Review Article Thyroid Hormones as Renal Cell Cancer...

Review ArticleThyroid Hormones as Renal Cell Cancer Regulators

Aukasz SzymaNski123 Damian Matak14 Ewa Bartnik25

Cezary Szczylik1 and Anna M Czarnecka1

1Department of Oncology Military Institute of Medicine Szaserow 128 04-141 Warsaw Poland2Institute of Genetics and Biotechnology Faculty of Biology Warsaw University Pawinskiego 5a 02-106 Warsaw Poland3Department of Microwave Safety Military Institute of Hygiene and Epidemiology Kozielska 4 01-163 Warsaw Poland4School of Molecular Medicine Medical University of Warsaw Zwirki i Wigury 61 02-091 Warsaw Poland5Institute of Biochemistry and Biophysics Pawinskiego 5a 02-106 Warsaw Poland

Correspondence should be addressed to Łukasz Szymanski lukas91szgmailcom

Received 28 October 2015 Accepted 23 February 2016

Academic Editor Leonidas C Platanias

Copyright copy 2016 Łukasz Szymanski et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

It is known that thyroid hormone is an important regulator of cancer development and metastasis What is more changes acrossthe genome as well as alternative splicing may affect the activity of the thyroid hormone receptors Mechanism of action of thethyroid hormone is different in every cancer therefore in this review thyroid hormone and its receptor are presented as a regulatorof renal cell carcinoma

1 Renal Cell Carcinoma

Renal cell carcinoma (RCC) is defined by the NationalCancer Institute (NCI) as the most common type of kidneycancer which develops in the lining of the renal tubulesof the kidney [1] Malignant kidney tumors account forapproximately 3 of all malignancies in adults Men sufferfrom kidney cancer twice as often as women The highestincidence of RCC between 1998 and 2006 was observedin North America and the Czech Republic [2] RCC is atumor that is resistant to chemotherapy and radiotherapyCytokine therapy is beneficial only to a small number ofpatients (without multiple unfavorable prognostic factors)and is associatedwith the occurrence of severe adverse effects

Even though substantial progress in general cancer diag-nosis techniques has been achieved as much as around 20ndash30 of patients are diagnosed with metastatic RCC (mRCC)What is more 20 of patients will relapse after nephrectomyand will develop mRCC in the first 12 months after surgery[3] Molecular therapies such as targeting the mammaliantarget of rapamycin (mTOR) and vascular endothelial growthfactor (VEGF) are the main achievements in modern RCCtreatment

Subtypes of RCC are as follows

(i) Clear cell 83(ii) Papillary (chromophil) 11(iii) Chromophobe about 4(iv) Collecting duct carcinoma about 1 [4]

RCC is one of the most vascularized solid cancers andangiogenesis plays a pivotal role in growth of renal tumors(especially ccRCC) because of upregulation of proangio-genic VEGF and platelet-derived growth factor (PDGF) Theupregulation is caused bymutation in the vonHippel-Lindau(VHL) gene which induces overexpression of hypoxia-inducible factor (HIF) [3 5 6]

The main function of tyrosine kinase is to transfer aphosphate group from ATP to a protein in a cell Tyrosinekinases function plays a pivotal role in many signal transduc-tion cascades in which extracellular signals are transmittedthrough the cell membrane to the cytoplasm or nucleuswhere gene expression is modulated [7] Tyrosine kinasereceptors (TKRs) are cell surface receptors formany polypep-tide growth factors hormones and cytokines TKRs are the

Hindawi Publishing CorporationJournal of Signal TransductionVolume 2016 Article ID 1362407 8 pageshttpdxdoiorg10115520161362407

2 Journal of Signal Transduction

key regulators of normal cellular processes and have a criticalrole in the development and progression of many types ofcancer [8] VEGF and PDGF receptors play crucial roles inangiogenesis mainly via induction of cell survival invasionand proliferation as well as exhibition of tyrosine kinaseactivity To block the physiological function of some of theTKR class receptors tyrosine kinase inhibitors (TKIs) weredeveloped Currently the Food and Drug Administration(FDA) approved the following TKIs sunitinib sorafenibaxitinib and pazopanib [5 9] for use in therapy Beva-cizumab which is an anti-VEGF monoclonal antibody [3] iscommonly used with clinical benefit Other new treatmentstrategies target the mTOR pathway which is responsiblefor angiogenesis Everolimus and temsirolimus are mTORinhibitors also approved by the FDA [9] Sunitinib (Sigma-Aldrich) is a tyrosine kinase receptor inhibitor which targetsVEGF-R1 VEGF-R2 VEGF-R3 PDGF-R120572 PDGF-R120573 KITFLT3 CSF-1R and RET Although novel treatment such asusing sunitinib significantly prolongs time to progression theoverall survival of patients diagnosed with RCC is still notsatisfactory which justifies the search for new methods andtherapy targets for which it is necessary to understand themechanisms responsible for the development and progres-sion of this cancer

2 The Thyroid HormonesTriiodothyronine and Thyroxine

The thyroid hormones (THs) thyroxine (T4) and its activeform triiodothyronine (T3) are produced by the thyroidgland In order for the thyroid gland to produce T3 andT4 iodine is needed The most common form of TH inblood is T4 (with the ratio T4T3 = 201) however T4 isconverted to four timesmore potent T3 by 51015840-iodinase withinthe cell Production of T3 and T4 is regulated via a closedloop feedbackmdashhigh levels of T3 and T4 in blood plasmainhibit the production of thyroid-stimulating hormone in thepituitary gland Despite the fact that T3 and T4 are lipophilicthey are not able to diffuse passively through the phospholipidmembrane of the cell Instead the T3 and T4 hormones aredependent on transmembrane iodothyronine transporters[10 11]

Thyroid hormones are known for their impact onmetabolism development and normal growthmostly duringfetal development In adults deregulation of thyroid hor-mone levels can cause hypo- and hyperthyroidism which isconnected with a vast number of clinical symptoms [12ndash15]What is more THs may play an important role in tumorpromotion or suppression [16]

