; Broutian et al 15 reported that PIM-1 affected the EGFR signaling in head and neck squamous cell carcinoma. However, whether PIM-1 can regulate the EGFR signaling in CC still needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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PIM-1 may function as an oncogene in cervical cancer via activating the EGFR signaling

Yang

Dong

et al. 2020

Int J Biol Markers

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Background: This work was designed to explore the roles of PIM-1 in the development of cervical cancer. Methods: There were 90 paired cervical tumor samples and the non-tumor adjacent tissue. The levels of PIM-1 in different samples were examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) methods. The potential diagnostic value of PIM-1 was analyzed by the receiver operating characteristic (ROC) curve; furthermore, the expression of EGFR in tumor samples was detected, and Pearson’s correlation analysis was performed to analyze the relationship between the expression of PIM-1 and EGFR. Finally, cervical cancer cell line Hela cells were cultured and treated by PIM-1 siRNA, and MTT assay and Pi/Annexin V assay were performed to explore the effects of PIM-1 siRNA on the growth and apoptosis ability of the Hela cells. Results: PIM-1 was significantly up-regulated in cervical cancer tissue compared to adjacent tissue, and the expression of PIM-1 in patients with cervical cancer is positively associated with the size and metastasis of the tumor. ROC analysis showed PIM-1 is a sensitive biomarker for the diagnosis of cervical cancer. Furthermore, EGFR was over-expressed in cervical cancer tumor tissues, and the levels of PIM-1 and EGFR in cervical cancer tissue were positively correlated. Finally, PIM-1 siRNA dramatically inhibited the viability and promoted the apoptosis of the Hela cells. Conclusion: Our findings prove that PIM-1 may function as an oncogene in cervical cancer and can regulate the EGFR signaling in cervical cancer.

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Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Cited by 14 publications

References 59 publications

Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art

Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

PIM-1 may function as an oncogene in cervical cancer via activating the EGFR signaling

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