Publications by authors named "Veronica Vella"

42 Publications

DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System.

Biomolecules 2021 Jun 22;11(7). Epub 2021 Jun 22.

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy.

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 part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR/IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.
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http://dx.doi.org/10.3390/biom11070926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301864PMC
June 2021

Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer.

Cancers (Basel) 2021 Feb 4;13(4). Epub 2021 Feb 4.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy.

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression.

Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay.

Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects.

Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.
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http://dx.doi.org/10.3390/cancers13040621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915817PMC
February 2021

Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling.

Front Cell Dev Biol 2020 8;8:608412. Epub 2020 Dec 8.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

The development and progression of the great majority of breast cancers (BCs) are mainly dependent on the biological action elicited by estrogens through the classical estrogen receptor (ER), as well as the alternate receptor named G-protein-coupled estrogen receptor (GPER). In addition to estrogens, other hormones and growth factors, including the insulin and insulin-like growth factor system (IIGFs), play a role in BC. IIGFs cooperates with estrogen signaling to generate a multilevel cross-communication that ultimately facilitates the transition toward aggressive and life-threatening BC phenotypes. In this regard, the majority of BC deaths are correlated with the formation of metastatic lesions at distant sites. A thorough scrutiny of the biological and biochemical events orchestrating metastasis formation and dissemination has shown that virtually all cell types within the tumor microenvironment work closely with BC cells to seed cancerous units at distant sites. By establishing an intricate scheme of paracrine interactions that lead to the expression of genes involved in metastasis initiation, progression, and virulence, the cross-talk between BC cells and the surrounding microenvironmental components does dictate tumor fate and patients' prognosis. Following (i) a description of the main microenvironmental events prompting BC metastases and (ii) a concise overview of estrogen and the IIGFs signaling and their major regulatory functions in BC, here we provide a comprehensive analysis of the most recent findings on the role of these transduction pathways toward metastatic dissemination. In particular, we focused our attention on the main microenvironmental targets of the estrogen-IIGFs interplay, and we recapitulated relevant molecular nodes that orientate shared biological responses fostering the metastatic program. On the basis of available studies, we propose that a functional cross-talk between estrogens and IIGFs, by affecting the BC microenvironment, may contribute to the metastatic process and may be regarded as a novel target for combination therapies aimed at preventing the metastatic evolution.
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http://dx.doi.org/10.3389/fcell.2020.608412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753049PMC
December 2020

The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer.

Cancers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, 95122 Catania, Italy.

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.
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http://dx.doi.org/10.3390/cancers12082249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465706PMC
August 2020

COVID-19 and Diabetes: The Importance of Controlling RAGE.

Front Endocrinol (Lausanne) 2020 14;11:526. Epub 2020 Jul 14.

Department of Clinical and Experimental Medicine, University of Catania, and ARNAS Garibaldi, P.O. Garibaldi-Nesima, Catania, Italy.

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http://dx.doi.org/10.3389/fendo.2020.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375019PMC
August 2020

Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.

Hormones (Athens) 2021 Mar 5;20(1):161-165. Epub 2020 Jun 5.

Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.

Background: Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome.

Case Presentation: A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of Tc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of Tc-pertechnatate and the presence of a "cool" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion.

Conclusion: We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.
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http://dx.doi.org/10.1007/s42000-020-00215-9DOI Listing
March 2021

Editorial: Resistance to Endocrine Therapies in Cancer.

Front Endocrinol (Lausanne) 2020 9;11:196. Epub 2020 Apr 9.

Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

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http://dx.doi.org/10.3389/fendo.2020.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160226PMC
April 2021

Thyroidectomy as Treatment of Choice for Differentiated Thyroid Cancer.

Int J Surg Oncol 2019 13;2019:2715260. Epub 2019 Oct 13.

Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Via Palermo 636, Catania, Italy.

Background: Despite a large amount of data, the optimal surgical management of differentiated thyroid cancer remains controversial. Current guidelines recommend total thyroidectomy if primary thyroid cancer is >4 cm, while for tumors that are between 1 and 4 cm in size, either a bilateral or a unilateral thyroidectomy may be appropriate as surgical treatment. In general, total thyroidectomy would seem to be preferable because subtotal resection can be correlated with a higher risk of local recurrences and cervical lymph node metastases; on the other hand, total thyroidectomy is associated with more complications.

