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Neuroblastoma arises from sympathoadrenal progenitors of the neural crest and expression of the neurotrophin receptor TrkB and its ligand, brain-derived neurotrophic factor (BDNF), is correlated with poor prognosis. Although activated TrkB signaling promotes a more aggressive phenotype in established neuroblastoma cell lines, whether TrkB signaling is sufficient to transform neural crest-derived cells has not been investigated. To address the role of TrkB signaling in malignant transformation, we removed two immunoglobulin-like domains from the extracellular domain of the full-length rat TrkB receptor to create a ΔIgTrkB that is constitutively active. In the pheochromocytoma-derived cell line PC12, ΔIgTrkB promotes differentiation by stimulating process outgrowth; however, in the rat neural crest-derived cell line NCM-1, ΔIgTrkB signaling produces a markedly transformed phenotype characterized by increased proliferation, anchorage-independent cell growth, anoikis resistance and matrix invasion. Furthermore, expression of ΔIgTrkB leads to the upregulation of many transcripts encoding cancer-associated genes including cyclind1, twist1 and hgf, as well as downregulation of tumor suppressors such as pten and rb1. In addition, ΔIgTrkB NCM-1 cells show a 21-fold increase in mRNA for MYCN, the most common genetic marker for a poor prognosis in neuroblastoma. When injected into NOD SCID mice, control GFP NCM-1 cells fail to grow whereas ΔIgTrkB NCM-1 cells form rapidly growing and invasive tumors necessitating euthanasia of all mice by 15 days post injection. In summary, these results indicate that activated TrkB signaling is sufficient to promote the formation of a highly malignant phenotype in neural crest-derived cells.
Avian leukosis virus (ALV) induces B-cell lymphomas and other malignancies in chickens through insertional activation of oncogenes, and c-myc activation has been commonly identified in ALV-induced tumors. Using ALV-transformed B-lymphoma-derived HP45 cell line, we applied in situ CRISPR-Cas9 editing of integrated proviral long terminal repeat (LTR) to examine the effects on gene expression and cell proliferation. Targeted deletion of LTR resulted in significant reduction in expression of a number of LTR-regulated genes including c-myc. LTR deletion also induced apoptosis of HP45 cells, affecting their proliferation, demonstrating the significance of LTR-mediated regulation of critical genes. Compared to the global effects on expression and functions of multiple genes in LTR-deleted cells, deletion of c-myc had a major effect on the HP45 cells proliferation with the phenotype similar to the LTR deletion, demonstrating the significance of c-myc expression in ALV-induced lymphomagenesis. Overall, our studies have not only shown the potential of targeted editing of the LTR for the global inhibition of retrovirus-induced transformation, but also have provided insights into the roles of LTR-regulated genes in ALV-induced neoplastic transformation.
Agmatine is an endogenous polyamine formed by the decarboxylation of L-arginine. We investigated the protective effects of agmatine against hypoxia-induced apoptosis of immortalized rat retinal ganglion cells (RGC-5). RGC-5 cells were cultured in a closed hypoxic chamber (5% O2) with or without agmatine. Cell viability was determined by lactate dehydrogenase (LDH) assay and apoptosis was examined by annexin V and caspase-3 assays. Expression and phosphorylation of mitogen-activated protein kinases (MAPKs; JNK, ERK p44/42, and p38) and nuclear factor-kappa B (NF-kappaB) were investigated by Western immunoblot analysis. The effects of agmatine were compared to those of brain-derived neurotrophic factor (BDNF), a well-known protective neurotrophin for retinal ganglion cells.