Triiodothyronine (T3) regulates cell proliferation anddifferentiation and cell cycle and apoptosis T3 can act as bothan activator and inhibitor of cell proliferation [17] THs actmainly by their nuclear receptors which serve as hormone-modulated transcriptional regulators

Thyroid hormone receptors (TRs) are encoded by twogenes 120572 and 120573 which are located on chromosome 17 andchromosome 3 respectively [18 19] The THR120573 gene residesin 3p21-25 chromosomal region which is known to be a hot

spot for mutations in genes involved in RCC pathogenesis[20] The transcripts of THR120572 and THR120573 are alternativelyspliced to produce three major isoforms of the receptorTR1205721 TR1205731 and TR1205732 Due to their ability to recruitcoactivators and corepressors those receptors are bipolar intheir transcriptional properties which means that they canactivate or repress target gene expression The chromatintemplate is modified by auxiliary proteins which interactwith general transcriptional machinery to produce appro-priate transcriptional output [21 22] Genetic alterations inTRs can cause diseases Mutations in THR120573 are usually thecause of resistance to thyroid hormone (RTH) syndromeDisturbed activity of TRs is also a common phenomenon inhuman cancers ccRCC is one of the cancers in which aber-rances in TR120573 are frequently observed due to localizationof the gene in the hot spot for mutations [23] TR1205731 is a T3dependent transcription factor In addition to its metabolicrole TR1205731 has been known for its tumor-suppressive function[24] Disrupted expression and activation of TR1205731 have beenpreviously described in tumors of the thyroid [25] lung [26]breasts [27] or insulinomas [28]

Based on research conducted on the cell lines of breastcancer and hepatocellular carcinoma it was proposed thathypothyroidism accelerates the development of metastasesand increases the invasiveness of tumor cells however tumorgrowth is slower Studies on those cell lines in amouse cancermodel also showed that changes in stromal cells of tumormicroenvironment generated in response to low thyroid hor-mone levels significantly alter the development of cancer [29]Activation of the kinase-signaling pathwaymdash3-phosphatidyl-inositol (PI3K) serine-threonine protein kinase AKT andprotein kinase Bmdashis associated with a mutation in the TR120573and the development of cancer [30] Moreover the functionof TR1205731 as tumor suppressor indicates that the low expressionof the receptor can affect the proliferation of cancer cells [31]For example in prostate cancer it was shown that the induc-tion of cells by T3 can increase the proliferation of tumorcells by reducing the B-cell translocation gene 2 (BTG2) geneexpression which is responsible for the regulation of the G1Stransition in the cell cycle [32]

Research on the role of thyroid hormone and its receptorhas proven over the years to be extremely complicatedThe role of thyroid hormones and the thyroid hormonereceptor is not yet understood The problem is the fact thatthe impact of thyroid hormone differs in different types ofcancer Moreover THs may control many different aspectsof the same cancermdashmetastasis apoptosis proliferation anddifferentiationmdashcompletely differently

3 THR120572 and THR120573 Genes Function inRenal Cancer

TR1205731 is known for its tumor-suppressive role [24] so it isunderstandable that expression of this receptor in cancercell lines is reduced Reports of the possibility of existenceof an alternative thyroid hormone-signaling pathway canbe found in literature Shibusawa et al [33] researchedthyroid hormone action in absence of thyroid hormone

Journal of Signal Transduction 3

Nuc

leus

Cyto

plas

m

ITGA

ITGB

ITGA

ITGB

Transporter

Transporter

Transporter

T3

T4

T3

T3

T3

T4

TR1205731

TR1205731

TR1205731

Ras

TR1205721

TR1205721

T3

D1D2

Src

MEK

PI3K AKTPKB mTOR signaling pathway

HIF1120572

C-Myc

Wnt

120573-catenin

Notch

HIF1120572

Figure 1 Thyroid hormone-signaling pathway

receptor It is known that thyroid hormones are essentialfor inner ear development therefore they checked if thesame effect occurs in TR120573minusminus mutant mice They concludedthat although not completely normal inner ear developmentcould occur in the absence of thyroid hormone receptorthus it is possible that an alternative and novel thyroidhormone-signaling pathway may exist Moreover analysis ofthe KEGG database showed that thyroid hormones couldinfluence the cell through MAPK and PI3K-AKT signalingpathways bypassing thyroid hormone receptors as it isshown in Figure 1 [34] Finally nongenomic (therefore not-THR mediated) actions of thyroid hormones include theregulation of ion channels mitochondrial gene transcriptionand oxidative phosphorylation [35]

T4 through its own mechanism of action can pro-mote angiogenesis and cell proliferation Mainly T4 actsthrough plasma membrane receptor on integrin 120572v1205733 120572v1205733is linked with MAP kinasemdashextracellular signal-regulatedkinase (ERK) 12mdashfor transduction of the signal initiatedby T4 [36] What is more Lin et al proposed a model ofaction for T3 and T4 at the receptor domain of 120572v1205733 Inthis two-site model site one (S1) is exclusively reserved forT3 and activates PI3K and Src kinase Activation of thosekinases leads to the transcription of HIF-1120572 Site two (S2)however can be activated by both T3 and T4 and act throughERK12 activation to cause tumor cell proliferation [36] Sincesignaling pathway activated by T4 via 120572v1205733 can lead to geneexpression thus both nongenomic effects of T3 and T4 aswell as genomic effects of T3 may overlap in the nucleus [37]

What is more tetrac which is a deaminated T4 analoghas been shown to block hormone binding at S1 and S2 ofintegrin 120572v1205733 Tetrac blocks nongenomic action of T3 at S1and both T3 and T4 action at S2 therefore tetrac suppressesthe proliferative nongenomic activity of thyroid hormone oncancer cells [36] This data is supported by finding of Yalcinet al who show that tetrac and tetrac nanoparticles reducedtumor volume in human RCC xenografts [38]

Effects of T3 differ between healthy and cancer cell linesThe effect of TH depends on the cell developmental state(stemprogenitordifferentiated) and type and physiologicalstate (canceroushealthy) [17] Since in this case healthy andcancer cell lines are compared it is understandable that theeffects of T3 hormone are different Effect of T3 on the cellcycle in RCC cell lines has never been described previouslyAccording to the literature effects of T3 can promote ordecrease the proliferation rate in different cell lines [17 3940] T3 is produced by (extrathyroidal) conversion of T4 byDI highly expressed in kidney The expression of DI has alsobeen reported as downregulated in RCC (in comparison tonormal kidney) [41]