Methods: This is a retrospective study conducted on 359 patients with differentiated thyroid cancer, subjected to total thyroidectomy. Our aim was to correlate clinical and pathological features (extrathyroid tumor growth, bilaterality, nodal and distant metastasis) with patient (gender and age) and tumor (size and histotype) characteristics. Moreover, we recorded postoperative complications, including hypoparathyroidism and laryngeal nerve damage.

Results: In our study, we found a high occurrence of pathological features indicating cancer aggressiveness (bilaterality, nodal metastases, and extrathyroid invasion). On the other hand, total thyroidectomy was associated with relatively low postsurgical complication rates.

Conclusions: Our data support the view that total thyroidectomy remains the first choice for the routine treatment of differentiated thyroid cancer.
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http://dx.doi.org/10.1155/2019/2715260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815575PMC
February 2020

Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation.

Cells 2019 09 1;8(9). Epub 2019 Sep 1.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania 95122, Italy.

Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting -ablated MCF7 (MCF7) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming.
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http://dx.doi.org/10.3390/cells8091017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770491PMC
September 2019

Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection.

Biochim Biophys Acta Mol Cell Res 2019 11 5;1866(11):118522. Epub 2019 Aug 5.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy. Electronic address:

The insulin/insulin-like growth factor system (IIGFs) plays a fundamental role in the regulation of prenatal and postnatal growth, metabolism and homeostasis. As a consequence, dysregulation of this axis is associated with growth disturbance, type 2 diabetes, chronic inflammation and tumor progression. A functional crosstalk between IIGFs and discoidin domain receptors (DDRs) has been recently discovered. DDRs are non-integrin collagen receptors that canonically undergo slow and long-lasting autophosphorylation after binding to fibrillar collagen. While both DDR1 and DDR2 functionally interact with IIGFs, the crosstalk with DDR1 is so far better characterized. Notably, the IIGFs-DDR1 crosstalk presents a feed-forward mechanism, which does not require collagen binding, thus identifying novel non-canonical action of DDR1. Further studies are needed to fully explore the role of this IIGFs-DDRs functional loop as potential target in the treatment of inflammatory and neoplastic disorders.
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http://dx.doi.org/10.1016/j.bbamcr.2019.118522DOI Listing
November 2019

Comment on "Shiatsu as an Adjuvant Therapy for Depression in Patients With Alzheimer's Disease: A Pilot Study".

J Evid Based Integr Med 2019 Jan-Dec;24:2515690X18825105

2 University "Kore" of Enna, Enna, Italy.

Recently, there has been increasing interest toward nonpharmacological approaches for dementia and associated clinical manifestations, such as depression, with the common goal to improve health and quality of life of both patients and caregivers. In this scenario, the role of Shiatsu is of clinical and research interest, although to date a definitive recommendation on a systematic use in clinical practice cannot be made. To overcome the heterogeneity of the previous studies, we tested Shiatsu as an add-on treatment for late-life depression in a dedicated community of patients with mild-to-moderate Alzheimer's disease. We found a significant adjuvant effect of Shiatsu for depression in these patients and hypothesized a neuroendocrine-mediated action on the neural circuits implicated in mood and affect regulation. However, this finding must be considered preliminary and requires confirmation in larger-scale controlled studies, possibly extending the range of outcome measures and including predictors of response. Future investigations should also include an objective assessment of the hypothalamus-pituitary-adrenocortical axis functioning. Nevertheless, starting from this pilot study, we suggest that a customized protocol applied for an adequate period in a controlled sample will represent a non-invasive and feasible advance for promoting patients' mood and, possibly, slowing cognitive decline.
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http://dx.doi.org/10.1177/2515690X18825105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351716PMC
September 2019

Short-term adverse effects of anticancer drugs in patients with type 2 diabetes.

J Chemother 2019 May 10;31(3):150-159. Epub 2019 Feb 10.

a Department of Clinical and Experimental Medicine , Endocrinology Section, University of Catania Medical School , Garibaldi-Nesima Hospital , Catania , Italy.