Epidemiological evidence supports that infection with high-risk types of human papillomavirus (HPV) can interact with host and environmental risk factors to contribute to the development of cervical, oropharyngeal, and other anogenital cancers. In this study, we established a mouse epithelial cancer cell line, designated as Chinese University Papillomavirus-1 (CUP-1), from C57BL/KsJ mice through persistent expression of HPV-16 E7 oncogene. After continuous culturing of up to 200 days with over 60 passages, we showed that CUP-1 became an immortalized and transformed epithelial cell line with continuous E7 expression and persistent reduction of retinoblastoma protein (a known target of E7). This model allowed in-vivo study of interaction between HPV and co-factors of tumorigenesis in syngeneic mice. Diabetes has been shown to increase HPV pathogenicity in different pathological context. Herein, with this newly-established cell line, we uncovered that diabetes promoted CUP-1 xenograft growth in syngeneic db/db mice. In sum, we successfully established a HPV-16 E7 transformed mouse epithelial cell line, which allowed subsequent studies of co-factors in multistep HPV carcinogenesis in an immunocompetent host. More importantly, this study is the very first to demonstrate the promoting effect of diabetes on HPV-associated carcinogenesis in vivo, implicating the importance of cancer surveillance in diabetic environment.
Müller cells (MCs), the major type of glial cell of the vertebrate retina, have a vital role in retinal physiology and pathology. They provide structural and functional support for retinal neurons, including photoreceptors, and are implicated in various retinal diseases. Primary and immortalized MCs are important experimental tools for MC research. Here we present high throughput RNA sequencing data of 3 populations of cultured rat MCs: primary cells, the spontaneously immortalized rat MC line, SIRMu-1, and the SV40-transformed rat MC line, rMC-1. These data were deposited in NCBI Gene Expression Omnibus (GEO ID: GSE123161). For data analysis, interpretation and discussion, please refer to the research article, "Characterization of the novel spontaneously immortalized rat Müller cell line SIRMu-1" (Kittipassorn et al., 2019). This dataset is valuable for gaining insight into gene expression profiles of different types of cultured MCs and the roles of MCs in health and disease.
2'-Z auraptene (1) is a synthesized monoterpene coumarin with anticancer activity against human gastric cancer cells. In order to find new potential anticancer agent, Mucor polymorphosporus was used to transform cis-auraptene. Four new terpene coumarins with notable changes in the skeletal backbone, 2'-Z auraptene A-D (2-5), were obtained and evaluated for their antiproliferative effects against human normal gastric epithelium cells and human gastric cancer cells. These new compounds showed selective cytotoxic activity against MGC-803 cells with IC50 values from 0.78 ± 0.13 to 10.78 ± 1.83 μM and the therapeutic index could also be significantly improved (TI = 59.0) compared with that of 1 (TI = 5.5). The structures of these metabolites were elucidated through extensive spectroscopic methods, and the possible biotransformation pathway of 1 by Mucor polymorphosporus was also proposed. Furthermore, the mechanism of the antiproliferative effects against MGC-803 cells of the most potent compound, 2'-Z auraptene A (2), was characterized. Annexin V/PI staining and abnormal expression of apoptosis-related protein suggested that compound 2 induces apoptosis in gastric cancer MGC-803 cells. Therefore, it is possible that compound 2 has the potential to be applied in gastric cancer therapy.
Muscle invasive urothelial carcinomas are divided into various molecular subtypes with basal and luminal subtypes being the prominent ones. The basal muscle-invasive urothelial carcinomas are generally more aggressive at presentation and significantly enriched with squamous features. Our laboratory has developed an in-vitro model of urothelial cancer by transforming the immortalized cell line UROtsa with arsenite (As3+) and cadmium (Cd2+). In this study, we characterized the tumors formed by these transformed cell lines as more basal-like based on their gene expression patterns with increased expression of KRT1, KRT5, KRT6, KRT14, KRT16, KRT17 and CD44. In addition, histological examination of these tumor transplants showed squamous features enriched in basal muscle invasive urothelial carcinomas. The expression of these genes increased in the transformed cell lines as well as in the urospheres, which are putative cancer initiating cells/stem cells derived from the cell lines. There was also increased expression of these genes in the urospheres derived from the parent UROtsa cell line. Thus, our data shows that the As3+ and Cd2+-transformed cell lines and their derived tumor transplants have gene expression profiles similar to the basal subtype of muscle invasive bladder carcinomas with tumors having enriched squamous features. The increased expression of basal markers in the urospheres suggests that stem cells may be involved in the development of squamous differentiation seen in some of the muscle invasive bladder carcinomas.
Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1alpha,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown.
