| 1. |
- Bellomo, Claudia, et al.
(författare)
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Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
- 2018
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 25:5, s. 885-903
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.
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| 2. |
- Caja, Laia, et al.
(författare)
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Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells
- 2018
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 37:19, s. 2515-2531
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.
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| 3. |
- Dadras, Mahsa Shahidi, et al.
(författare)
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The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma
- 2021
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.
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| 4. |
- Fukuda, Tomohiko, et al.
(författare)
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BMP signaling is a therapeutic target in ovarian cancer
- 2020
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Ingår i: Cell Death Discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- BMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in the TCGA dataset. Both BMP2 and BMPR2 enhanced OC cell proliferation, whereas BMP receptor kinase inhibitors inhibited OC cell growth in cell culture as well as in a mouse model. BMP2 also augmented sphere formation, migration, and invasion of OC cells, and induced EMT. High BMP2 expression was observed after chemotherapy of OC patients in the GSE109934 dataset. In accordance, carboplatin, used for the treatment of OC patients, increased BMP2 secretion from OC cells, and induced EMT partially via activation of BMP signaling. Our data suggest that BMP signaling has tumor-promoting effects in OC, and that BMP inhibitors might be useful therapeutic agents for OC patients. Considering that carboplatin treatment augmented BMP2 secretion, the possibility to use a combination of BMP inhibitors and carboplatin in the treatment of OC patients, would be worth exploring.
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| 5. |
- Fukuda, Tomohiko, et al.
(författare)
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BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells
- 2021
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Ingår i: Cellular Signalling. - : Elsevier. - 0898-6568 .- 1873-3913. ; 87
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the downstream effectors of BMP signaling in gynecological cancer cells have not been clearly elucidated. In this study, we performed RNA-sequencing of Ishikawa endometrial and SKOV3 ovarian cancer cells after BMP2 stimulation, and identified TNFRSF12A, encoding fibroblast growth factor-inducible 14 (FN14) as a common BMP2-induced gene. FN14 knockdown suppressed BMP2-induced cell proliferation and migration, confirmed by MTS and scratch assays, respectively. In addition, FN14 silencing augmented chemosensitivity of SKOV3 cells. As a downstream effector of BMP signaling, FN14 modulated both c-KIT and SNAIL expression, which are important for growth and migration of ovarian and endometrial cancer cells. These results support the notion that the tumor promoting effects of BMP signaling in gynecological cancers are partially attributed to FN14 induction.
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| 6. |
- Fukuda, Tomohiko, et al.
(författare)
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Tumor Promoting Effect of BMP Signaling in Endometrial Cancer
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:15
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Tidskriftsartikel (refereegranskat)abstract
- The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-beta) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high mRNA expressions of BMP ligands and receptors were observed in EC patients of the TCGA and MSK-IMPACT datasets. Ishikawa cells secreted higher amounts of BMP2 compared with ovarian cancer cell lines. Exogenous BMP2 stimulation enhanced EC cell sphere formation via c-KIT induction. BMP2 also induced EMT of EC cells, and promoted migration by induction of SLUG. The BMP receptor kinase inhibitor LDN193189 augmented the growth inhibitory effects of carboplatin. Analyses of mRNAs of several BMP antagonists revealed that TWSG1 mRNA was abundantly expressed in Ishikawa cells. TWSG1 suppressed BMP7-induced, but not BMP2-induced, EC cell sphere formation and migration. Our results suggest that BMP signaling promotes EC tumorigenesis, and that TWSG1 antagonizes BMP7 in EC. BMP signaling inhibitors, in combination with chemotherapy, might be useful in the treatment of EC patients.
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| 7. |
- Gélabert, Caroline, et al.
