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PubMed1996

Human papilloma virus, vulvar dystrophy, and vulvar carcinoma: differential expression of human papillomavirus and vulvar dystrophy in the presence and absence of squamous cell carcinoma of the vulva.

In situ hybridization (ISH) and polymerase chain reaction (PCR) for several common HPV types were performed on 41 cases of vulvar dystrophy, 19 of which were associated with previous or simultaneous invasive squamous cell carcinoma of the vulva. Three of the 19 cases (16%) of dystrophy associated with cancer were found to contain HPV-16/18 by PCR. In contrast, 12 of the 22 cases (55%) of dystrophy not associated with carcinoma contained HPV-16/18 by PCR (P < 0.01). A control group of 10 vulvar specimens without dystrophy or carcinoma was negative for all HPV types tested. ISH was negative for all HPV types in all 41 cases. The data confirm the association between vulvar carcinoma and hypertrophic/mixed dystrophy, and provide evidence for an association between HPV-16/18 and some cases of vulvar dystrophy. Cases of vulvar dystrophy not associated with HPV-16/18 may be at increased risk for the development of vulvar carcinoma.

Blotting, Southern↗
PubMed1997

Physical status and expression of HPV genes in cervical cancers.

It is known that E2 protein of oncogenic human papillomavirus (HPV) inhibits the expression of E6 and E7 genes from their major promoters in vitro and suppresses the proliferation of cervical cancer cells. This suggests that the loss of functional E2 gene may provide selective advantages in the development of cervical cancer. Investigation of the relationship between the disruption of HPV-16/18 E2 genes by DNA integration and clinical outcome of cervical cancer may not only help to understand the mechanism of HPV-related cervical carcinogenesis, but may also provide novel management of cervical cancer. It was noted that integrated HPV-16/18 DNA was predominant in most patients with cervical cancers, marking 51 of a total of 68 cases (75%); episomal HPV DNAs were found in 5 cases (7.4%), and finally mixed forms of HPV DNAs with episome and integration were found in 12 cases (17.6%). Whole portions of E2 DNA of HPV-16 could be amplified by PCR in 19 (36.5%) of 52 cases of cervical intraepithelial neoplasia. It was shown that there was not statistically significant association with the different stages, but integrated HPV DNAs were detectable only in the patients with far-advanced stage of cervical cancers, which also means no episomal forms were detected. Episomal forms of HPV DNA were detectable in 14 (25.9%) of 54 squamous cell carcinomas (4 pure episomal forms and 10 mixed forms), whereas only 1 (8.3%) of 12 adenocarcinomas and adenosquamous cell carcinomas contained episomal viral DNA. When HPV DNA forms were compared with initial tumor size, lymphovascular space involvement, and frequency of nodal metastasis, statistically significant relationships were not found. The association of DNA integration with invasive cervical cancers was seen regardless of HPV type; however, there were differences between the integration profiles of HPV-16 and HPV-18 DNA. Of the 51 HPV-16-containing cancers, 36 (70.6%) revealed purely integrated HPV DNA, and another 10 cases (19.6%) displayed both integrated and episomal HPV DNAs. However, 5 (9.8%) cases showed only episomal copies of the HPV-16 genome. In contrast, all 17 HPV-18-containing cancers (5 cases positive for HPV-18 and 12 cases positive for both HPV-16 and -18) revealed only the integrated form of HPV-18 DNA. The expression of E6 and E7 transcripts of HPV-16/18 is uniformly correlated with the physical status of HPV DNAs. HPV E2 mRNAs were constantly expressed in the presence of the intact virus in cases with episome and mixed forms of HPV DNA. In general, amplified signals from HPV E2 RT-PCR are more intensive than those from DNA-PCR in the same patients. It is suggested that RT-PCR is a valuable method to evaluate dynamic expression of the specific gene and seems to be more sensitive than the DNA-PCR method in detecting intact E2 gene because of the gene copy numbers.

Base Sequence↗
PubMed2000

Retrovirus-mediated delivery of HPV16 E7 antisense RNA inhibited tumorigenicity of CaSki cells.