Marek's disease (MD) is caused by the oncogenic Marek's disease virus (MDV), and is a highly contagious avian infection with a complex underlying pathology that involves lymphoproliferative neoplasm formation. MicroRNAs (miRNAs) act as oncogenes or tumor suppressors in most cancers. The gga-miR-155 is downregulated in the MDV-infected chicken tissues or lymphocyte lines, although its exact role in tumorigenesis remains unclear. The aim of this study was to analyze the effects of gga-miR-155 on the proliferation, apoptosis and invasiveness of an MDV-transformed lymphocyte line MSB1 and elucidate the underlying mechanisms.
As a factor contributing to the tumor cell drug resistance, tumor microenvironment (TME) is being paid increasingly attention. However, the drug resistance of malignantly transformed cells in TME has rarely been revealed. This paper is designed to investigate the sensitivity of malignantly transformed cell line (ihDCTC) induced by glioma stem cells (GSCs) in TME to chemotherapeutic drugs.
Increasing evidence suggests a possible relationship between mesenchymal stem cells (MSCs) and sarcoma. MSCs are hypothesized to be the cells initiating sarcomagenesis, and cancer stem cells (CSCs) sharing features of MSCs have been identified in sarcomas. Here, we report on the characteristics of a bone marrow-derived rat mesenchymal stem cell line that spontaneously transformed in long-term culture. The rat transformed mesenchymal stem cells (rTMSCs) produced soft-tissue fibrosarcomas in immunocompromised mice and immunocompetent rats. In vitro, the rTMSCs displayed increased proliferation capacity compared to the untransformed cell line. The transformed MSCs maintained the mesenchymal phenotype by expression of the stem cell marker CD 90 and the lack of hematopoietic and endothelial markers. Cytogenetic analysis detected trisomy 6 in the rTMSCs. Side population (SP) isolation and tumorsphere cultivation of the transformed cells confirmed the presence of CSCs among the rTMSCs. Importantly, the rTMSCs retained their differentiation capacity towards osteogenic and adipogenic lineages. This transformed MSC-based cell line may be valuable in examining the balance in a mixed cell population between cancer stem cell properties and the ability to differentiate to specific non-transformed cell populations. Moreover, it may also be a useful tool to evaluate the efficacy of novel targeted immunotherapies in vivo.
Presence of unperfused regions containing cells under hypoxia and nutrient starvation contributes to radioresistance in solid human tumors. It is well known that hypoxia causes cellular radioresistance, but little is known about the effects of nutrient starvation on radiosensitivity. We have reported that nutrient starvation induced decrease of mTORC1 activity and decrease of radiosensitivity in an SV40-transformed human fibroblast cell line, LM217, and that nutrient starvation induced increase of mTORC1 activity and increase of radiosensitivity in human liver cancer cell lines, HepG2 and HuH6 (Murata et al., BBRC 2015). Knockdown of mTOR using small interfering RNA (siRNA) for mTOR suppressed radiosensitivity under nutrient starvation alone in HepG2 cells, which suggests that mTORC1 pathway regulates radiosensitivity under nutrient starvation alone. In the present study, effects of hypoxia and nutrient starvation on radiosensitivity were investigated using the same cell lines.
Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are resistant to reprogramming. Epigenetic barriers must block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using oncogenic transgenes and discovered transformed cell lines compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed at an early stage, whilst other lines seemed to progress through a conventional reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperacetylated active epigenetic state. This study reveals that diverse epigenetic barriers underly resistance to reprogramming of transformed cells.
