Summary

Iron is an essential micronutrient for both benign and neoplastic cells. An adequate balance of iron is critical for health, since iron deficiency leads to anemia, a major world-wide public health problem, and iron overload increases the oxidative stress of body tissues leading to inflammation, cell death, system organ dysfunction, and cancer.

Hereditary Hemochromatosis (HH) is a genetic disorder caused by excessive iron absorption. This disease is one of the most common recessive genetic disorders in the Caucasian population and is mainly due to mutations in the HFE gene. Elevated iron stores are linked to an increased risk of cancer and cancer mortality. One third of HH patients will develop hepatocellular carcinoma if treatment is not established on time. Patients with the same genetic defect present different grades of iron accumulation and therefore different clinical severity.

Cellular iron homeostasis is controlled post-transcriptionally by the IRP/IRE regulatory system. The iron regulatory proteins (IRP1 and IRP2) can recognize a cis-regulatory mRNA motif termed IRE (iron responsive element), a conserved RNA element located in the untranslated regions (UTR) of mRNAs that encode proteins involved in iron metabolism. Recent findings suggest that the IRP/IRE regulatory network is wider than previously though, and include genes involved in cancer progression and metastasis.

Our Research

  • Connections between iron metabolism and cancer

Our recent work has identified new genes that interact with the IRPs (iron regulatory proteins), including genes involved in cell cycle, cancer progression and metastasis. We would like to study the molecular connections between the IRP/IRE regulatory system and cancer applying molecular and cellular biology techniques.

  • Prevention of cancer in iron-overload patients by early and personalized genetic diagnosis

Hereditary Hemochromatosis (HH, OMIM 235200) is a genetic heterogenous disorder caused by excessive iron absorption. The clinical features of HH include liver cirrhosis, hepatocarcinoma, arrhythmias, heart failure, diabetes, arthritis, hypermelanotic pigmentation and hypogonadism. So far, mutations in 5 genes (HFE, HJV, HAMP, TFR2 and FPN) have been implicated in 4 types of iron-overload Hemochromatosis disorders.
Therapeutic phlebotomy, erythrocyte-aphaeresis and iron chelation therapy to remove excess iron are the main treatments for HH patients. Importantly, HH patients diagnosed and treated in an early stage of the illness have a normal life expectancy.
Since these iron-overload diseases can be easily treated, research on them represents a major opportunity for cancer prevention.

  • Study of modifiers genes for clinical severity of Hereditary Hemochromatosis

One third of HH patients will develop hepatocarcinoma if treatment is not established on time. It has been observed that HH patients with the same mutation (e.g. C282Y of HFE gene) present different grades of iron accumulation and therefore different clinical severity. This phenotypic heterogeneity has led to the proposal that modifier genes contribute to the severity of the disease and its progression to cancer. To identify such modifier genes of cancer risk in HH patients, we will study the transcriptomic and proteomic changes in HH patients grouped according to their clinical affection and genetic defect.

  • Discovery of novel genes involved in human diseases of iron imbalance

We are interested in the identification of causative gene mutations in human iron disorders and the study of their molecular mechanism of action. This goal will be accomplished with a combination of strategies including gene candidate approaches and genome-wide next generation sequencing.
The identification of the specific genetic causes in patients with iron metabolism disorders will allow the establishment of guidelines for diagnosis and preventive treatment, avoiding disease progression and life quality threatening complications.

Group Members:

Previous Members of Lab:

  • Ricky Joshi

Colaboraciones

  • Prof. Matthias W. Hentze, M.D. Associate Director of European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Prof. Martina U. Muckenthaler, PhD. Head of Molecular Medicine. University of Heidelberg, Germany.
  • Dr. Vladimir Benes, PhD. Head of GeneCore Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Dr. Albert Altés, M.D. President of Spanish Hemochromatosis Association, Spain.
  • Dr. Rafael Oliva, PhD. , M.D. Geneticist Hospital Clinic of Barcelona, Spain.

Projects

  • Molecular Studies In Rare Genetic Disorders of Iron Metabolism.

    Investigador principalFinanciamientoFecha de inicioFecha de finalización
    Mayka Sanchez ISCIII01-01-201031-12-2012
  • Towards improved diagnosis and treatment of rare inherited microcytic hypochromic anemias related to iron metabolism.

    Investigador principalFinanciamientoFecha de inicioFecha de finalización
    Mayka Sanchez EU01-01-201031-12-2012
  • Competitive grant to help Junior Groups in hiring Technician Support for Research in Health

    Investigador principalFinanciamientoFecha de inicioFecha de finalización
    Mayka Sanchez ISCIII01-01-201131-12-2013

Contacto

Mayka Sanchez
msanchez@imppc.org

Office 2-12, Lab 2-20 (second floor)
(+34) 93 554 3077


Cancer and Iron

Publicaciones relevantes

Luscieti S, Tolle G, Aranda J, Campos CB, Risse F, Moran E, Muckenthaler MU, Sanchez M. Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome. Orphanet J Rare Dis 2013 Feb; 8: 30

Liu Z, Lanford R, Mueller S, Gerhard GS, Luscieti S, Sanchez M, Devireddy L. Siderophore-mediated iron trafficking in humans is regulated by iron. J. Mol. Med. 2012 Oct; 90(10): 1209-21

Sanchez M, Galy B, Schwanhaeusser B, Blake J, Bähr-Ivacevic T, Benes V, Selbach M, Muckenthaler MU, Hentze MW. Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood 2011 Nov; 118(22): e168-79

Kannengiesser C, Sanchez M, Sweeney M, Hetet G, Kerr B, Moran E, Fuster Soler JL, Maloum K, Matthes T, Oudot C, Lascaux A, Pondarré C, Sevilla Navarro J, Vidyatilake S, Beaumont C, Grandchamp B, May A. Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia. Haematologica 2011 Jun; 96(6): 808-13

Campillos M, Cases I, Hentze MW, Sanchez M. SIREs: searching for iron-responsive elements. Nucleic Acids Res. 2010 Jul; 38: W360-7

Ramsay AJ, Quesada V, Sanchez M, Garabaya C, Sardà MP, Baiget M, Remacha A, Velasco G, López-Otín C. Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum. Mol. Genet. 2009 Oct; 18(19): 3673-83

Sanchez M, Galy B, Hentze MW, Muckenthaler MU. Identification of target mRNAs of regulatory RNA-binding proteins using mRNP immunopurification and microarrays. Nat Protoc 2007; 2(8): 2033-42

Sanchez M, Galy B, Muckenthaler MU, Hentze MW. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat. Struct. Mol. Biol. 2007 May; 14(5): 420-6

Sanchez M, Galy B, Dandekar T, Bengert P, Vainshtein Y, Stolte J, Muckenthaler MU, Hentze MW. Iron regulation and the cell cycle: identification of an iron-responsive element in the 3'-untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy. J. Biol. Chem. 2006 Aug; 281(32): 22865-74

Sanchez M, Villa M, Ingelmo M, Sanz C, Bruguera M, Ascaso C, Oliva R. Population screening for hemochromatosis: a study in 5370 Spanish blood donors. J. Hepatol. 2003 Jun; 38(6): 745-50

Sanchez M, Bruguera M, Bosch J, Rodés J, Ballesta F, Oliva R. Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls. J. Hepatol. 1998 Nov; 29(5): 725-8


Ver todas

Generalitat de Catalunya

Unió Europea

CSIC

Universitat Autònoma de Barcelona

Ajuntament de Badalona

Institut Català de la Salut

Germans Trias i Pujol Hospital

Fundació Institut d'investigació en Ciències de la Salut Germans Trias i Pujol

Back to Top