OBJECTIVE: In cervical cancer, high-risk human papillomavirus (HPV) genes are expressed solely in cancerous cells and have been proposed to be the most important etiological factors for cervical cancer, thus making them suitable targets for gene therapy. In this study, we aim to inactivate the HPV16 E7 in CaSki cells and test the possibility of reducing the tumorigenicity of these cells. METHODS: The full-length HPV16 E7 cDNA was cloned in the pBabe-puro or pWZL-Hygro retrovirus vector in reverse orientation and was stably transfected into CaSki cells by replication-defective retrovirus infection giving rise to CaSki-E7AS and CaSki-E7AS2X cells. Immunoprecipitation/Western analysis and real-time RT-PCR were performed to document the levels of HPV16 E7 gene product. Flow cytometry was performed to study changes in the cell cycle in response to reduced E7 protein. The expression of bcl-2, RB, and E2F-1 was studied using Western blot analysis. Tumorigenicity of CaSki, CaSki-E7AS, and CaSki-E7AS2X cells was assayed with subepidermal tumor growth in nude mice. RESULTS: We have documented that the delivery of the antisense gene construct resulted in the reduction of HPV16 E7 protein expression and cell proliferation in CaSki cells. Furthermore, we demonstrated that these changes were accompanied by cell cycle arrest, up-regulation of RB, and down-regulation of E2F-1 and bcl-2 proteins. More importantly, dose-dependent transduction of the antisense HPV16E7 construct was able to inhibit and/or retard the tumorigenicity of CaSki cells in vivo. CONCLUSIONS: Down-regulation of HPV16 E7 with antisense RNA is beneficial in reducing the tumorigenicity of CaSki cells and can potentially be useful for HPV-associated malignancy gene therapy.

Animals↗
PubMed1995

Oncogene activation and oncogene cooperation in MMTV-induced mouse mammary cancer.

In this short review, we will give an overview of the various genes that can be activated by insertion of proviral DNA of the mouse mammary tumor virus during the formation of mammary cancer. These genes fall within three families: Wnt genes, FGF genes and Notch-related genes. We will summarize our current understanding of the roles of these genes in tumorigenesis and in normal development, and the mechanisms of action of their gene products. Finally, we will give some examples of cooperation between these genes in various biological settings.

Animals↗
PubMed1999

High levels of IL-4 and IL-10 mRNA and low levels of IL-2, IL-9 and IFN-gamma mRNA in MuLV-induced lymphomas.

The expression of cytokines may influence the development of lymphoma in retrovirally infected animals in at least two ways: (1) cytokines in the tumor environment may stimulate the proliferation of tumor cells and/or (2) cytokines in the tumor environment may diminish the cell-mediated antitumor immune response. To evaluate these possibilities, a semiquantitative RT-PCR approach was utilized to permit a broad screening of cytokine mRNAs in a large number of tissue samples. Examination of MuLV-induced end-stage lymphomas revealed the absence of mRNA for cytokines known to stimulate the proliferation of T cells (i.e., IL-2, IL-9), the absence of mRNA for cytokines known to enhance cell-mediated antitumor immune responses (i.e., IL-2, IFNgamma), and the presence of mRNA for cytokines known to diminish such responses (i.e., IL-4, IL-10). Similar patterns of cytokine mRNA expression were detected in tumor-derived cell lines. Spleen and thymus from animals collected longitudinally during infection and from age-matched uninfected mice also demonstrated a similar pattern, except that IFNgamma mRNA was readily detectable. These findings do not support the hypothesis that the developing tumor depends on cytokines to provide proliferative signals. The findings suggest that cytokines in the immediate environment of the lymphoma support tumor development by acting to diminish an effective antitumor immune response.

Animals↗
PubMed1996

Preservation of the bystander cytocidal effect of irradiated herpes simplex virus thymidine kinase (HSV-tk) modified tumor cells.

In vitro and animal experiments have demonstrated the potential efficacy of using the bystander effect alone in the treatment of brain tumors. A known problem in some in vitro and in vivo experiments is that a fraction of cells engineered to express the herpes simplex virus thymidine kinase (HSV-tk) gene survive ganciclovir (GCV) treatment and undergo cell division. To prevent the recurrent growth of HSV-tk+ cells in the presence of GCV we examined the potential use of lethal or sublethal irradiation of Walker 256 carcinosarcoma cells selected for expression of the HSV-tk gene (Walker-tk+). Western blot analysis of Walter-tk+ cells showed similar levels of HSV-tk protein expression at 0, 1, 3, 6 and 9 days after lethal gamma-irradiation. In vitro, there was no difference in the bystander effect exerted by non-irradiated, sublethally irradiated or lethally irradiated Walker-tk+ cells on wild-type Walker cells in the presence of GCV. In vivo experiments demonstrated long-term survival (100 days) in rats implanted intrathecally with sublethally or lethally irradiated Walker-tk+ cells with GCV treatments. Intrathecal implantation of irradiated Walker-tk+ cells either pre-mixed with Walker cells or used in in situ treatment of established Walker tumors resulted in prolonged animal survival compared to controls (p < 0.05). These experiments suggest that the bystander tumoricidal effect is preserved despite gamma-irradiation of the HSV-tk modified tumor cells and that irradiation could be an effective method to prevent long-term resistance to GCV in HSV-tk+ tumor cells.