The short-term adverse effects of anticancer drugs (AD) in patients with type 2 diabetes (T2D) are poorly studied and their management still represents an important challenge for clinicians. We carried out a retrospective single-center study in 168 patients with T2D and cancer, evaluating both the short-term effects of first-line AD on glycemic control and chronic diabetes complications. Average glycated hemoglobin significantly increased after AD compared to values before treatment (7.5 vs. 7.1%, p < 0.005). In 46.4% of patients, diabetes therapy had to be potentiated, in most cases (82.1%) by shifting to insulin. The use of alkylating agents and high-dose glucocorticoids predicted the need to potentiate diabetes therapy. After AD transaminase values significantly increased, whereas the estimated glomerular filtration rate decreased (in 12.5% <60 mL/min). Kinase inhibitors significantly increased the risk of microalbuminuria onset or progression. The present study provides a real-life information on the effects of different AD on the management of patients with T2D affected by several types of cancer.
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http://dx.doi.org/10.1080/1120009X.2019.1572297DOI Listing
May 2019

Effect of Combined Epigenetic Treatments and Ectopic NIS Expression on Undifferentiated Thyroid Cancer Cells.

Anticancer Res 2018 Dec;38(12):6653-6662

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Background: Poorly differentiated (PDTC) and anaplastic thyroid (ATC) cancer cells are characterized by the acquisition of epigenetic abnormalities, leading to the silencing of both the sodium iodide co-transporter and the Coxsackie adenovirus receptor. As aberrant histone acetylation and DNA methylation represent epigenetic mechanisms involved in neoplastic transformation, our study investigated the anticancer properties of epigenetic modifiers in thyroid carcinoma.

Materials And Methods: The cytotoxicity and gene expression modulation of histone deacetylase and DNA methyltransferase inhibitors were evaluated in both PDTC and ATC.

Results: Epigenetic treatments were cytotoxic to tumor thyrocytes and restored sodium iodide co-transporter and Coxsackie adenovirus receptor, expression as well as radioiodine uptake, in PDTC but not in ATC. However, ectopic expression sodium iodide co-transporter re-activated radioiodine incorporation in ATC.

Conclusion: The ability of epigenetic treatments to interfere with tumor proliferation and induce Coxsackie adenovirus receptor expression, coupled with the ability of ectopic sodium iodide co-transporter to restore radioiodine uptake, raise the possibility that these therapeutic approaches may provide clinical benefit to patients with thyroid carcinoma refractory to radioiodine treatment.
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http://dx.doi.org/10.21873/anticanres.13032DOI Listing
December 2018

The Emerging Role of Insulin Receptor Isoforms in Thyroid Cancer: Clinical Implications and New Perspectives.

Int J Mol Sci 2018 Nov 30;19(12). Epub 2018 Nov 30.

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.

Thyroid cancer (TC) is the most common endocrine tumor. Although the majority of TCs show good prognoses, a minor proportion are aggressive and refractory to conventional therapies. So far, the molecular mechanisms underlying TC pathogenesis are incompletely understood. Evidence suggests that TC cells and their precursors are responsive to insulin and insulin-like growth factors (IGFs), and often overexpress receptors for insulin (IR) and IGF-1 (IGF-1R). IR exists in two isoforms, namely IR-A and IR-B. The first binds insulin and IGF-2, unlike IR-B, which only binds insulin. IR-A is preferentially expressed in prenatal life and contributes to development through IGF-2 action. Aggressive TC overexpresses IR-A, IGF-2, and IGF-1R. The over-activation of IR-A/IGF-2 loop in TC is associated with stem-like features and refractoriness to some targeted therapies. Importantly, both IR isoforms crosstalk with IGF-1R, giving rise to the formation of hybrids receptors (HR-A or HR-B). Other interactions have been demonstrated with other molecules such as the non-integrin collagen receptor, discoidin domain receptor 1 (DDR1), and the receptor for the hepatocyte growth factor (HGF), Met. These functional networks provide mechanisms for IR signaling diversification, which may also exert a role in TC stem cell biology, thereby contributing to TC initiation and progression. This review focuses on the molecular mechanisms by which deregulated IR isoforms and their crosstalk with other molecules and signaling pathways in TC cells and their precursors may contribute to thyroid carcinogenesis, progression, and resistance to conventional treatments. We also highlight how targeting these alterations starting from TC progenitors cells may represent new therapeutic strategies to improve the clinical management of advanced TCs.
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http://dx.doi.org/10.3390/ijms19123814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321330PMC
November 2018

Insulin Receptor Isoforms in Cancer.

Int J Mol Sci 2018 Nov 16;19(11). Epub 2018 Nov 16.

Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
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http://dx.doi.org/10.3390/ijms19113615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274710PMC
November 2018

DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop.