(författare)
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Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Metabolic reprogramming is one of the hallmarks of cancer. Glutamine is one of the most important nutrients that fuels the TCA cycle and therefore takes part in the production of energy. Glutamine is used as starting metabolite for the synthesis of nucleotides, fatty acids and nonessential amino acids. Since nutrients are uptaken from the blood stream, and considering the 3- dimensional state of solid tumors, access of nutrients is highly dependent on the location of individual cells within a tumor, which results in affecting their metabolic activity. This gives rise to two disctincts cell population: the ones that have access to nutrient and the ones that are nutrientdeprived. We studied the effect of the lack of glutamine by creating glutamine-resistent hepatocellular carcinoma cell lines chosen based on their epithelial (Hep3B) or mesenchymal phenotype (SNU-499 and HLF). We found that glutamine deprivation decreased the proliferation rate, clonogenicity and stemness frequency of the three cell lines but in a greater extent of the mesenchymal cells. Transcriptomic analysis performed in HLF cells showed that glutamine deprivation decreased the activation of signaling pathways involved in cell-cell junction, cellextracellular matrix interactions and decreased the expression of the hallmarks of epithelial-tomesenchymal transition. We therefore investigated the role of TGFβ, a master regulator of these three processes, by transcriptomic and functional analyses in epithelial (Hep3B) and mesenchymal cells (HLF). We found that the lack of glutamine strongly impared the activation of TGFβ signaling which correlated with an altered regulation of TGFβ target genes: the expression of mesenchymal genes was no longer induced by TGFβ while the epithelial genes were more strongly induced. Functional analyses showed that glutamine deprivation abolished the invasive capacities of HCCs and decreased cell adhesion. Altogehter, our results show that glutamine metabolism is necessary to maintain a mesenchymal phenotype and to maintain an efficient TGFβ signaling in hepatocellularcarcinoma.
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| 8. |
- Gélabert, Caroline, et al.
(författare)
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The long non-coding RNA LINC00707 interacts with Smad proteins to regulate TGFβ signaling and cancer cell invasion
- 2023
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Ingår i: Cell Communication and Signaling. - : BioMed Central (BMC). - 1478-811X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long non-coding RNAs (lncRNAs) regulate cellular processes by interacting with RNAs or proteins. Transforming growth factor β (TGFβ) signaling via Smad proteins regulates gene networks that control diverse biological processes, including cancer cell migration. LncRNAs have emerged as TGFβ targets, yet, their mechanism of action and biological role in cancer remains poorly understood.Methods: Whole-genome transcriptomics identified lncRNA genes regulated by TGFβ. Protein kinase inhibitors and RNA-silencing, in combination with cDNA cloning, provided loss- and gain-of-function analyses. Cancer cell-based assays coupled to RNA-immunoprecipitation and protein screening sought mechanistic evidence. Functional validation of TGFβ-regulated lncRNAs was based on new transcriptomics and by combining RNAscope with immunohistochemical analysis in tumor tissue.Results: Transcriptomics of TGFβ signaling responses revealed down-regulation of the predominantly cytoplasmic long intergenic non-protein coding RNA 707 (LINC00707). Expression of LINC00707 required Smad and mitogen-activated protein kinase inputs. By limiting the binding of Krüppel-like factor 6 to the LINC00707 promoter, TGFβ led to LINC00707 repression. Functionally, LINC00707 suppressed cancer cell invasion, as well as key fibrogenic and pro-mesenchymal responses to TGFβ, as also attested by RNA-sequencing analysis. LINC00707 also suppressed Smad-dependent signaling. Mechanistically, LINC00707 interacted with and retained Smad proteins in the cytoplasm. Upon TGFβ stimulation, LINC00707 elimination allowed Smad accumulation in the nucleus. In vivo, LINC00707 expression was negatively correlated with Smad2 activation in tumor tissues.Conclusions: TGFβ signaling decreases LINC00707 expression, which facilitates Smad-dependent signaling, favoring cancer cell invasion.
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| 9. |
- Hamidi, Anahita, et al.
(författare)
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TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α
- 2017
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Ingår i: Science Signaling. - : American Association for the Advancement of Science. - 1945-0877 .- 1937-9145. ; 10:486
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- TGF-β signaling stimulates various intracellular pathways that can promote migration in tumor cells. These pathways are generally thought to be either dependent or independent of transcription factors called SMADs. One of the SMAD-independent pathways (PI3K-AKT) is mediated by a direct interaction between PI3K and the TGF-β type I receptor. However, Hamidi et al. found that the TGF-β–induced activation of PI3K depends on another ubiquitin ligase–mediated mechanism and a SMAD protein but is independent of the kinase function of TβRI. The binding of TGF-β to its receptor triggered the recruitment of PI3K and the ubiquitin ligase TRAF6, which polyubiquitylated the regulatory PI3K subunit p85α, thus enabling phosphorylation of the catalytic PI3K subunit p110, but only in the presence of SMAD7. The abundance of ubiquitylated p85α correlated with migration in cultured cells and prostate tumor grade in patient samples. TRAF6 mediates activation of the other “SMAD-independent” (JNK) pathway. These data suggest that, although distinct, the TGF-β signaling pathways are not as insulated from each other as was once thought.
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| 10. |
- Heldin, Carl-Henrik, 1952-, et al.
(författare)
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Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
- 2018
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 283:1, s. 16-44
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Forskningsöversikt (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.
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