Animals↗
PubMed1999

[The role of oncogenic human papillomaviruses in tonsillar squamous cell carcinomas with functional inactivation of the retinoblastoma protein].

In order to identify squamous cell carcinomas of the head and neck (HNSCC) with common biological and clinical features, we investigated the incidence and properties of carcinomas lacking retinoblastoma protein (pR6) cell cycle control. Of 208 HNSCC investigated, 23 (11%) showed a lack of pRb expression. The majority of these tumors (65%) were tonsillar carcinomas. The pRb-negative tonsillar tumors were all stage IV, had metastasized to lymph nodes at the time of diagnosis and were in general poorly differentiated or undifferentiated. Very significantly, the pRb-negative phenotype was strongly associated with the presence of oncogenic human papilloma viruses, implying a viral etiology and functional inactivation of pRb by the viral E7 oncoprotein. Despite the very adverse histopathological factors, patients with pRb-negative tonsillar carcinomas had a better clinical outcome, which was consistent with a uniform favorable responsiveness of these tumors to postoperative radiation therapy.

Carcinoma, Squamous Cell↗
PubMed2001

Expression pattern of AP-2 transcription factors in cervical cancer cells and analysis of their influence on human papillomavirus oncogene transcription.

The AP-2 family of transcription factors consists of three known members, namely AP-2alpha, AP-2beta, and AP-2gamma. In experimental systems AP-2 factors possess tumor suppressor-like activities, and alterations in the AP-2 expression pattern have been described for some tumor entities. In addition, AP-2 has been implicated in the transcriptional control of human papillomaviruses (HPVs). We investigated here the expression pattern of AP-2alpha, AP-2beta, and AP-2gamma, as well as that of the cellular AP-2 target gene c-erbB-2, in a series of cervical cancer cell lines. In addition, we analyzed the influence of AP-2 factors on the activity of the HPV16 and HPV18 E6/E7 oncogene promoter. We found that, with the exception of HPV-negative C33A cells, all investigated cervical cancer cell lines expressed all three AP-2 family members, although at varying levels. No linear correlation between AP-2 and c-erbB-2 levels was observed. Although AP-2alpha, AP-2beta, and AP-2gamma can activate the c-erbB-2 promoter in reporter gene assays, they do not stimulate the HPV16 or HPV18 E6/E7 promoter. These results indicate that, although a rare event, loss of AP-2 expression occurs in cervical cancer cells. Moreover, AP-2alpha, AP-2beta, and AP-2gamma are neither sufficient nor required to activate the viral E6/E7 promoter.

Antibody Specificity↗
PubMed2005

Suppression of Epstein-Barr nuclear antigen 1 (EBNA1) by RNA interference inhibits proliferation of EBV-positive Burkitt's lymphoma cells.

PURPOSE: Epstein-Barr virus (EBV) is associated with the development of several lymphoid and epithelial malignancies, including Burkitt's lymphoma. The EBV latent protein, EBV Nuclear Antigen 1 (EBNA1), is detectable in almost all types of EBV-associated tumors and is essential for replication and maintenance of the latent episome of EBV. We here examined whether the RNA interference (RNAi) technique could be employed to suppress expression of EBNA1 in EBV-positive Burkitt's lymphoma cells. METHODS: A Raji cell line expressing small hairpin RNAs (shRNAs) against EBNA1 was established and EBNA1 mRNA level was determined by real-time RT-PCR analysis. We investigated the effects of EBNA1 silence on lymphoma cell growth and cell cycle progression. RESULTS: Transfection of an EBNA1 RNAi plasmid resulted in substantial loss of EBNA1 mRNA and significantly inhibited proliferation of Raji cells relative to the control plasmid case. Suppression of EBNA1 was also associated with downregulation of EBV oncogene EBNA2, a decreased PCNA labeling index and increased G0/G1 fraction in cell cycle analysis. CONCLUSIONS: These findings point to potential therapeutic applications for vector-mediated siRNA delivery to control EBV-associated malignant disorders.

Apoptosis↗
PubMed1995

Pleural-based mesothelioma in immune competent rats: a model to study adenoviral gene transfer.