Endocr Relat Cancer 2019 01;26(1):197-214

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

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 differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.
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http://dx.doi.org/10.1530/ERC-18-0310DOI Listing
January 2019

Shiatsu as an adjuvant therapy for depression in patients with Alzheimer's disease: A pilot study.

Complement Ther Med 2018 Jun 5;38:74-78. Epub 2018 May 5.

School of Human and Social Science, University "Kore" of Enna, Enna, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale - CeSI-Met, Chieti, Italy.

Objectives: Among the complementary and alternative medicine, Shiatsu might represent a feasible option for depression in Alzheimer's disease (AD). We evaluated Shiatsu on mood, cognition, and functional independence in patients undergoing physical activity.

Design: Single-blind randomized controlled study.

Setting: Dedicated Community Center for patients with AD.

Interventions: AD patients with depression were randomly assigned to the "active group" (Shiatsu + physical activity) or the "control group" (physical activity alone). Shiatsu was performed by the same therapist once a week for ten months.

Main Outcome Measures: Global cognitive functioning (Mini Mental State Examination - MMSE), depressive symptoms (Geriatric Depression Scale - GDS), and functional status (Activity of Daily Living - ADL, Instrumental ADL - IADL) were assessed before and after the intervention.

Results: We found a within-group improvement of MMSE, ADL, and GDS in the active group. However, the analysis of differences before and after the interventions showed a statistically significant decrease of GDS score only in the active group.

Conclusions: The combination of Shiatsu and physical activity improved depression in AD patients compared to physical activity alone. The pathomechanism might involve neuroendocrine-mediated effects of Shiatsu on neural circuits implicated in mood and affect regulation.
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http://dx.doi.org/10.1016/j.ctim.2018.04.013DOI Listing
June 2018

Editorial: Clinical and Molecular Epidemiology of Thyroid Cancer of Follicular Origin.

Front Endocrinol (Lausanne) 2018 12;9:67. Epub 2018 Mar 12.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

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http://dx.doi.org/10.3389/fendo.2018.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857554PMC
March 2018

A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer.

Cell Adh Migr 2018 23;12(4):305-314. Epub 2018 Mar 23.

a Endocrinology, Department of Clinical and Experimental Medicine , University of Catania, Garibaldi-Nesima Hospital , Catania , Italy.

In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of insulin, IGF-1 and IGF-2. Conversely, DDR1 is upregulated by IGF-1, IGF-2 and insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non-canonical estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to hormones, growth factors, and signals coming from the extracellular matrix.
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http://dx.doi.org/10.1080/19336918.2018.1445953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363032PMC
June 2019

Metabolic Alterations of Thyroid Cancer as Potential Therapeutic Targets.

Biomed Res Int 2017 6;2017:2545031. Epub 2017 Nov 6.

School of Human and Social Science, University "Kore" of Enna, Enna, Italy.

Thyroid cancer (TC) is the most frequent endocrine tumor with a growing incidence worldwide. Besides the improvement of diagnosis, TC increasing incidence is probably due to environmental factors and lifestyle modifications. The actual diagnostic criteria for TC classification are based on fine needle biopsy (FNAB) and histological examination following thyroidectomy. Since in some cases it is not possible to make a proper diagnosis, classical approach needs to be supported by additional biomarkers. Recently, new emphasis has been given to the altered cellular metabolism of proliferating cancer cells which require high amount of glucose for energy production and macromolecules biosynthesis. Also TC displays alteration of energy metabolism orchestrated by oncogenes activation and tumor suppressors inactivation leading to abnormal proliferation. Furthermore, TC shows significant metabolic heterogeneity within the tumor microenvironment and metabolic coupling between cancer and stromal cells. In this review we focus on the current knowledge of metabolic alterations of TC and speculate that targeting TC metabolism may improve current therapeutic protocols for poorly differentiated TC. Future studies will further deepen the actual understandings of the metabolic phenotype of TC cells and will give the chance to provide novel prognostic biomarkers and therapeutic targets in tumors with a more aggressive behavior.
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http://dx.doi.org/10.1155/2017/2545031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694990PMC
July 2018

Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer?

Front Endocrinol (Lausanne) 2017 14;8:314. Epub 2017 Nov 14.

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.