4 THR120572 and THR120573 Genes Mutations inRenal Cancer

It had been previously shown that the THR120573 gene isfrequently mutated in RCC [42ndash44] however it was onlyshown for tissue samples but not established cell lines Infirst report Kamiya et al [42] found that 409 of tested


ccRCC samples had at least one TR mutation howeverthere is no information about the reference sequence orthe percentage of mutations in samples derived from thehealthy kidney Nevertheless mutations were reported to befound in seven of twenty-two investigated cancer samplesFinally if the ccRCC samples were compared with samplesfrom the healthy kidney there is no information if sequencesobtained from control samples were identical to each otherFuture sequencing research with a broader panel of RCCcell lines and with different primers is needed howeverit is possible that commercially available cell lines are aninadequate model to investigate mutations in RCC THR120573mutations were further studied functionally and it was shownthat most of these RCC mutants result in expression ofa receptor that is impaired in T3-mediated transcriptionalactivity Moreover receptors that are not fully functional aredominant-negative inhibitors of wild type THR1205731 expressedfrom second allele Mutations in the T3-binding domains ofthe receptormdashS380F E299K H412R Y321H and L456Smdashreduce T3 binding activity at different rate between 35 and60 In specific cases including Q252RW219L F451S F451IF417L and A387P up to 100 of T3 binding activity is lostMutations in DNA binding domainmdashlike K155Emdashmay resultin the 100 loss of DNA binding activity of thyroid hormonereceptor [42] In selected mutants loss of transcriptionalactivity results from lower avidity and defective T3 bind-ing In other cases transcriptional inefficiency reported forTHR1205731mutants results fromaltered corepressors binding andrelease These mutants may require significantly higher hor-mone concentration to release the corepressor and activatetranscription In selected cases increase in corepressor affinityis accompanied with modified corepressor and corepressorsplice variants specificity and thismay renderTHR1205731mutantstoward resistance repression inhibition [45] Finally THR1205731mutants were shown to harbor greatly expanded target genespecificity that is not homologous with that of the wildtype THR1205731 Interestingly upregulation of the von Hippel-Lindau (VHL) tumor suppressor was found in rc15-TR1205731mutant cells [44] In functional study T3 had no direct effecton transcription of HIF-1120572 but activation of THR1205731RXR-120572 (retinoid X receptor alpha) heterodimer by T3 stimulatedexpression of HLF (hepatic leukemia factor) which finallypromoted HIF-1120572 expression [46]

5 THR120572 and THR120573 Genes Expression inRenal Cancer

Disrupted TR1205731 activity may be the result of reduced TR1205731expression loss of heterozygosity at the THRB locus [47]decreased intracellular concentrations of T3 mutation inDNA at the THRB locus [42] altered interaction withcoregulators [45] aberrant splicing and sequence of TR1205731UTRs or increased expression of miRNAs that interactwith the THR1205731 31015840 UTR [31] In first reports THR1205731 at thetranscriptome level (mRNA) was reported as overexpressedin 30 and downregulated in 70 of tumor samples Inthe same set of tissues at the proteome level expressionof THR1205731 was decreased 17 times in tumors tissues when

compared to healthy kidney from the same patients In thisreport THR1205731 protein expression was analyzed in nuclearextracts from RCC tumors It was revealed that decreasedTHR1205731 protein level was found in 87 (2023) cancer sampleswhen compared with normal adjacent tissue from the samekidney THR1205731 protein was decreased 12 to 16 times depend-ing on case [48] Another dissonance between the relativeamount of THR120573 mRNA and protein in the cancer cell linewhen compared to healthy (control) cells was observed byMaster et al [31] Expression of THR120573 was correlated withTHR120572 in cancer ccRCC tissues but not in normal kidneysamples [48]THR120573 protein level in cancer tissues was almostnondetectable [48] In more recent study TR1205731 mRNA andprotein levels were reduced by 70 and 91 [31] This 70reduction was reported on THR120573 mRNA coding sequencebut reduced expression of 51015840UTR variants 119860 and 119865 hasbeen reported in 75 and 62 tumors respectively [31] InRCC cell culture model it was shown that weakly foldedvariant 119860 (AY2864651) of 51015840UTR promotes the highestlevel of THR120573 expression while strongly folded variants 119865(AY2864701) and 1198651 (GQ456950) result in low transcriptionand translation rates and low THR120573 expression and in RCCthe delicate balance between119860 and1198651198651 variants is disturbed[31] Reported discordance in TR1205731 mRNA level and proteinalong with mutations in THR120573 51015840UTRs deregulating mRNAstability and transcription rate suggests thatTHR120573 expressionis regulated mostly by posttranscriptional events along withepigenetic modifications and specific transcription initiationcontrol [31 45 49]

6 Thyroid Function andRenal Cancer Treatment

Tyrosine kinase inhibitor RCC therapy is associated withdevelopment of hypothyroidism in up to 25 of patients asper registered trials (average value for subclinical and clinicalhyperthyroidism) [50ndash52] and up to 100 in selectedmdashAsianmdashcohorts [53] It is important to notice that subnormallevels of serum TSH do not always reflect the presence ofsubclinical hyperthyroidism and in themajor part of availableliterature the definition of hypothyroidism is unclear Amongpatients treated with sorafenib sunitinib pazopanib and axi-tinib those treated with axitinib develop thyroid dysfunctionfaster and more pronounced compared to the others [53]The mechanism through which this tyrosine kinase inhibitor(TKI) causes changes in function of the thyroid is not yet fullyunderstood however emerging evidence suggests that suni-tinib induces hypothyroidism by altering T4T3 metabolismand thyroid capillary regression Sunitinib was found tohave antithyroperoxidase activity with potency equivalentto 25 of propylthiouracil (6-propyl-2-sulfanylpyrimidin-4-one) It was found that on sunitinib treatment oxidationof iodide ions to iodine atoms required for the synthesisof T4 is reduced [54] In cell culture model sunitinib wasshown to induce thyroid cells proliferation inhibition (IC