Epstein-Barr virus (EBV) transforms human peripheral B cells into lymphoblastoid cell lines (LCLs) that secrete specific antibodies. In contrast to peripheral blood B cells, LCLs express the activation-induced cytidine deaminase (AID) gene, a key enzyme in the generation of somatic hypermutation (SHM) in immunoglobulin variable genes. We have previously studied an LCL that secretes a rheumatoid factor (RF: an IgM(lambda) anti-IgG antibody) and identified the accumulation of SHM at a frequency of 1.5 x 10(-3)mut/bp in the rearranged variable region heavy chain gene (VH) of its RF sub-culture (i.e., RF-2004). The aim of the present work was to find out whether SHM was initiated as an early event following EBV transformation. Our results show that already the earliest RF-culture (RF-1983) mutates its VH at a somewhat higher frequency of 1.9 x 10(-3). Overall, we detected 17 point mutations in the RF-2004 culture and in 26 cellular clones derived from the RF-1983 and RF-2004 cultures. Most of the mutations were due to C to T or G to A transitions, with preferential targeting to WRCH/DGYW hotspot motifs, indicating that they were due to the initial phase of AID-directed mutations. A genealogical tree demonstrates that mutations were accumulated in a stepwise manner with 1-2 mutations per cell division. However, no mutations were found in the rearranged V-lambda (Vlambda) gene in the same RF-cultures and their subclones (i.e., <1.2 x 10(-4)mut/bp). To our knowledge this is the first reported clonal cell line that generates SHM in the VH, but not in the Vlambda. It may be due to abrogation of a cis-regulatory element(s) in the Vlambda or to a lack of a specific trans-acting factor which differentially direct the SHM machinery to this gene. Out of the 17 point mutations detected in both cell lines there were, 1 stop codon, 3 mutations which obliterated the binding of the RF antibody to its IgG antigen and 1 or 2 mutations which enhanced antigen-binding affinity. These results show that the evolutionary developed germline encoded antibody combining site is highly sensitive to amino acid replacements. Our combined findings that the RF cells accumulate in a stepwise manner up to 1-2 point mutations/sequence per cell division and the generation of high percentage of functionally deleterious mutations, are in accord with the 'multiphase-recycling model' of SHM, which states that B cells in the germinal center are subjected to multiple rounds of somatic mutations interchanged with periods of antigenic selection.
Adenosine (A) to inosine (I) RNA editing is the most prevalent RNA editing mechanism in humans and plays critical roles in tumorigenesis. However, the effects of radiation on RNA editing were poorly understood, and a deeper understanding of the radiation-induced cancer is imperative. Here, we analyzed BEP2D (a human bronchial epithelial cell line) and radiation-induced malignantly transformed cell lines with next generation sequencing. By performing an integrated analysis of A-to-I RNA editing, we found that single-nucleotide variants (SNVs) might induce the downregulation of ADAR2 enzymes, and further caused the abnormal occurrence of RNA editing in malignantly transformed cell lines. These editing events were significantly enriched in differentially expressed genes between normal cell line and malignantly transformed cell lines. In addition, oncogenes CTNNB1 and FN1 were highly edited and significantly overexpressed in malignantly transformed cell lines, thus may be responsible for the lung cancer progression. Our work provides a systematic analysis of RNA editing from cell lines derived from human bronchial epithelial cells with high-throughput RNA sequencing and DNA sequencing. Moreover, these results provide further evidence for RNA editing as an important tumorigenesis mechanism.
The human REL proto-oncogene encodes a transcription factor in the nuclear factor (NF)-kappaB family. Overexpression of REL is acutely transforming in chicken lymphoid cells, but has not been shown to transform any mammalian lymphoid cell type. In this report, we show that overexpression of a highly transforming mutant of REL (RELDeltaTAD1) increases the oncogenic properties of the human B-cell lymphoma BJAB cell line, as shown by increased colony formation in soft agar, tumor formation in SCID (severe combined immunodeficient) mice, and adhesion. BJAB-RELDeltaTAD1 cells also show decreased activation of caspase in response to doxorubicin. BJAB-RELDeltaTAD1 cells have increased levels of active nuclear REL protein as determined by immunofluorescence, subcellular fractionation and electrophoretic mobility shift assay. Overexpression of RELDeltaTAD1 in BJAB cells has transformed the gene expression profile of BJAB cells from that of a germinal center B-cell subtype of diffuse large B-cell lymphoma (DLBCL) (GCB-DLBCL) to that of an activated B-cell subtype (ABC-DLBCL), as evidenced by increased expression of many ABC-defining mRNAs. Upregulated genes in BJAB-RELDeltaTAD1 cells include several NF-kappaB targets that encode proteins previously implicated in B-cell development or oncogenesis, including BCL2, IRF4, CD40 and VCAM1. The cell system we describe here may be valuable for further characterizing the molecular details of REL-induced lymphoma in humans.