In the past few decades, the incidence of thyroid cancer (TC), namely of its papillary hystotype (PTC), has shown a steady increase worldwide, which has been attributed at least in part to the increasing diagnosis of early stage tumors. However, some evidence suggests that environmental and lifestyle factors can also play a role. Among the potential risk factors involved in the changing epidemiology of TC, particular attention has been drawn to insulin-resistance and related metabolic disorders, such as obesity, type 2 diabetes, and metabolic syndrome, which have been also rapidly increasing worldwide due to widespread dietary and lifestyle changes. In accordance with this possibility, various epidemiological studies have indeed gathered substantial evidence that insulin resistance-related metabolic disorders might be associated with an increased TC risk either through hyperinsulinemia or by affecting other TC risk factors including iodine deficiency, elevated thyroid stimulating hormone, estrogen-dependent signaling, chronic autoimmune thyroiditis, and others. This review summarizes the current literature evaluating the relationship between metabolic disorders characterized by insulin resistance and the risk for TC as well as the possible underlying mechanisms. The potential implications of such association in TC prevention and therapy are discussed.
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http://dx.doi.org/10.3389/fendo.2017.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694441PMC
November 2017

Anaplastic Thyroid Cancer in Sicily: The Role of Environmental Characteristics.

Front Endocrinol (Lausanne) 2017 20;8:277. Epub 2017 Oct 20.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Background: Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive cancer of the thyroid, contributing up to 30-40% of thyroid cancer-specific mortality. We analyzed ATC characteristics and survival rates in Sicily to evaluate the possible influence of environmental factors. With this aim, data regarding ATC incidences in urban/rural and industrial, iodine-deficient, and volcanic vs control areas were compared in Sicily as well as ATC data from Sicily and USA.

Methods: Using the Sicilian Register of Thyroid Cancer (SRTC) database incidence, age, gender, tumor size and histotype, extrathyroidal extension, stage, and coexistence with pre-existing differentiated thyroid cancer (DTC) were evaluated in different areas of Sicily and also compared with Surveillance Epidemiology and End Results data in USA.

Results: Forty-three ATCs were identified in Sicily in the period 2002-2009. In our series only age <70 years at diagnosis ( = 0.01), coexistence with DTC ( = 0.027) and tumor size ≤6 cm ( = 0.012) were significant factors for increased survival at univariate analysis (only age at multivariate analysis). No difference in ATC incidence was found in urban vs rural areas and in iodine-deficient and industrial vs control areas. By contrast, in the volcanic area of Sicily, where DTC incidence is doubled relative to the rest of the island, also ATC incidence was increased. ATC data in Sicily were similar to those reported in the same period in the USA where overall survival rate at 6 and 12 months, however, was smaller.

Conclusion: The similar ATC data observed in Sicily and USA (having different genetic background and lifestyle) and the increased ATC incidence in the volcanic area of Sicily paralleling the increased incidence of papillary thyroid cancer are compatible with the possibility that casual additional mutations, more frequent in a background of increased cell replication like DCT, are the major causes of ATC rather than genetic background and/or direct environmental influences.
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http://dx.doi.org/10.3389/fendo.2017.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662896PMC
October 2017

Insulin Receptor Isoforms in Physiology and Disease: An Updated View.

Endocr Rev 2017 10;38(5):379-431

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy.

The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.
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http://dx.doi.org/10.1210/er.2017-00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629070PMC
October 2017

Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells.

Oncotarget 2017 06;8(26):43248-43270

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.

The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis.We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF-2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas.These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer.
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http://dx.doi.org/10.18632/oncotarget.18020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522143PMC
June 2017

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis.

Front Endocrinol (Lausanne) 2017 22;8:31. Epub 2017 Feb 22.

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro , Catanzaro , Italy.

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.
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http://dx.doi.org/10.3389/fendo.2017.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319972PMC
February 2017

Recent views of heavy metals as possible risk factors and potential preventive and therapeutic agents in prostate cancer.

Mol Cell Endocrinol 2017 Dec 20;457:57-72. Epub 2016 Oct 20.

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. Electronic address:

Prostate cancer is the most common cancer in men in many industrialized countries. A role for androgens in prostate tumor progression is well recognized, while estrogens may cooperate with androgens in prostate carcinogenesis. The incidence of prostate cancer is highly variable in the different countries, suggesting an important role of environmental factors. Heavy metals are common environmental contaminants and some of them are confirmed or suspected human carcinogens. Some metals are endowed with estrogenic and/or androgenic activities and may play a role as cancer risk factors through this mechanism. Moreover, prostate cancer may present alterations in the intracellular balance of trace metals, such as zinc and copper, which are involved in several regulatory proteins. Herein, we review the possible role of environmental heavy metals and of metal-dyshomeostasis in prostate cancer development and promotion as well as the potential use of some metals in the prevention and therapy of prostate cancer.
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http://dx.doi.org/10.1016/j.mce.2016.10.020DOI Listing
December 2017

IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.

