The HPV-positive tumors are not more curable based on increased epithelial sensitivity to cisplatin or radiation therapy. Instead, radiation and cisplatin induce an immune response to this antigenic cancer. The implications of these results may lead to novel therapies that enhance tumor eradication for HPV-positive cancers.

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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...

To provide a manipulatable system to study the mechanism of human papillomavirus 16 (HPV16) E6related transformation of an epithelial cell type affected by HPV16 in humans. Design: Biochemical and physiological studies of mouse tonsil epithelial cells (MTECs) transformed with HPV16 oncogenes plus H-ras in vitro and in vivo.

BackgroundRadiation-induced gastrointestinal syndrome (RIGS) results from the acute loss of intestinal stem cells (ISC), impaired epithelial regeneration, and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, sepsis, and mortality. The high radiosensitivity of the intestinal epithelium limits effective radiotherapy against abdominal malignancies and limits the survival of victims of nuclear accidents or terrorism. Currently, there is no approved therapy to mitigate radiation toxicity in the intestine. Here we demonstrate that BCN057, an anti-neoplastic small molecular agent, induces ISC proliferation and promotes intestinal epithelial repair against radiation injury.MethodsBCN057 (90 mg/kg body weight, subcutaneously) was injected into C57Bl6 male mice (JAX) at 24 h following abdominal irradiation (AIR) and was continued for 8 days post-irradiation. BCN057-mediated rescue of Lgr5-positive ISC was validated in Lgr5-EGFP-Cre-ERT2 mice exposed to AIR. The regenerative response of Lgr5-positive ISC was examined by lineage tracing assay using Lgr5-EGFP-ires-CreERT2-TdT mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from surgical specimens of human colon or from mice jejunum and were used to examine the radio-mitigating role of BCN057 on ISC ex vivo. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test.ResultsTreatment with BCN057 24 h after a lethal dose of AIR rescues ISC, promotes regeneration of the intestinal epithelium, and thereby mitigates RIGS. Irradiated mice without BCN057 treatment suffered from RIGS, resulting in 100% mortality within 15 days post-radiation. Intestinal organoids developed from mice jejunum or human colon demonstrated a regenerative response with BCN057 treatment and mitigated radiation toxicity. However, BCN057 did not deliver radio-protection to mouse or human colon tumor tissue.ConclusionBCN057 is a potential mitigator against RIGS and may be useful for improving the therapeutic ratio of abdominal radiotherapy. This is the first report demonstrating that a small molecular agent mitigates radiation-induced intestinal injury by inducing ISC self-renewal and proliferation.Electronic supplementary materialThe online version of this article (10.1186/s13287-017-0763-3) contains supplementary material, which is available to authorized users.