50

146 120583M) and dose-related increase of (125) I-iodide uptake[55] Computed tomography volumetry of thyroid gland onsunitinib treatment revealed thatmore than 50 reduction in


volume may develop in half of the patients [56] Histologicalstudy revealed that thyroid atrophy of thyroid follicles withdegeneration of follicular epithelial cells is found on autopsyof patients treated with sunitinib for RCC Surprisingly nodecease in vascular volume in the thyroid gland was foundin these patients [56]

In clinical research it was also shown that iodine uptakeis impaired in RCC patients treated with sunitinib and thelowest uptake is reported at the end of on-drug period ofsunitinib treatment (end of 4th week of treatment) [57] Mostrecently it was investigated if autoimmunity is coresponsi-ble for thyroid dysfunction in RCC patients treated withsunitinib It was found that up to 25 of patients developanti-thyroid peroxidase (TPOAb) autoantibodies within 12ndash18 month of therapy with sunitinib Moreover it was foundthat progression-free survival (PFS) is significantly longer inpatients developing these TPOAb in comparison to thosewho do not develop autoimmune response (108 monthsversus 58 months) [58]

There are also a few other possible explanations TKI-induced inhibition of VEGF receptor tyrosine kinases on thy-roid cells that result in capillary regression [59 60] inhibitionof iodine uptake [57] and inhibition of the protein productof the RET protooncogene [61] Moreover hypothyroidisminduced by TKIs such as sunitinib may not be an unwantedtoxicity because T3 promotes proliferation of cancer stemcells and metastatic and primary cell lines Moreover it wasproven that T3 reportedly increased the growth of gliomacells [62] Schmidinger et al [63] showed that patients whodeveloped subclinical hypothyroidism during treatment withsunitinib had a significantly greater probability of respondingto treatment

Although correlations between hypothyroidism andtreatment outcome have been noticed [64] and manyresearchers confirmed an association between progression-free survival (PFS) and hypothyroidism [65] the rate ofobjective remission (ORR) (hypothyroid patients versuseuthyroid patients 467 versus 137 resp 119875 = 0001)and the median overall survival (hypothyroid patients versuseuthyroid patients 39 versus 20 months resp 119875 = 0019)[66] some researchers argue that there is no certaintythat hypothyroidism can be considered as an independentprognostic marker because it is still unclear if the inductionof hypothyroidism is the mode of sunitinib action or thisphenomenon is dependent on pharmacokinetics height andweight of the patient or affinity to tyrosine kinase receptor[63] It was suggested that although PFS is longer in thesepatients there might be no difference in overall survival ofhypothyroid patients [67]

Finally in their study Schmidinger et al [63] reportedthat there is a statistically significant correlation betweenhypothyroidism during the treatment of kidney cancer usingtyrosine kinase inhibitors and the percentage remission(patients with hypothyroidism versus euthyroid patients283 versus 33 resp 119875 lt 0001) and the mean survivaltime (above and below 139 months resp 119875 = 0016)In another study hypothyroidism was associated with alonger PFS in patients treated with sunitinib or sorafenib

(160 months versus 60 months) and replacement with l-thyroxine did not show influence on PFS [64] Recent meta-analysis that covered 250 patients has shown that there is nosignificant statistical difference in PFS between patients withhypothyroidism on sunitinib and patients without acquiredhypothyroidism (HR = 082 and 119875 = 022) Similarresult was calculated for OS (HR = 052 and 119875 = 001)This leads the authors to the conclusion that developmentof hypothyroidism during tyrosine kinase inhibitor therapymay not be an independent predictive factor in patients withmetastatic renal cell cancer [68]

7 Conclusion and Future Perspectives

It is known for a long time that T3 has high impact oncancer development and maintenance however there isno fundamental and comprehensive analysis of the roleof thyroid hormone in different populations of cancer Ofcourse many research groups study T3 influence on cancerhowever those findings are not structured and cannot becompared to each other because thyroid hormone can actdifferently in different types of cancer Many research groupsprovided very important data about T3 and cancer forexample it has been shown by Poplawski and Nauman thatT3 promotes cell proliferation in RCC in vitro but does nothave the same effect on a cell line derived fromhealthy kidney[69] What is more Puzianowska-Kuznicka et al [48] andMaster et al [31] observed that cells derived from RCC havedisrupted TR120573 expression on both the mRNA and proteinlevel therefore disrupted posttranscriptional regulation hasbeen proven for RCC Research by Kamiya et al [42] showednumerous mutations in the THR120573 transcript in the samplesderived from RCC patients However it is important tomention that studies cited in this paper used supraphysiologicconcentrations of T3 in in vitro experiments Concentrationof T3 in human sera was described in numerus studies bymany groups as 307 nM [70] 192 nM [71] 169 nM [72]and 507 nM [73] Therefore it is important to conduct anexperiment with physiological concentrations of T3 Whatis more based on these and many other publications it ispossible to design and perform functional analysis of theTR1205731 in different populations of cancer representing primarytumor metastatic tumor and cancer stem cell populationsof RCC It is extremely important to understand the mecha-nisms responsible for the disrupted influence of T3 hormoneon cells of renal cell carcinoma because of its role as a cancerregulator and its link to therapy with sunitinib and othermultitargeted receptor tyrosine kinase inhibitors

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by the Military Institute ofMedicine statutory founding and Ministry of Science and


Higher Education Juventus Plus no IP2011008171 Grant0081IP201171

References

[1] Definition of Renal Cell CancermdashNCI Dictionary of Can-cer Terms National Cancer Institute httpwwwcancergovdictionary

[2] W-H Chow L M Dong and S S Devesa ldquoEpidemiology andrisk factors for kidney cancerrdquo Nature Reviews Urology vol 7no 5 pp 245ndash257 2010

[3] M Buczek B Escudier E Bartnik C Szczylik and A Czar-necka ldquoResistance to tyrosine kinase inhibitors in clear cellrenal cell carcinoma from the patientrsquos bed to molecular mech-anismsrdquo Biochimica et Biophysica ActamdashReviews on Cancer vol1845 no 1 pp 31ndash41 2014