Oncotarget 2016 Feb;7(7):7683-700

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer. In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I. These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis.
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http://dx.doi.org/10.18632/oncotarget.6524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884947PMC
February 2016

Thyrospheres From Normal or Malignant Thyroid Tissue Have Different Biological, Functional, and Genetic Features.

J Clin Endocrinol Metab 2015 Sep 7;100(9):E1168-78. Epub 2015 Jul 7.

Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy.

Context: Cancer stem cells from several human malignancies, including poorly differentiated thyroid carcinoma and thyroid cancer cell lines, have been cultured in vitro as sphere-forming cells. These thyroid cancer stem cells were proven to be able to reproduce the original tumor in a xenograft orthotopic model.

Objectives: The objective of the study was to characterize papillary thyroid carcinoma (PTC) spheres from well-differentiated thyroid cancer and normal thyroid (NT) spheres obtained from the contralateral thyroid tissue of the same patient.

Design: Thyrospheres from PTCs and NTs were isolated.

Main Outcome Measures: Gene expression analysis by real-time PCR, immunofluorescence studies, and fluorescence-activated cell sorter analysis in thyrospheres from PTCs and NTs have been evaluated.

Conclusions: Compared with NT spheres, PTC spheres are larger, more irregular, and more clonogenic and have a higher rate of symmetric division. Moreover, PTC spheres express higher levels of stem cell markers and lower levels of thyroid-specific genes compared with NT spheres. Under appropriate conditions, NT spheres differentiated into thyrocytes, whereas PTC spheres did not, displaying a defect in the differentiation potential. Immunofluorescence experiments indicated that, in NT spheres, progenitor cells are mainly present in the sphere core, and the sphere periphery contains thyroid precursor cells already committed to differentiation. PTC spheres are not polarized like NT spheres. Unlike cells differentiated from NT spheres, TSH did not significantly stimulate cAMP production in cells differentiated from PTC spheres. A microarray analysis performed in paired samples (NT and PTC spheres from the same patient) indicated that NT and PTC spheres display a gene expression pattern typical of stem/progenitor cells; however, compared with NT spheres, PTC spheres display a unique gene expression pattern that might be involved in PTC progression.
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http://dx.doi.org/10.1210/JC.2014-4163DOI Listing
September 2015

Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses.

Oncotarget 2015 Jun;6(18):16084-105

Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.

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 responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599258PMC
http://dx.doi.org/10.18632/oncotarget.3177DOI Listing
June 2015

Type 3 deiodinase: role in cancer growth, stemness, and metabolism.

Front Endocrinol (Lausanne) 2014 17;5:215. Epub 2014 Dec 17.

School of Human and Social Science, University "Kore" of Enna , Enna , Italy ; Department of Clinical and Molecular Bio-Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Medical Center , Catania , Italy.

Deiodinases are selenoenzymes that catalyze thyroid hormones (THs) activation (type 1 and type 2, D1 and D2, respectively) or inactivation (type 3, D3). THs are essential for proper body development and cellular differentiation. Their intra- and extra-cellular concentrations are tightly regulated by deiodinases with a pre-receptorial control thus generating active or inactive form of THs. Changes in deiodinases expression are anatomically and temporally regulated and influence the downstream TH signaling. D3 overexpression is a feature of proliferative tissues such as embryo or cancer tissues. The enhanced TH degradation by D3 induces a local hypothyroidism, thus inhibiting THs transcriptional activity. Of note, overexpression of D3 is a feature of several highly proliferative cancers. In this paper, we review recent advances in the role of D3 in cancer growth, stemness, and metabolic phenotype. In particular, we focus on the main signaling pathways that result in the overexpression of D3 in cancer cells and are known to be relevant to cancer development, progression, and recurrence. We also discuss the potential role of D3 in cancer stem cells metabolic phenotype, an emerging topic in cancer research.
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http://dx.doi.org/10.3389/fendo.2014.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269192PMC
January 2015
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