Abstract 4612: In breast cancer cells IGF-I induces upregulation of DDR1 by suppressing miR-199a-5p via the PI3K/Akt pathway (original) (raw)
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Oncotarget, 2015
The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological ...
Oncotarget, 2014
Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies.
Cancer Research, 2013
In the US, African American women have a significantly higher rate of mortality due to breast cancer compared to Caucasian American women. Molecular differences in tumor biology exist between racial groups; however, their contribution to cancer disparity is not well understood. Our studies have identified a race-specific, mechanistic link between microRNA-204 and the IGF2R. The IGF2R is a tumor suppressor gene in several cancers including breast cancer and IGF2R levels are found at significantly lower levels in African American women with breast cancer when compared to their Caucasian counterparts. We observed elevated levels of miR-204 in serum of African American women with breast cancer when compared to Caucasian American women and identified IGF2R as a direct target of miR-204. We show mechanistically that miR-204 mediated inhibition of IGF2R leads to activation of the IGF1R signaling pathway resulting in increased proliferation, migration and invasion, processes that are required for tumor progression. We developed a unique doxycycline-inducible miR-204 transgenic mouse model to define in vivo the oncogenic potential of miR-204 and the mechanism and functional consequences of IGF2R loss. We observed a significant increase in tumor growth and increased metastasis in these animals when compared to non-transgenic controls. This is the first characterization of miR-204 in an in vivo model. These data support a mechanism whereby miR-204 promotes tumor aggression through the IGF2-mediated hyperactivation of the IGF1R signaling pathway in response to direct negative regulation of the tumor suppressor IGF2R and that this could be a potential mechanism promoting breast cancer disparity.
Breast Cancer Research and Treatment, 2011
Although estrogen receptor (ER) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of gene transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3hr or 24hr. IGF-I regulated mRNA of 5-10-fold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer patients. Closer examination revealed enrichment of repressed transcripts (compared to induced transcripts).. Interestingly, a number of potential tumor suppressors were downregulated by IGF-I and estradiol, suchas the B-cell linker BLNK Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ER. However, repression by IGF-I or estradiol required common downstream kinases, such as PI3K and MEK, suggesting downstream conversion of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and the down-regulation by E2 and IGF-I is independent at the receptor level. This may be important clinically, as tumors with active ER and IGF-IR signaling may require co-targeting of both pathways.
IGF-I Receptor, Cell–Cell Adhesion, Tumour Development and Progression
Journal of Molecular Histology, 2003
The insulin-like growth factor I receptor (IGF-IR) has been implicated in the development and progression of many common cancers and other neoplastic diseases. The tumorigenic potential of IGF-IR relies on its antiapoptotic and transforming activities. The molecular mechanisms by which IGF-IR controls the proliferation and survival of tumour cells have been extensively studied and many pathways have been delineated. However, the role of IGF-IR in the regulation of non-mitogenic cell functions is less well understood. Here we focus on IGF-IR-dependent cell-cell adhesion. Limited studies suggested that IGF-IR can regulate cell aggregation and intercellular adhesion mediated by cadherins and cadherin-associated proteins. We review the mechanisms of this process and discuss the impact of IGF-IR-dependent cell-cell adhesion on the phenotype of tumour cells. The insulin-like growth factor-I receptor (IGF-IR) Insulin-like growth factor-I receptor (IGF-IR) is an evolutionary conserved, ubiquitous transmembrane tyrosine kinase structurally similar to the insulin receptor (Ullrich et al. 1986). IGF-IR is composed of two extracellular α subunits and two intracellular β subunits. The α subunits bind IGF-IR ligands (IGF-I, IGF-II, and insulin at supraphysiological doses), while β subunits transmit ligand-induced signals. Binding of ligands to IGF-IR induces its autophosphorylation and tyrosine phosphorylation of IGF-IR substrates, especially the insulin receptor substrate 1 (IRS-1) and src-and collagen-homology (SHC) protein. Tyrosine phosphorylated IRS-1 and SHC bind different effector proteins (enzymes and/or adapters) inducing multiple signalling cascades, among them several interconnecting pathways controlling cell survival and proliferation (
Journal of Cellular Physiology, 2003
The insulin-like growth factor-I receptor (IGF-IR) is a ubiquitous multifunctional tyrosine kinase that has an important role in normal cell growth and development. However, abnormal stimulation of IGF-IR signaling has been implicated in the development of different types of tumors. The strong antiapoptotic activity of IGF-IR has been recognized as critical in IGF-I-dependent tumorigenesis, however, the impact of other IGF-IR functions, such as regulation of cell-cell and cell-matrix adhesion are also increasingly acknowledged. Here, on the model of breast cancer cells, we discuss how IGF-IR-dependent regulation of intercellular adhesion may affect cell survival, resistance to antiestrogens, and invasion.
DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop
Endocrine-Related Cancer, 2019
Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differe...
Nucleic acids research, 2018
The oncofetal IGF2 mRNA binding proteins (IGF2BPs) are upregulated in most cancers but their paralogue-specific roles in tumor cells remain poorly understood. In a panel of five cancer-derived cell lines, IGF2BP1 shows highly conserved oncogenic potential. Consistently, the deletion of IGF2BP1 impairs the growth and metastasis of ovarian cancer-derived cells in nude mice. Gene expression analyses in ovarian cancer-derived cells reveal that the knockdown of IGF2BPs is associated with the downregulation of mRNAs that are prone to miRNA regulation. All three IGF2BPs preferentially associate upstream of miRNA binding sites (MBSs) in the 3'UTR of mRNAs. The downregulation of mRNAs co-regulated by miRNAs and IGF2BP1 is abrogated at low miRNA abundance or when miRNAs are depleted. IGF2BP1 associates with these target mRNAs in RISC-free complexes and its deletion enhances their association with AGO2. The knockdown of most miRNA-regulated target mRNAs of IGF2BP1 impairs tumor cell proper...
Biomolecules, 2021
The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in pa...