Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1

Weekes, Daniel; Kashima, Takeshi; Zandueta, Carolina; Perurena, Naiara; Thomas, D.; Sunters, Andrew; Vuillier, Céline; Bözec, Aline; El-Emir, Ethaar; Milétich, Isabelle; Patiño‐García, Ana; Lecanda, Fernando; Grigoriadis, Agamemnon E.

doi:10.1038/onc.2015.344

Cited by 64 publications

(61 citation statements)

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“…PI3K‐AKT signaling pathway regulates pleiotropic effects in the cell and is a major target to prevent progression. Upstream targets such as FGFR1 (Weekes et al., 2015) or IGF‐IR (Wang et al., 2012) have also suggested to be efficient therapies in osteosarcoma. Nevertheless, targeted therapy combining PI3K‐AKT inhibitors plus other drugs to match additional alterations present in the patient was not sufficient to prevent progression (Subbiah et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

miR‐200c and phospho‐AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis

et al. 2016

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Lung metastasis is the major cause of death in osteosarcoma patients. However, molecular mechanisms underlying this metastasis remain poorly understood. To identify key molecules related with pulmonary metastasis of pediatric osteosarcomas, we analyzed high‐throughput miRNA expression in a cohort of 11 primary tumors and 15 lung metastases. Results were further validated with an independent cohort of 10 primary tumors and 6 metastases. In parallel, we performed immunohistochemical analysis of activated signaling pathways in 36 primary osteosarcomas. Only phospho‐AKT associated with lower overall survival in primary tumors, supporting its role in osteosarcoma progression. CTNNB1 expression also associated with lower overall survival but was not strong enough to be considered an independent variable. Interestingly, miR‐200c was overexpressed in lung metastases, implicating an inhibitory feed‐back loop to PI3K‐AKT. Moreover, transfection of miR200c‐mimic in U2‐OS cells reduced phospho‐AKT levels but increased cellular migration and proliferation. Notably, miR‐200c expression strongly correlated with miR‐141 and with the osteogenic inhibitor miR‐375, all implicated in epithelial to mesenchymal transition. These findings contrast epithelial tumors where reduced miR‐200c expression promotes metastasis. Indeed, we noted that osteosarcoma cells in the lung also expressed the epithelial marker CDH1, revealing a change in their mesenchymal phenotype. We propose that miR‐200c upregulation occurs late in osteosarcoma progression to provide cells with an epithelial phenotype that facilitates their integration in the metastatic lung niche. Thus, our findings identify phospho‐AKT in the primary tumor and miR‐200c later during tumor progression as prognostic molecules and potential therapeutic targets to prevent progression and metastasis of pediatric osteosarcomas.

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Section: Discussionmentioning

confidence: 99%

miR‐200c and phospho‐AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis

et al. 2016

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“…In a study expression of c-Fos and c-Jun in breast tumor samples was significantly lower than adjacent non-tumor tissues [65]. The reduction of these two genes would be related to apoptotic effects of AP1 complex [66,67]. JNK (MAPK8) showed a total reducing trend from N>M in the first dataset while p38 (MAPK14) did not show a considerable change.…”

Section: Ros Promotes the Erk1 Activation And This Activation Increasmentioning

confidence: 95%

“…ERK1 activation also activates c-Fos which is a component of activation protein 1 (AP1). JNK is also activated by ROS which enhances c-Jun activation another component of AP1 [66]. AP1 complex enters the nucleus and activates expression of genes promoting cell proliferation [67].…”

Section: Ros Promotes the Erk1 Activation And This Activation Increasmentioning

confidence: 99%

Gene Expression Signature and Molecular Mechanism of Redox Homeostasis in Colorectal Cancer

