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BACKGROUND Glioblastoma (GBM) is one of the most common primary brain tumors, which accounts up to 80% of malignant brain tumors and the 5-year relative survival rate is below 5%. Recent studies showed that the lipid metabolism played an essential role in GBM development. As a peroxisome proliferators-activated receptors γ (PPAR-γ) agonist, telmisartan improves the lipid metabolism and has been used to treat hypertension for long time. It has also been shown to have anticancer function, such as in lung cancer and melanoma. METHODS Incucyte real-time live cell imaging system was used to assess the effect of telmisartan on glioma cell lines U87 and U251 proliferation. Transwell assay and colony formation assay were conducted to detect the effect of telmisartan on oncogenicity of GBM cell lines. Western blot and immunofluorescence analysis were used to detect the effect of telmisartan on the expression of PPAR-γ and hydroxyacyl-coenzyme A dehydrogenase alpha subunit (HADHA). RESULTS We demonstrate that telmisartan inhibits two glioma cell lines U87 and U251 proliferation in a time- and dose-dependent manner, and arrests the cell cycle at S phase. We further show that telmisartan decreases the oncogenicity of GBM cell lines. Our data show that telmisartan treatment significantly increases the PPAR-γ expression level, enhances the lipid oxidation, and upregulates the level of fatty acid oxidation key enzyme HADHA. CONCLUSIONS Telmisartan inhibits the proliferation and oncogenicity while it also increases the lipid oxidation of human GBM cells.

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment.

MicroRNAs (miRNAs) act as crucial regulators of biological pathways/processes by reinforcing transcriptional programs and moderating transcripts. Emerging evidences have shown the involvement of dysregulated miRNAs in pathophysiology of human diseases including several cancer types. Recently, miR-197-3p has been reported to play different roles in different cancers; however, its role in fibrosarcoma, a highly aggressive and malignant soft tissue sarcoma originated from the mesenchymal tissues, has not yet been studied. Therefore, this study aims to investigate the possible regulatory roles of miR-197-3p in the oncogenicity of fibrosarcoma. For this, we initially performed qRT-PCR of miR-197-3p, which we found to be downregulated in HT1080 human fibrosarcoma cells compared with IMR90-tert normal fibroblast cells. Subsequently, we performed gain-of-function study by employing several methods such as MTT assay, clonogenic assay, wound healing, flow cytometry cell cycle analysis, and acridine orange staining after transfecting HT1080 cells with miR-197-3p mimic. From these assays, we observed that miR-197-3p significantly inhibits viability, colony forming, and migration ability as well as triggers G2/M phase cell cycle arrest and autophagy in fibrosarcoma cells. To understand the mechanism through which miRNA performs these functions, we predicted its targets using TargetScan and performed pathway enrichment analysis after screening them by their expression in fibrosarcoma. Among the enriched targets, we found RAN (ras-related nuclear protein) to be a crucial target through which miR-197-3p represses tumorigenesis by binding to its 3´ UTR, validated by luciferase reporter assay. The tumor suppressive role of the miRNA was further confirmed by transfecting its mimic in RAN-overexpressed cells which showed significant attenuation in tumorigenic effect of RAN in fibrosarcoma as seen in different assays. Taken together, our study unveiled that miR-197-3p acts as an oncosuppressor in fibrosarcoma through G2/M phase arrest and induction of autophagy, and raises the possibility to act as a novel therapeutic intervention for the malignancy.

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase (RPTK), plays an oncogenic role by activating an unidentified TKI-258 (dovitinib)-sensitive RPTK in esophageal squamous cell carcinoma (ESCC) cells. Here, we demonstrate that among TKI-258–sensitive RPTKs, fibroblast growth factor receptor (FGFR) 1 is significantly up-regulated in ESCC tissues and cell lines. We show that PTK7 colocalizes with FGFR1 and binds it via its extracellular domain in human embryonic kidney 293 and ESCC TE-10 cells. PTK7 knockdown not only reduced ligand-free and fibroblast growth factor (FGF)-induced phosphorylation of FGFR1 but also the interaction of signaling adaptor proteins with FGFR1 and activation of downstream signaling proteins in TE-10 cells. In addition, PTK7 knockdown reduced FGF-induced oncogenic phenotypes including proliferation, anchorage-independent colony formation, wound healing, and invasion in ESCC cells. Taken together, our data demonstrate that PTK7 binds and activates FGFR1 independent of FGF and thus increases oncogenicity of PTK7- and FGFR1-positive cancers such as ESCC.—Shin, W.-S., Lee, H. W., Lee, S.-T. Catalytically inactive receptor tyrosine kinase PTK7 activates FGFR1 independent of FGF.

Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide. This study clarified the oncogenic role of miR-134 in OSCC. Reporter assays, using both wild-type and mutant constructs, confirmed that Programmed Cell Death 7 (PDCD7) gene was a potential target of miR-134. The OSCC cells exogenously expressed miR-134 exhibited reduced PDCD7 expression. As expected, exogenous miRZip-134 expression increased PDCD7 expression in the OSCC cells; additionally, PDCD7 expression suppressed the oncogenicity of the OSCC cells. By contrast, PDCD7 knockout through gene editing increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 transactivated E-cad expression via the GC-box in the promoter. Moreover, miR-134-associated cellular transformation and E-cad downregulation was attenuated by PDCD7. Downregulation of both PDCD7 and E-cad and high levels miR-134 expression was observed in OSCC tumor tissues. Activation of the miR-134-PDCD7-E-cad pathogenesis cascade occurred early during the human and murine oral carcinogenesis process. In conclusion, the oncogenic effect of miR-134 in oral carcinoma is mediated by reducing PDCD7 and E-cad expression.

Objective Heightened levels of sEcad are found in the serum of patients with cancer and correlate with an unfavorable prognosis and later-stages of disease. In this study, we explored whether sEcad is elevated in human OPSCC specimens and FaDu cells. Additionally, we investigated sEcad-EGFR and sEcad-IGF-1R interactions and performed a functional analysis of sEcad in OPSCC cancers. Materials and Methods sEcad, EGFR, and IGF-1R levels were examined in human OPSCC specimens and cells by immunoblotting. sEcad-EGFR and sEcad-IGF-1R interactions were examined by immunoprecipitation and immunoblot assays. Levels of sEcad on EGFR and IGF-1R pathway components were evaluated by IB. The effects of sEcad on OPSCC proliferation, migration, and invasion were assessed using standard cellular assays. Results Statistical analysis demonstrated that sEcad levels were significantly higher in OPSCC primary tumors and cells compared with normal controls. IP studies indicated that sEcad associated with EGFR and IGF-1R, and addition of sEcad resulted in a statistically significant increase in downstream signaling. Finally, cell-based assays demonstrated enhanced sEcad-induced proliferation, migration, and invasion, which was blocked by EGFR and IGF-1R inhibitors. Conclusions These findings suggest that sEcad may play an important role in OPSCC oncogenicity via its interaction and activation of EGFR and IGF-1R.

The phosphatases of regenerating liver (PRLs) are an intriguing family of dual specificity phosphatases due to their oncogenicity. The three members are small, single domain enzymes. We provide an overview of the phosphatases of regenerating liver, compare them to related phosphatases, and review recent reports about each phosphatase. Finally, we discuss similarities and differences between the phosphatases of regenerating liver, focusing on their molecular mechanisms and signalling pathways.

Sarcomas comprise some of the most aggressive solid tumours that, for the most part, respond poorly to chemo- and radiation therapy and are associated with a sombre prognosis when surgical removal cannot be performed or is incomplete. Partly because of their lower frequency, sarcomas have not been studied as intensively as carcinomas and haematopoietic malignancies, and the molecular mechanisms that underlie their pathogenesis are only beginning to be understood. Even more enigmatic is the identity of the primary cells from which these tumours originate. Over the past 25 years, however, several non-random chromosomal translocations have been found to be associated with defined sarcomas. Each of these translocations generates a fusion gene believed to be directly related to the pathogenesis of the sarcoma in which it is expressed. The corresponding fusion proteins provide a unique tool not only to study the process of sarcoma development, but also to identify cells that are permissive for their putative oncogenic properties. This is the first of two reviews that cover the mechanisms whereby specific fusion/mutant gene products participate in sarcoma development and the cellular context that may provide the necessary permissiveness for their expression and oncogenicity. Part 1 of the review focuses on sarcomas that express fusion genes containing TET gene family products, including EWSR1, TLS/FUS, and TAFII68. Part 2 (J Pathol 2007; DOI: 10.1002/path.2008) summarizes our current understanding of the genetic and cellular origins of sarcomas expressing fusion genes exclusive of TET family members; it also covers soft tissue malignancies harbouring specific mutations in RTK-encoding genes, the prototype of which are gastrointestinal stromal tumours (GIST).

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control. Despite decades of research, the function of other viral proteins still remains unclear. While prophylactic vaccines to block genital HPV infection will soon be available, the widespread nature of HPV infection requires greater understanding of both the HPV life cycle as well as the mechanisms underlying HPV-induced carcinogenesis.

Turkey poults were inoculated with lymphoproliferative disease virus (LPDV) of turkey, and the organotropism of the inoculated virus was determined from the kinetics of virus expression and tumor formation. Molecular hybridization experiments, conducted to determine the level of viral RNA expression in the various organs of infected birds, established lymphoid tissues, including bone marrow, as the target for LPDV infection. Of these, bone marrow was the first to be infected but subsequently virus replication extended to the thymus, the spleen and the bursa Of Fabricius. The low level of LPDV expression in non-target organs probably stemmed from infiltration of infected lymphatic cells. The fact that the main organs for virus replication were not invariably the ones most clinically involved suggests that the target cells for virus infection need not necessarily be the targets for virus oncogenicity. A possible mode for LP[DV infection and transformation is proposed.

Rat embryo cells were transformed by adenovirus type 2 at different multiplicities of infection. The oncogenic potential of the resulting transformed lines varied considerably but a relationship was found to exist between transforming virus dose and oncogenicity of the resulting transformed lines. Possible reasons for the considerable variation in oncogenicity of the transformed lines are discussed, giving particular consideration to cellular antigenicity and recent molecular biology studies of adenovirus type 2 transformed cell lines.

