Differentially expressed genes between oncogene-transformed and non-transformed fetal liver progenitor cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: E-GEOD-43991 | BioStudies |
REPOSITORIES: biostudies
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Project description:The activation of different oncogenic signals may primarily contribute to the heterogeneity of cancer cells. However, the exact mechanisms underlying different oncogenic transformation are still unclear. We used the c-Myc, H-Ras and Akt transformed liver cell model to define mRNA expression profiles in the non-transformed and the three types of oncogene-transformed cells Purified p53-/- mouse fetal liver progenitor cells were transformed by three oncogenic genetic factors, c-Myc, H-RasV12 and myristoylated-AKT1(myr-Akt). The gene expression profilings of transformed cells and control cells were analyzed through microarray.
2013-02-02 | E-GEOD-43991 | ArrayExpress
Project description:At the initial stage of carcinogenesis, when RasV12-transformed cells are surrounded by normal epithelial cells, RasV12 cells are apically extruded from epithelia through cell competition with the surrounding normal cells. In this study, we demonstrate that expression of cyclooxygenase (COX)-2 is upregulated in normal cells surrounding RasV12-transformed cells. Addition of COX inhibitor or COX-2-knockout promotes apical extrusion of RasV12 cells. Furthermore, production of Prostaglandin (PG) E2, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE2 suppresses apical extrusion of RasV12 cells. In a cell competition mouse model, expression of COX-2 is elevated in pancreatic epithelia harbouring RasV12-exressing cells, and the COX inhibitor ibuprofen promotes apical extrusion of RasV12 cells. Moreover, caerulein-induced chronic inflammation substantially suppresses apical elimination of RasV12 cells. These results indicate that intrinsically or extrinsically mediated inflammation can promote tumour initiation by diminishing cell competition between normal and transformed cells.
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Project description:Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or ?-catenin (?N90-?-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ?N90-?-catenin alone as well as co-expression of SKP2 and ?N90-?-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with ?-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.
2015-01-01 | S-EPMC4385847 | BioStudies
Project description:At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer. For instance, when RasV12-transformed cells are surrounded by normal cells, RasV12 cells are apically extruded from the epithelium. However, the underlying mechanisms of this tumor-suppressive process still remain enigmatic. We first show by electron microscopic analysis that characteristic finger-like membrane protrusions are projected from both normal and RasV12 cells at their interface. In addition, FBP17, a member of the F-BAR proteins, accumulates in RasV12 cells, as well as surrounding normal cells, which plays a positive role in the formation of finger-like protrusions and apical elimination of RasV12 cells. Furthermore, cdc42 acts upstream of these processes. These results suggest that the cdc42/FBP17 pathway is a crucial trigger of cell competition, inducing "protrusion to protrusion response" between normal and RasV12-transformed cells.
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Project description:Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.
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Project description:Twist1 is a master regulator of epithelial mesenchymal transition and carcinoma metastasis. Twist1 has also been associated with increased malignancy of human glioma. However, the impact of inhibiting Twist1 on tumorigenicity has not been characterized in glioma models in the context of different oncogenic transformation paradigms. Here we used an orthotopic mouse glioma model of transplanted transformed neural progenitor cells (NPCs) to demonstrate the effects of Twist1 loss of function on tumorigenicity. Decreased tumorigenicity was observed after shRNA mediated Twist knockdown in HPV E6/7 Ha-RasV12 transformed NPCs and Cre mediated Twist1 deletion in Twist1 fl/fl NPCs transformed by p53 knockdown and Ha-RasV12 expression. By contrast, Twist1 deletion had no effect on tumorigenicity of NPCs transformed by co-expression of Akt and Ha-RasV12. We demonstrated a dramatic off-target effect of Twist1 deletion with constitutive Cre expression, which was completely reversed when Twist1 deletion was achieved by transient administration of recombinant Cre protein. Together these findings demonstrate that the function of Twist1 in these models is highly dependent on specific oncogenic contexts of NPC transformation. Therefore, the driver mutational context in which Twist1 functions may need to be taken into account when evaluating mechanisms of action and developing therapeutic approaches to target Twist1 in human gliomas.
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Project description:Recent studies have revealed that newly emerging RasV12-transformed cells are often apically extruded from the epithelial layer. During this cancer preventive process, cytoskeletal proteins plectin and Epithelial Protein Lost In Neoplasm (EPLIN) are accumulated in RasV12 cells that are surrounded by normal cells, which positively regulate the apical elimination of transformed cells. However, the downstream regulators of the plectin-EPLIN complex remain to be identified. In this study, we have found that paxillin binds to EPLIN specifically in the mix culture of normal and RasV12-transformed cells. In addition, paxillin is accumulated in RasV12 cells surrounded by normal cells. Paxillin, plectin and EPLIN mutually influence their non-cell-autonomous accumulation, and paxillin plays a crucial role in apical extrusion of RasV12 cells. We also demonstrate that in RasV12 cells surrounded by normal cells, acetylated tubulin is accumulated. Furthermore, acetylation of tubulin is promoted by paxillin that suppresses the activity of histone deacetylase (HDAC) 6. Collectively, these results indicate that in concert with plectin and EPLIN, paxillin positively regulates apical extrusion of RasV12-transformed cells by promoting microtubule acetylation. This study shed light on the unexplored events occurring at the initial stage of carcinogenesis and would potentially lead to a novel type of cancer preventive medicine.
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Project description:Interferons have been ascribed to mediate antitumor effects. IRF-1 is a major target gene of interferons. It inhibits cell proliferation and oncogenic transformation. Here we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of non-transformed cells by IRF-1. These include cell cycle regulating genes. Activation of IRF-1 decreases cyclin D1 expression and CDK4 kinase activity concomitant with dephosphorylation of pRb. These effects of IRF-1 are mediated by inhibition of the MEK-ERK pathway and a transcriptional repression of cyclin D1. IRF-1 mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Ablation of cyclin D1 by RNA interference experiments prevents transformation and tumor growth in nude mice. The data demonstrate that cyclin D1 is a key target for IRF-1 mediated tumor suppressive effects. Experiment Overall Design: 3 samples were analysed, two replicates per sample. NIH3T3 cells were compared with myc/ras transformed NIH3T3 cells and with IRF1 expressing myc/ras transformed cells.
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Project description:Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.
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Project description:In many cancer types, integrin-mediated signaling regulates proliferation, survival and invasion of tumorigenic cells. However, it is still unclear how integrins crosstalk with oncogenes to regulate tumorigenesis and metastasis. Here we show that oncogenic K-RasV12 upregulates ?6-integrin expression in Madin-Darby canine kidney (MDCK) cells via activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)/Fos-related antigen 1-signaling cascade. Activated ?6-integrins promoted metastatic capacity and anoikis resistance, and led to perturbed growth of MDCK cysts. Transcriptomic analysis of K-RasV12-transformed MDCK cells also revealed robust downregulation of ?V-class integrins. Re-expression of ?V-integrin in K-RasV12-transformed MDCK cells synergistically upregulated the expression of Zinc finger E-box-binding homeobox 1 and Twist-related protein 1 and triggered epithelial-mesenchymal transition leading to induced cell motility and invasion. These results delineate the signaling cascades connecting oncogenic K-RasV12 with ?6- and ?V-integrin functions to modulate cancer cell survival and tumorigenesis, and reveal new possible strategies to target highly oncogenic K-RasV12 mutants.
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