Piran

Darayee

Piran

et al. 2020

Preprint

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Cellular redox homeostasis is the important tool for normal cell function and survival. Oxidants, reductants and antioxidants are the players to maintain cellular homeostasis balance. However, in some conditions like cancer, the concentration and activation of these players are disturbed.This study walks you through the molecular mechanism of redox homeostasis to describe how expression level of these players would help colorectal cancer (CRC) cells continue proliferation and survive in the hypoxic environment of tumor. We proposed that O2concentration is not detrimentally high in CRC cells since expression level of MnSOD didn't change noticeably. We also suggested that High proliferative CRC cells obtain their energy by oxidation of H2S in or Electron transport chain (ETC) and keep the adequate concentration of H2S by diminishing the expression level of enzymes involved in sulfide oxidation pathway. Reduction in hydrogen sulfide oxidation results in a decrease in the level of GSH. Glutathione peroxidase enzyme requires GSH to convert H2O2 into oxygen and water. Therefore, Level of hydrogen peroxide stays high which leads to an increase in cell proliferation. Furthermore, we analyzed the expression level of transcription factors sensitive to redox messengers. to cell proliferation while a severe increment and long-lasting in the concentration of these molecules causes cell death. As a result, if redox homeostasis is disturbed, oxidative stress contributes to aberrant cell growth/death and disease [2]. This happens by changes in cells environment and impaired antioxidants generation which modulate the concentration of oxidants [5]. ROS includes radical species such as superoxide (O2 -), hydroxyl radical ( . OH) and non-radical species like Hydrogen peroxide (H2O2). RNS involves nitric oxide (NO) and Peroxynitrite (ONOO -) [2, 6]. Moreover, there are two types of antioxidants, enzymatic and non-enzymatic (small molecules). SODs (Superoxide dismutase), Glutathione peroxidase (GPx) and Catalase are examples of enzymatic antioxidants but Glutathione (GSH), Thioredoxin (Tnx) and Peroxiredoxin (Prx) are examples of small molecule antioxidants. One of the primary ROS molecules is O2made in the ETC by transferring electrons from complex one and Three to a dioxygen molecule or by NAD(P)H oxidases (NOX) activation [7-10]. Superoxide is then converted into hydrogen peroxide using Superoxide dismutase enzymes [9]. Among the three kinds of SODs, SOD1 (CuZnSOD) is present in the cytoplasm, mitochondrial inter-membrane space, nucleus, and lysosomes while SOD2 (MnSOD) and SOD3 (Ec-SOD) are present in Mitochondria and Extra Cellular Matrix (ECM) respectively [2]. Next, H2O2 is turned into water and oxygen molecules by GPx enzyme which oxidizes reduced Glutathione (GSH) into oxidized glutathione (GSSG) [11]. GSSG is converted into GSH by Glutathione reductase (GR/GSR) and in the meantime, an NADPH is turned into NADP + . GSH can enter the oxidation cycle again and NADP + enters the glycolysis to be reduced into NADPH [12]. In the p...

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“…FGFR overexpression and activating 4 mutations have recently been demonstrated to play an important role in several types of cancer, including sarcoma (e.g. osteosarcoma, rhabdomyosarcoma (RMS) and soft tissue sarcoma) (4)(5)(6)(7)(8). In addition, the FGFR-specific downstream signaling adaptor, the FGFR substrate 2 (FRS2), is overexpressed in liposarcoma and renders these cells sensitive to FGFR inhibitors (9, 10).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, aberrant FGF signaling is often involved in cancer development (1,3). FGFR overexpression and activating 4 mutations have recently been demonstrated to play an important role in several types of cancer, including sarcoma (e.g. osteosarcoma, rhabdomyosarcoma (RMS) and soft tissue sarcoma) (4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors

Kostas

Haugsten

Zhen

et al. 2018

Molecular & Cellular Proteomics

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Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (e.g. FRS2, PLCG1, RSK2, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

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Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1

Cited by 64 publications

References 50 publications

miR‐200c and phospho‐AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis

miR‐200c and phospho‐AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis

Gene Expression Signature and Molecular Mechanism of Redox Homeostasis in Colorectal Cancer

Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors

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