[4] J C Cheville C M Lohse H Zincke A L Weaver and M LBlute ldquoComparisons of outcome andprognostic features amonghistologic subtypes of renal cell carcinomardquoAmerican Journal ofSurgical Pathology vol 27 no 5 pp 612ndash624 2003

[5] J Mattei R D da Silva D Sehrt W R Molina and F JKim ldquoTargeted therapy in metastatic renal carcinomardquo CancerLetters vol 343 no 2 pp 156ndash160 2014

[6] C Lv Z Bai Z Liu P Luo and J Zhang ldquoRenal cell carcinomarisk is associated with the interactions of APOE VHL andMTHFR gene polymorphismsrdquo International Journal of Clinicaland Experimental Pathology vol 8 pp 5781ndash5786 2015

[7] V Radha S Nambirajan and G Swarup ldquoAssociation ofLyn tyrosine kinase with the nuclear matrix and cell-cycle-dependent changes in matrix-associated tyrosine kinase activ-ityrdquo European Journal of Biochemistry vol 236 no 2 pp 352ndash359 1996

[8] E Zwick J Bange andAUllrich ldquoReceptor tyrosine kinase sig-nalling as a target for cancer intervention strategiesrdquo Endocrine-Related Cancer vol 8 no 3 pp 161ndash173 2001

[9] E Diamond J Riches B Faltas S T Tagawa and D MNanus ldquoImmunologics and chemotherapeutics for renal cellcarcinomardquo Seminars in Interventional Radiology vol 31 no 1pp 91ndash97 2014

[10] A J Hulbert ldquoThyroid hormones and their effects a newperspectiverdquo Biological Reviews of the Cambridge PhilosophicalSociety vol 75 no 4 pp 519ndash631 2000

[11] G Hennemann R Docter E C H Friesema M De Jong EP Krenning and T J Visser ldquoPlasma membrane transport ofthyroid hormones and its role in thyroid hormone metabolismand bioavailabilityrdquo Endocrine Reviews vol 22 no 4 pp 451ndash476 2001

[12] D Forrest L C Erway L Ng R Altschuler and T CurranldquoThyroid hormone receptor 120573 is essential for development ofauditory functionrdquo Nature Genetics vol 13 no 3 pp 354ndash3571996

[13] L Wikstrom C Johansson C Salto et al ldquoAbnormal heartrate and body temperature in mice lacking thyroid hormonereceptor 1205721rdquoTheEMBO Journal vol 17 no 2 pp 455ndash461 1998

[14] A Oetting and P M Yen ldquoNew insights into thyroid hormoneactionrdquo Best Practice and Research in Clinical Endocrinology andMetabolism vol 21 no 2 pp 193ndash208 2007

[15] S-Y Cheng J L Leonard and P J Davis ldquoMolecular aspects ofthyroid hormone actionsrdquo Endocrine Reviews vol 31 no 2 pp139ndash170 2010

[16] L C Moeller and D Fuhrer ldquoThyroid hormone thyroid hor-mone receptors and cancer a clinical perspectiverdquo Endocrine-Related Cancer vol 20 no 2 pp R19ndashR29 2013

[17] M Puzianowska-Kuznicka M Pietrzak O Turowska andA Nauman ldquoThyroid hormones and their receptors in theregulation of cell proliferationrdquo Acta Biochimica Polonica vol53 no 4 pp 641ndash650 2006

[18] P M Yen ldquoPhysiological and molecular basis of thyroid hor-mone actionrdquo Physiological Reviews vol 81 no 3 pp 1097ndash11422001

[19] W G Kim and S-Y Cheng ldquoThyroid hormone receptors andcancerrdquo Biochimica et Biophysica ActamdashGeneral Subjects vol1830 no 7 pp 3928ndash3936 2013

[20] J M Hagenkord Z Gatalica E Jonasch and F A MonzonldquoClinical genomics of renal epithelial tumorsrdquo Cancer Geneticsvol 204 no 6 pp 285ndash297 2011

[21] S-Y Cheng ldquoMultiple mechanisms for regulation of the tran-scriptional activity of thyroid hormone receptorsrdquo Reviews inEndocrine and Metabolic Disorders vol 1 no 1 pp 9ndash18 2000

[22] N J McKenna R B Lanz and B W OrsquoMalley ldquoNuclear recep-tor coregulators cellular and molecular biologyrdquo EndocrineReviews vol 20 no 3 pp 321ndash344 1999

[23] V K K Chatterjee ldquoResistance to thyroid hormone andperoxisome-proliferator-activated receptor 120574 resistancerdquo Bio-chemical Society Transactions vol 29 no 2 pp 227ndash231 2001

[24] O Martınez-Iglesias S Garcia-Silva S P Tenbaum et alldquoThyroid hormone receptor 1205731 acts as a potent suppressor oftumor invasiveness andmetastasisrdquoCancer Research vol 69 no2 pp 501ndash509 2009

[25] C J Guigon and S-Y Cheng ldquoNovel non-genomic signaling ofthyroid hormone receptors in thyroid carcinogenesisrdquoMolecu-lar and Cellular Endocrinology vol 308 no 1-2 pp 63ndash69 2009

[26] Y Iwasaki N Sunaga Y Tomizawa et al ldquoEpigenetic inactiva-tion of the thyroid hormone receptor 1205731 gene at 3p242 in lungcancerrdquo Annals of Surgical Oncology vol 17 no 8 pp 2222ndash2228 2010

[27] S Sato K Muraishi J Tani et al ldquoClinical characteristicsof thyroid abnormalities induced by sunitinib treatment inJapanese patients with renal cell carcinomardquo Endocrine Journalvol 57 no 10 pp 873ndash880 2010

[28] C Verga Falzacappa V Patriarca B Bucci et al ldquoThe TR1205731is essential in mediating T3 action on Akt pathway in humanpancreatic insulinoma cellsrdquo Journal of Cellular Biochemistryvol 106 no 5 pp 835ndash848 2009

[29] O Martınez-Iglesias S Garcıa-Silva J Regadera and AAranda ldquoHypothyroidism enhances tumor invasiveness andmetastasis developmentrdquo PLoS ONE vol 4 no 7 Article IDe6428 2009