Colorectal cancer (CRC) is the fourth most lethal disease worldwide. Despite an urgent need for therapeutic advance, selective target identification in a preclinical phase is hampered by molecular and metabolic variations between cellular models. To foster optimal model selection from a translational perspective, we performed untargeted ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry-based polar metabolomics and lipidomics to non-transformed (CCD841-CON and FHC) and transformed (HCT116, HT29, Caco2, SW480 and SW948) colon cell lines as well as tissue samples from ten colorectal cancer patients. This unveiled metabolic signatures discriminating the transformed from the non-transformed state. Metabolites involved in glutaminolysis, tryptophan catabolism, pyrimidine, lipid and carnitine synthesis were elevated in transformed cells and cancerous tissue, whereas those involved in the glycerol-3-phosphate shuttle, urea cycle and redox reactions were lowered. The degree of glutaminolysis and lipid synthesis was specific to the colon cancer cell line at hand. Thus, our study exposed pathways that are specifically associated with the transformation state and revealed differences between colon cancer cell lines that should be considered when targeting cancer-associated pathways.
The shrub Thuja orientalis is extensively used as a herbal medicine in Korea and China. In the present study extracts of the plant were subjected to fractionation and purification, with seven compounds (myricitrin, isoquercitrin, hypoletin-7-O-β-D-xylopyranoside, quercitrin, kaempferin, kaempferol, and amentoflavone) being isolated. Of these seven compounds, isoquercitrin was found to be the most effective at attenuating the death of RGC-5 cells in culture caused by exposure to hydrogen peroxide (H(2)O(2)). It was found that an insult of H(2)O(2) to RGC-5 cells caused them to die by apoptosis, demonstrated not only by staining dead cells for phosphatidylserine but also by the up-regulation (cleaved PARP, AIF, p53) and down-regulation (Bcl-2) of proteins associated with apoptosis and survival. Subsequent studies showed that isoquercitrin acts as a powerful antioxidant. It scavenges ROS generally as demonstrated by staining of cultures as well as the generation of individual radical species (H(2)O(2), OH* and O(2)(*-)). Moreover, isoquercitrin reduced the depletion of glutathione (GSH) caused by elevation of specific radical species (H(2)O(2), OH* and O(2)(*-)) in RGC-5 cells in culture and blunted the decrease in catalase and glutathione peroxidase 1 (Gpx-1) caused by exposure of RGC-5 cells to H(2)O(2). Furthermore, isoquercitrin potently attenuated the lipid peroxidation of rat brain homogenates initiated by nitric oxide, with an IC(50) value of 1.04 μM. Since isoquercitrin can be tolerated when taken orally it is suggested that this substance might reach the retina and therefore be potentially useful for treating glaucoma, in which oxidative stress is thought to play a major role in the demise of retinal ganglion cells.
Recent studies using direct live cell imaging have reported that individual B lymphocytes have correlated transit times between their G1 and S/G2/M phases. This finding is in contradiction with the influential model of Smith and Martin that assumed the bulk of the total cell cycle time variation arises in the G1 phase of the cell cycle with little contributed by the S/G2/M phase. Here we extend these studies to examine the relation between cell cycle phase lengths in two B lymphoma cell lines. We report that transformed B lymphoma cells undergo a short G1 period that displays little correlation with the time taken for the subsequent S/G2/M phase. Consequently, the bulk of the variation noted for total division times within a population is found in the S/G2/M phases and not the G1 phase. Models that reverse the expected source of variation and assume a single deterministic time in G1 followed by a lag + exponential distribution for S/G2/M fit the data well. These models can be improved further by adopting two sequential distributions or by using the stretched lognormal model developed for primary lymphocytes. We propose that shortening of G1 transit times and uncoupling from other cell cycle phases may be a hallmark of lymphocyte transformation that could serve as an observable phenotypic marker of cancer evolution.
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