Scientists must consider not only the direct hazards of virulence or oncogenicity in genetic research but the possibility of indirect harm or costs. This 2nd-order or world-view effect is the concept whereby the kinds of models that society adapt influence their ideas about the casual ordering of the world. A genetic model encourages a view containing moral assumptions about the relationship of people to their environment and responsibility for their disease or behavior not tenable from an environmental standpoint. 3 related questions are: 1) possible human costs by erroneously or prematurely incorporating unsubstantiated genetic models into social policy 2) potential costs of inappropriately utilizing valid genetic models of behavior or disability and 3) costs to using genetic models per se for studying human traits or behaviors. Genetic hypotheses are usually tentative to facilitate investigation into complex areas. Nonscientists may move such theory into the area of social policy reordering our values and social priorities to the detriment of our society.

A chicken lymphoblastoid cell line (TLT)-6855 originally established from an avian oncornavirus-induced lymphoma (Siegfried and Olson, 1972) was studied for the presence and expression of Marek's disease virus (MDV) genome. By nucleic acid hybridization a significant amount of MDV DNA was found in this cell line. This virus DNA, however, was not expressed in either virus-specific intracellular or membrane antigens or the MD-associated tumour-specific surface antigen (MATSA). Moreover, MDV-specific antigens could not be activated in this cell line by treatment with 5-IdUrd. In several experiments, when chickens were inoculated with the cell line a herpesvirus was repeatedly isolated from the kidneys. This herpesvirus was antigenically similar to MDV but was low in oncogenicity for chickens.

Subcutaneous hamster tumors induced by Simian adenovirus SA7, strains C8, B105 and C626, were found to be poorly differentiated sarcomas having morphological features which distinguish them from tumors induced at the same site by papovaviruses and the Rous sarcoma virus. In general, the adenovirus-induced tumors were morphologically alike, C8-induced sarcomas showing some differences. Tumors induced by this strain in the subcutaneous tissue, muscles, peritoneum and mediastinum were morphologically identical. Tumors found in the brain were mainly malignant ependymomas and choroid plexus carcinomas, generally originating in neuroectoderm. The oncogenicity of adenovirus SA7 (C8) in meso- and ectodermal cells has thus been demonstrated.

Virus variants from Af mouse tumours induced by syngeneic cultured cells infected with Carr-Zilber strain of Rous sarcoma virus were studies. These variants were highly oncogenic for adult mice and golden hamsters thus differing from the original Carr-Zilber strain. The coat antigens of these viruses were not different from those of the original strain. By means of fusion with normal chicken fibroblasts an RSV variant was isolated from transformed non-malignant cultures. This virus did not differ, in its oncogenicity for adult hamsters and mice, from variants isolated from mouse tumours. Mutants du virus de Rous On a etudie les mutants de virus isoles sur des tumeurs de souris Af induites au moyen de cultures de cellules syngeneiques infectees par la souche Carr-Zilber du virus du sarcome de Rous. Ces mutants sont fortement oncogenes envers les souris et les hamsters dores adultes et different ainsi de la souche Carr-Zilber initiale. Les antigenes de couverture de ces virus sont analogues a ceux de la souche initiale. Par fusion avec des fibroblastes de poulets normaux, on a isole un mutant du VSR dans des cultures transformees non malignes. Ce virus n'etait pas different — de par son oncogenicite envers les hamsters et les souris adultes — des mutants isoles dans des tumeurs de souris.

A cytopathic effect was induced by the Schmidt-Ruppin strain of Rous sarcoma virus (RSV-SR) in five of nine rat tumor cell lines tested in vitro. The cells showed irreversible cytopathic change as early as 24-48 h after infection. Of the leukemogenic and tumorigenic viral agents tested, only RSV-SR induced the rapid Rous cytopathic effect. Virus was recovered 8 days after inoculation of the tumor cell lines XC and M41. The effect was neutralized by specific anti-RSV-SR antiserum. Correlation between oncogenicity of the rat tumor lines in the syngeneic host and their susceptibility to RSV-SR was incomplete.

Cultures of cells from embryos of Af, C3H-Hp/2 and (CBAT6T6 × Af)F1 mice rapidly developed oncogenicity for syngeneic animals after exposure to RSV (Carr-Zilber strain). The tumours of mice were virogenic and contained the group-specific antigen of avian sarcoma-leukosis complex. However, when the infected cells became transformed in morphology, they lost their oncogenicity for syngeneic animals. Transformation par le VSR Des cultures de cellules d'embryons de souris Af, C3H - H1 et (CBAT6T6 × Af) F2 sont rapidement devenues oncogenes envers les animaux syngeneiques apres exposition au VSR (souche Carr-Zilber). Les tumeurs des souris etaient virogenes et contenaient l'antigene specifique de groupe du complexe sarcome-leucose aviaire. Toutefois, lorsque les cellules infectees se sont transformees morphologiquement, elles ont perdu leur oncogenicite envers les animaux syngeneiques.