[30] F Furuya J A Hanover and S-Y Cheng ldquoActivation ofphosphatidylinositol 3-kinase signaling by a mutant thyroidhormone 120573 receptorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 6 pp 1780ndash1785 2006

[31] A Master A Wojcicka A Piekiełko-Witkowska et alldquoUntranslated regions of thyroid hormone receptor beta 1mRNA are impaired in human clear cell renal cell carcinomardquoBiochimica et Biophysica ActamdashMolecular Basis of Disease vol1802 no 11 pp 995ndash1005 2010

[32] K-H Tsui W-C Hsieh M-H Lin P-L Chang and H-H Juang ldquoTriiodothyronine modulates cell proliferation of


human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2rdquo The Prostate vol 68 no 6 pp 610ndash619 2008

[33] N Shibusawa K Hashimoto A A Nikrodhanond et alldquoThyroid hormone action in the absence of thyroid hormonereceptor DNA-binding in vivordquo The Journal of Clinical Investi-gation vol 112 no 4 pp 588ndash597 2003

[34] KEGG PATHWAY Thyroid Hormone Signaling PathwaymdashHomo sapiens (Human) httpwwwgenomejpkegg-binshowpathwayorg name=hsaampmapno=04919ampmapscale=ampshow de-scription=hide

[35] J H D Bassett C B Harvey and G R Williams ldquoMechanismsof thyroid hormone receptor-specific nuclear and extra nuclearactionsrdquo Molecular and Cellular Endocrinology vol 213 no 1pp 1ndash11 2003

[36] H-Y Lin M Sun H-Y Tang et al ldquoL-thyroxine vs3531015840-triiodo-L-thyronine and cell proliferation Activation ofmitogen-activated protein kinase and phosphatidylinositol 3-kinaserdquo The American Journal of PhysiologymdashCell Physiologyvol 296 no 5 pp C980ndashC991 2009

[37] P J Davis F Goglia and J L Leonard ldquoNongenomic actionsof thyroid hormonerdquoNature Reviews Endocrinology vol 12 pp111ndash121 2016

[38] M Yalcin D J Bharali L Lansing et al ldquoTetraidothyroaceticacid (tetrac) and tetrac nanoparticles inhibit growth of humanrenal cell carcinoma xenograftsrdquo Anticancer Research vol 29no 10 pp 3825ndash3831 2009

[39] E Porlan O G Vidaurre and A Rodrıguez-Pena ldquoThyroidhormone receptor-120573 (TR1205731) impairs cell proliferation by thetranscriptional inhibition of cyclins D1 E and A2rdquo Oncogenevol 27 no 19 pp 2795ndash2800 2008

[40] J M Gonzalez-Sancho A Figueroa M Lopez-Barahona ELopez H Beug and A Munoz ldquoInhibition of proliferation andexpression of T1 and cyclin D1 genes by thyroid hormone inmammary epithelial cellsrdquoMolecular Carcinogenesis vol 34 no1 pp 25ndash34 2002

[41] J Pachucki M Ambroziak Z Tanski J Luczak J Nauman andA Nauman ldquoType I 51015840-iodothyronine deiodinase activity andmRNA are remarkably reduced in renal clear cell carcinomardquoJournal of Endocrinological Investigation vol 24 no 4 pp 253ndash261 2001

[42] Y Kamiya M Puzianowska-Kuznicka P McPhie J NaumanS-Y Cheng and A Nauman ldquoExpression of mutant thyroidhormone nuclear receptors is associated with human renal clearcell carcinomardquo Carcinogenesis vol 23 no 1 pp 25ndash33 2002

[43] S-Y Cheng ldquoThyroid hormone receptor mutations in cancerrdquoMolecular and Cellular Endocrinology vol 213 no 1 pp 23ndash302003

[44] M D Rosen I H Chan and M L Privalsky ldquoMutant thyroidhormone receptors (TRs) isolated from distinct cancer typesdisplay distinct target gene specificities a unique regulatoryrepertoire associated with two renal clear cell carcinomasrdquoMolecular Endocrinology vol 25 no 8 pp 1311ndash1325 2011

[45] M D Rosen and M L Privalsky ldquoThyroid hormone receptormutations found in renal clear cell carcinomas alter corepressorrelease and reveal helix 12 as key determinant of corepressorspecificityrdquo Molecular Endocrinology vol 23 no 8 pp 1183ndash1192 2009

[46] T Otto and J Fandrey ldquoThyroid hormone induces hypoxia-inducible factor 1120572 gene expression through thyroid hormone

receptor 120573retinoid X receptor 120572-dependent activation of hep-atic leukemia factorrdquo Endocrinology vol 149 no 5 pp 2241ndash2250 2008

[47] M Chen Y Ye H Yang et al ldquoGenome-wide profiling ofchromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arraysrdquo InternationalJournal of Cancer vol 125 no 10 pp 2342ndash2348 2009

[48] M Puzianowska-Kuznicka A Nauman A Madej Z TanskiS-Y Cheng and J Nauman ldquoExpression of thyroid hormonereceptors is disturbed in human renal clear cell carcinomardquoCancer Letters vol 155 no 2 pp 145ndash152 2000

[49] A Wojcicka A Piekielko-Witkowska H Kedzierska et alldquoEpigenetic regulation of thyroid hormone receptor beta inrenal cancerrdquo PLoS ONE vol 9 no 5 Article ID e97624 2014

[50] R J Motzer T E Hutson P Tomczak et al ldquoSunitinib versusinterferon alfa in metastatic renal-cell carcinomardquo The NewEngland Journal of Medicine vol 356 no 2 pp 115ndash124 2007

[51] B I Rini I Tamaskar P Shaheen et al ldquoHypothyroidismin patients with metastatic renal cell carcinoma treated withsunitinibrdquo Journal of the National Cancer Institute vol 99 no1 pp 81ndash83 2007

[52] F Illouz D Braun C Briet U Schweizer and P RodienldquoEndocrine side-effects of anti-cancer drugs thyroid effects oftyrosine kinase inhibitorsrdquo European Journal of Endocrinologyvol 171 no 3 pp R91ndashR99 2014