BACKGROUND: Despite multimodality approaches, pleural-based malignant mesothelioma remains a disease with a very poor prognosis. Novel therapeutic strategies such as gene therapy clearly are needed to improve the survival of patients with this neoplasm. To aid in the evaluation of new treatment strategies, animal models that closely mimic human disease are required. This article describes the establishment of a pleural-based model of malignant mesothelioma in immune-competent Fischer rats. METHODS: Via a modified left anterior lateral thorocotomy, a syngeneic malignant mesothelioma cell line, called II-45, was placed into the pleural cavity of Fischer rats. RESULTS: Placement of II-45 cells into the pleural cavity of Fischer rats results in a model of pleural mesothelioma that closely resembles the disease seen in patients and is highly reproducible, with animals dying within 1 month. We also demonstrate the feasibility of adenoviral-mediated gene transfer to normal mesothelial cells lining the pleural cavity, as well as to malignant cells deep within the substance of pleural-based malignant mesothelioma. CONCLUSIONS: The model described here offers the opportunity to study a variety of new treatment modalities, especially somatic gene transfer, against pleural-based malignant mesothelioma in an immune competent setting.

Adenoviridae↗
PubMed1992

Suboptimal and optimal activation signals modulate differently the expression of HIV-1 and cytokine genes.

Expression of HIV-1 and cytokine genes was investigated in chronically infected lymphocytic and promonocytic cell lines. As in normal human peripheral blood lymphocytes (PBL), a suboptimal activation signal with phorbol myristate acetate (PMA) did not trigger significant cytokine expression, whereas optimal activation signal (PMA + ionomycin) did. In contrast, a suboptimal activation was sufficient to up-regulate expression of HIV transcripts with kinetics similar to that observed in cells infected de novo by HIV. The level of HIV RNA in the promonocytic line was very low and markedly delayed when compared to the lymphocytic lines. We concluded that HIV induction required weaker activation signals than cytokine induction and that kinetics and level of HIV expression were not modified by induction of these cytokines. However, HIV expression appeared to alter the regulation of genes involved in proliferation and functional differentiation such as a decreased expression of IL-2 and IL-2R alpha and an increased expression of IFN gamma and TNF alpha mRNA.

Antigens, CD↗
PubMed1993

Study of Epstein-Barr virus early RNA 1 (EBER1) expression by in situ hybridization in thymic epithelial tumors of Chinese patients in Taiwan.

Forty-one thymic epithelial tumors from Chinese patients in Taiwan, including 14 noninvasive thymomas, seven invasive thymomas, and 20 thymic carcinomas, were investigated for the presence of Epstein-Barr virus transcripts by in situ hybridization using digoxigenin-labeled riboprobes for EBER1 expressions. None of the 14 noninvasive thymomas or seven invasive thymomas had detectable EBER1. Only one of 20 thymic carcinomas was positive for EBER1. This positive tumor was a lymphoepithelioma-like carcinoma found in a 19-year-old patient. Four different cases of lymphoepithelioma-like carcinoma were negative. Of note, the present case and all previously reported cases of Epstein-Barr virus-associated thymic carcinomas were lymphoepithelioma-like carcinomas. These results are consistent with those of several Western studies and do not support the view that there are geographic or racial differences affecting the role of Epstein-Barr virus in the pathogenesis of thymic epithelial tumors.

Adult↗
PubMed1995

Methylation of cottontail rabbit papillomavirus DNA and tissue-specific expression in transgenic rabbits.

Transgenic rabbits carrying multiple copies of CRPV genomic DNA were described previously (Peng et al. (1993) J. Virol. 67, 1698-1701). CRPV DNA was detectable in all tissues of the transgenic rabbits, however, the transcripts of CRPV genes only were found in skin and skin tumors. Tumor development was also restricted to skin. To study the mechanism involving tissue-specific expression of CRPV genes in rabbits, cellular DNAs, isolated from different normal tissues and skin tumors, were digested with the two isoschizomeric restriction endonucleases MspI (methylation resistant) and HpaII (methylation sensitive), respectively, and analyzed by Southern blot. CRPV DNA, especially its upstream regulatory region (URR), was extensively methylated in all normal tissues, but methylation was remarkably reduced in skin tumors. These data suggest that extensive methylation of CRPV genome, especially in the URR, might be a factor in controlling its tissue-specific expression.

5-Methylcytosine↗
PubMed1995

Differential gene expression in experimental hepatocellular carcinoma induced by woodchuck hepatitis B virus.

Hepatitis B virus infection is closely linked to hepatocellular carcinoma (HCC), the pathological mechanism of hepatocarcinogenesis by this virus is not well understood. In order to gain further insight into the molecular mechanism of HCC, we constructed and screened a subtracted c-DNA library which was specific to HCC cells of a woodchuck infected with woodchuck hepatitis B virus. Among eight clones that were isolated based on their differential expressions, we determined nucleotide sequences of two genes whose expressions were most significantly stimulated in HCC. Our results indicate that these two genes appear to be woodchuck counterpart genes of hemopexin (HPX) and alpha-1 acid glycoprotein (AGP), suggesting that the expression of HPX and AGP genes are strongly augmented in tumor cells partly due to transcriptional regulation.

Amino Acid Sequence↗