Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

Schreiber, Karin; Cannon, Ronald E.; Karrison, Theodore; Beck-Engeser, Gabriele; Huo, Dezheng; Tennant, Raymond W.; Jensen, Heather; Kast, W. Martin; Krausz, Thomas; Meredith, Stephen C.; Chen, Lieping; Schreiber, Hans

doi:10.1038/sj.onc.1207507

Cited by 33 publications

(38 citation statements)

References 52 publications

(53 reference statements)

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“…We hypothesized that other cellular changes are required to support invasive growth in vivo. The idea that cells would require another mutation or oncogene for neoplastic growth is supported by the observation that Ras signaling is frequently aberrant in HNSCC; furthermore, in past studies Ras has been shown to act synergistically with E6 in mouse skin cancer models (23,24,32,36 (Fig. 1C), although it is possible that E6 alters the downstream signaling of Ras pathways.…”

Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 91%

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

Spanos

Hoover

Harris

et al. 2008

J Virol

118

124

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The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras v12 , resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.Significant associative evidence supports a role for human papillomavirus type 16 (HPV16) in the carcinogenic progression of at least 25% of head and neck squamous cell cancer (HNSCC) cases (27, 38). In particular, the incidence of HNSCC of the tonsillar region is increasing (18,20,38). The epithelial surfaces surrounding the tonsil (oropharynx) are cancerous in a very high (60%) proportion of cases that are HPV positive, and these cases present with more metastatic and advanced disease states (34, 38) than HPV-negative cases. The incidence of HPV-related HNSCC is also increased in individuals with human immunodeficiency virus/AIDS disease (10). While the data presented in the following studies pertain to HPV-related HNSCC they may also be applicable to cases of HPV-related cervical cancer, which remains the second leading cause of cancer-related death in women. Therefore, understanding the viral mechanisms that lead to cancer will help meet a need for HPV-specific targeted therapy.One of the major HPV viral oncogenes that allow progression to cancer is HPV16 E6. E6 has many potential carcinogenic effects, including telomerase activation and p53 degradation (26, 35). However, an understood mechanism that potentiates malignant progression has been associated with a PDZ (PSD-95, Discs Large, ZO-1) binding motif (PDZBM), a specific amino acid sequence that mediates protein-protein interactions with corresponding PDZ domain-containing proteins. High-risk HPV virus types 16, 18, 31, and 33 possess this binding motif at the E6 C terminus. In addition to this correlative evidence of increased malignant potential in humans, mouse studies demonstrated that PDZBM is required for HPV-related malignancy (37).The studies described below explored the role of the E6 PDZBM in binding and inducing loss of a PDZ domain containing phosphatase PTPN13. PTPN13 is a member of the nonreceptor phosphatases and specifically falls into a cl...

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Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 91%

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

Spanos

Hoover

Harris

et al. 2008

J Virol

118

124

View full text Add to dashboard Cite

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“…Ras activation upregulated the gene expression levels of E6 and E7 (34). Ras was reported to contribute to cellular transformation in cooperation with E6 and E7 in the mouse model (19,47). With clinical samples, the rate of ras mutation was reported to increase in association with the lesion's grade of cervical neoplasia (2).…”

mentioning

confidence: 99%

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Yoshida

Kajitani

Satsuka

et al. 2008

J Virol

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Infection by human papillomavirus (HPV) is a major risk factor for human cervical carcinoma. However, the HPV infection alone is not sufficient for cancer formation. Cervical carcinogenesis is considered a multistep process accompanied by genetic alterations of the cell. Ras is activated in approximately 20% of human cancers, and it is related to the metastatic conversion of tumor cells. We investigated how Ras activation was involved in the malignant conversion of HPV-infected lesions. The active form of H-ras was introduced into human primary keratinocytes expressing the HPV type 18 (HPV18) oncoproteins E6 and/or E7. We analyzed the keratinocytes' growth potentials and found that the activation of the Ras pathway induced senescence-like growth arrest. Senescence could be eliminated by high-risk E7 expression, suggesting that the pRb pathway was important for Ras-induced senescence. Then we analyzed the effect of Ras activation on epidermis development by using an organotypic "raft" culture and found that the E7 and H-ras coexpressions conferred invasive potential on the epidermis. This invasiveness resulted from the upregulation of MT1-MMP and MMP9 by H-ras and E7, respectively, in which the activation of the MEK/extracellular signal-regulated kinase pathway was involved. These results indicated that the activation of Ras or the related signal pathways promoted the malignant conversion of HPV-infected cells.

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“…High-risk HPV strains also synergize with activation of Ras or the epidermal growth factor receptor (EGFR) to promote cell transformation in vitro (Storey and Banks, 1993;Woodworth et al, 2000) and tumourigenesis in vivo (Schreiber et al, 2004). These data, combined with the observed loss of Scribble in cancers such as colon and breast Gardiol et al, 2006) prompted us to directly test whether loss of Scribble cooperates with activation of Ras in mammalian oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

et al. 2008

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Activating mutations in genes of the Ras-mitogenactivated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.

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Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

Cited by 33 publications

References 52 publications

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

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