[53] M Daimon T Kato W Kaino et al ldquoThyroid dysfunctionin patients treated with tyrosine kinase inhibitors sunitinibsorafenib and axitinib for metastatic renal cell carcinomardquoJapanese Journal of Clinical Oncology vol 42 no 8 Article IDhys076 pp 742ndash747 2012

[54] E Wong L S Rosen M Mulay et al ldquoSunitinib induceshypothyroidism in advanced cancer patients and may inhibitthyroid peroxidase activityrdquo Thyroid vol 17 no 4 pp 351ndash3552007

[55] A K Salem M S Fenton K M Marion and J M HershmanldquoEffect of sunitinib on growth and function of FRTL-5 thyroidcellsrdquoThyroid vol 18 no 6 pp 631ndash635 2008

[56] N Shinohara M Takahashi T Kamishima et al ldquoThe inci-dence and mechanism of sunitinib-induced thyroid atrophy inpatients with metastatic renal cell carcinomardquo British Journal ofCancer vol 104 no 2 pp 241ndash247 2011

[57] D Mannavola P Coco G Vannucchi et al ldquoA noveltyrosine-kinase selective inhibitor sunitinib induces transienthypothyroidism by blocking iodine uptakerdquo Journal of ClinicalEndocrinology and Metabolism vol 92 no 9 pp 3531ndash35342007

[58] F Pani F Atzori G Baghino et al ldquoThyroid dysfunction inpatients with metastatic carcinoma treated with sunitinib isthyroid autoimmunity involvedrdquo Thyroid vol 25 no 11 pp1255ndash1261 2015

[59] F Baffert T Le G Thurston and D M McDonald ldquoAngio-poietin-1 decreases plasma leakage by reducing number andsize of endothelial gaps in venulesrdquo The American Journal ofPhysiologymdashHeart andCirculatory Physiology vol 290 no 1 ppH107ndashH118 2006

[60] T Kamba B Y Y Tam H Hashizume et al ldquoVEGF-dependent plasticity of fenestrated capillaries in the normaladult microvasculaturerdquo The American Journal of PhysiologymdashHeart and Circulatory Physiology vol 290 no 2 pp H560ndashH576 2006

[61] M A Skinner S D Safford and A J Freemerman ldquoRETtyrosine kinase and medullary thyroid cells are unaffected by


clinical doses of STI571rdquo Anticancer Research vol 23 no 5 pp3601ndash3606 2003

[62] F B Davis H-Y Tang A Shih et al ldquoActing via a cell surfacereceptor thyroid hormone is a growth factor for glioma cellsrdquoCancer Research vol 66 no 14 pp 7270ndash7275 2006

[63] M Schmidinger UMVoglM Bojic et al ldquoHypothyroidism inpatients with renal cell carcinoma blessing or curserdquo Cancervol 117 no 3 pp 534ndash544 2011

[64] L M Riesenbeck S Bierer I Hoffmeister et al ldquoHypothy-roidism correlates with a better prognosis in metastatic renalcancer patients treated with sorafenib or sunitinibrdquo WorldJournal of Urology vol 29 no 6 pp 807ndash813 2011

[65] L Liwanpo C Ro S Haq and J M Hershman ldquoSunitinib doesnot block thyroid peroxidase in patientsrdquoThyroid vol 24 no 8pp 1325ndash1326 2014

[66] O Bozkurt H Karaca I Hacıbekiroglu et al ldquoIs sunitinib-induced hypothyroidism a predictive clinical marker for betterresponse inmetastatic renal cell carcinoma patientsrdquo Journal ofChemotherapy 2015

[67] D Kust M Prpic J Murgic et al ldquoHypothyroidism as apredictive clinical marker of better treatment response tosunitinib therapyrdquo Anticancer Research vol 34 no 6 pp 3177ndash3184 2014

[68] A Nearchou A Valachis P Lind O Akre and P SandstromldquoAcquired hypothyroidism as a predictive marker of outcomein patients with metastatic renal cell carcinoma treated withtyrosine kinase inhibitors a literature-based meta-analysisrdquoClinical Genitourinary Cancer vol 13 no 4 pp 280ndash286 2015

[69] P Poplawski and A Nauman ldquoThyroid hormonemdashtriiodothy-roninemdashhas contrary effect on proliferation of human proximaltubules cell line (HK2) and renal cancer cell lines (Caki-2 Caki-1)mdashrole of E2F4 E2F5 and p107 p130rdquoThyroid Research vol 1no 1 article 5 2008

[70] K Sterling D Bellabarba E S Newman and M A BrennerldquoDetermination of triiodothyronine concentration in humanserumrdquo The Journal of Clinical Investigation vol 48 no 6 pp1150ndash1158 1969

[71] J E H Stafford S Lees and D Watson ldquoSerum triiodothyro-nine determination in clinical userdquo Journal of Clinical Pathologyvol 29 no 7 pp 642ndash647 1976

[72] P R Larsen ldquoDirect immunoassay of triiodothyronine inhuman serumrdquoThe Journal of Clinical Investigation vol 51 no8 pp 1939ndash1949 1972

[73] J A Nauman A Nauman and S C Werner ldquoTotal andfree triiodothyronine in human serumrdquoThe Journal of ClinicalInvestigation vol 46 no 8 pp 1346ndash1355 1967

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

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Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

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Signal TransductionJournal of


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Evolutionary BiologyInternational Journal of



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ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Virolog y

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Stem CellsInternational



Enzyme Research



Microbiology


key regulators of normal cellular processes and have a criticalrole in the development and progression of many types ofcancer [8] VEGF and PDGF receptors play crucial roles inangiogenesis mainly via induction of cell survival invasionand proliferation as well as exhibition of tyrosine kinaseactivity To block the physiological function of some of theTKR class receptors tyrosine kinase inhibitors (TKIs) weredeveloped Currently the Food and Drug Administration(FDA) approved the following TKIs sunitinib sorafenibaxitinib and pazopanib [5 9] for use in therapy Beva-cizumab which is an anti-VEGF monoclonal antibody [3] iscommonly used with clinical benefit Other new treatmentstrategies target the mTOR pathway which is responsiblefor angiogenesis Everolimus and temsirolimus are mTORinhibitors also approved by the FDA [9] Sunitinib (Sigma-Aldrich) is a tyrosine kinase receptor inhibitor which targetsVEGF-R1 VEGF-R2 VEGF-R3 PDGF-R120572 PDGF-R120573 KITFLT3 CSF-1R and RET Although novel treatment such asusing sunitinib significantly prolongs time to progression theoverall survival of patients diagnosed with RCC is still notsatisfactory which justifies the search for new methods andtherapy targets for which it is necessary to understand themechanisms responsible for the development and progres-sion of this cancer

2 The Thyroid HormonesTriiodothyronine and Thyroxine

The thyroid hormones (THs) thyroxine (T4) and its activeform triiodothyronine (T3) are produced by the thyroidgland In order for the thyroid gland to produce T3 andT4 iodine is needed The most common form of TH inblood is T4 (with the ratio T4T3 = 201) however T4 isconverted to four timesmore potent T3 by 51015840-iodinase withinthe cell Production of T3 and T4 is regulated via a closedloop feedbackmdashhigh levels of T3 and T4 in blood plasmainhibit the production of thyroid-stimulating hormone in thepituitary gland Despite the fact that T3 and T4 are lipophilicthey are not able to diffuse passively through the phospholipidmembrane of the cell Instead the T3 and T4 hormones aredependent on transmembrane iodothyronine transporters[10 11]

Thyroid hormones are known for their impact onmetabolism development and normal growthmostly duringfetal development In adults deregulation of thyroid hor-mone levels can cause hypo- and hyperthyroidism which isconnected with a vast number of clinical symptoms [12ndash15]What is more THs may play an important role in tumorpromotion or suppression [16]

Triiodothyronine (T3) regulates cell proliferation anddifferentiation and cell cycle and apoptosis T3 can act as bothan activator and inhibitor of cell proliferation [17] THs actmainly by their nuclear receptors which serve as hormone-modulated transcriptional regulators

Thyroid hormone receptors (TRs) are encoded by twogenes 120572 and 120573 which are located on chromosome 17 andchromosome 3 respectively [18 19] The THR120573 gene residesin 3p21-25 chromosomal region which is known to be a hot

spot for mutations in genes involved in RCC pathogenesis[20] The transcripts of THR120572 and THR120573 are alternativelyspliced to produce three major isoforms of the receptorTR1205721 TR1205731 and TR1205732 Due to their ability to recruitcoactivators and corepressors those receptors are bipolar intheir transcriptional properties which means that they canactivate or repress target gene expression The chromatintemplate is modified by auxiliary proteins which interactwith general transcriptional machinery to produce appro-priate transcriptional output [21 22] Genetic alterations inTRs can cause diseases Mutations in THR120573 are usually thecause of resistance to thyroid hormone (RTH) syndromeDisturbed activity of TRs is also a common phenomenon inhuman cancers ccRCC is one of the cancers in which aber-rances in TR120573 are frequently observed due to localizationof the gene in the hot spot for mutations [23] TR1205731 is a T3dependent transcription factor In addition to its metabolicrole TR1205731 has been known for its tumor-suppressive function[24] Disrupted expression and activation of TR1205731 have beenpreviously described in tumors of the thyroid [25] lung [26]breasts [27] or insulinomas [28]

Based on research conducted on the cell lines of breastcancer and hepatocellular carcinoma it was proposed thathypothyroidism accelerates the development of metastasesand increases the invasiveness of tumor cells however tumorgrowth is slower Studies on those cell lines in amouse cancermodel also showed that changes in stromal cells of tumormicroenvironment generated in response to low thyroid hor-mone levels significantly alter the development of cancer [29]Activation of the kinase-signaling pathwaymdash3-phosphatidyl-inositol (PI3K) serine-threonine protein kinase AKT andprotein kinase Bmdashis associated with a mutation in the TR120573and the development of cancer [30] Moreover the functionof TR1205731 as tumor suppressor indicates that the low expressionof the receptor can affect the proliferation of cancer cells [31]For example in prostate cancer it was shown that the induc-tion of cells by T3 can increase the proliferation of tumorcells by reducing the B-cell translocation gene 2 (BTG2) geneexpression which is responsible for the regulation of the G1Stransition in the cell cycle [32]

Research on the role of thyroid hormone and its receptorhas proven over the years to be extremely complicatedThe role of thyroid hormones and the thyroid hormonereceptor is not yet understood The problem is the fact thatthe impact of thyroid hormone differs in different types ofcancer Moreover THs may control many different aspectsof the same cancermdashmetastasis apoptosis proliferation anddifferentiationmdashcompletely differently

3 THR120572 and THR120573 Genes Function inRenal Cancer

TR1205731 is known for its tumor-suppressive role [24] so it isunderstandable that expression of this receptor in cancercell lines is reduced Reports of the possibility of existenceof an alternative thyroid hormone-signaling pathway canbe found in literature Shibusawa et al [33] researchedthyroid hormone action in absence of thyroid hormone


Nuc

leus

Cyto

plas

m

ITGA

ITGB

ITGA

ITGB

Transporter

Transporter

Transporter

T3

T4

T3

T3

T3

T4

TR1205731

TR1205731

TR1205731

Ras

TR1205721

TR1205721

T3

D1D2

Src

MEK


HIF1120572

C-Myc

Wnt

120573-catenin

Notch

HIF1120572















50











Competing Interests


Acknowledgments




References






















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Nuc

leus

Cyto

plas

m

ITGA

ITGB

ITGA

ITGB

Transporter

Transporter

Transporter

T3

T4

T3

T3

T3

T4

TR1205731

TR1205731

TR1205731

Ras

TR1205721

TR1205721

T3

D1D2

Src

MEK


HIF1120572

C-Myc

Wnt

120573-catenin

Notch

HIF1120572















50











Competing Interests


Acknowledgments




References






















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








50











Competing Interests


Acknowledgments




References






















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










Competing Interests


Acknowledgments




References






















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



References






















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Review Article Thyroid Hormones as Renal Cell Cancer...

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Transcript of Review Article Thyroid Hormones as Renal Cell Cancer...