Endocrinol Metab > Volume 30(2); 2015 > Article
Lee, Chang, Kang, Yi, Lee, Joung, Kim, and Shong: Mitochondrial Energy Metabolism and Thyroid Cancers

Abstract

Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.

INTRODUCTION

Energy metabolism in most cancer cells differs markedly from that in normal cells to meet the energy needs during tumor progression. Currently, thyroid cancer originating from follicular epithelial cells is classified based on pathological features. The four major types of primary thyroid cancers-papillary, follicular, poorly differentiated, and anaplastic carcinomas-show substantial differences in biological and clinical behaviors. Even among the same pathological types, there is wide variability in the clinical course of disease progression. It is clear that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor in determining the clinical phenotypes of cancer. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade [1,2,3,4,5,6]. However, the role and nature of energy metabolism in thyroid cancer remain unclear.
Mitochondria provide 90% of the cellular energy required for various biological functions through oxidative phosphorylation (OxPhos) in the inner mitochondrial membrane [7]. In addition, mitochondria regulate cellular metabolism, including steroid hormone and porphyrin synthesis, the urea cycle, lipid metabolism, and interconversion of amino acids [8]. They also play central roles in apoptosis, cell proliferation, and cellular Ca2+ homeostasis, which affect numerous other cell signaling pathways [8,9]. Thus, mitochondria play an important role in energy metabolism in the normal thyroid gland as well as in thyroid tumors. The roles of functional and structural alterations in mitochondria in tumorigenesis and tumor progression in the thyroid gland need to be explored. This review article focuses on current knowledge of mitochondrial metabolism and its exploitation by thyroid cancer. We give an overview of metabolic changes, mitochondrial alterations, and the significance of mitochondria in slow-growing and fast-growing thyroid cancers.

MITOCHONDRIAL OxPhos FUNCTION IN THE THYROID GLAND

The thyroid gland is an endocrine organ with a high energy demand, in which oxidative processes are indispensable for thyroid hormone synthesis. It is thought that huge amounts of reactive oxygen species (ROS), which are generated from electron transport within the inner mitochondrial membrane, are produced in the thyroid under physiological conditions. Because of the cellular toxicity of excess amounts of ROS, such as H2O2, mitochondria of follicular cells contain various antioxidant defense systems, such as glutathione peroxidase, catalase, superoxide dismutases, and peroxiredoxins, to detoxify H2O2 and other ROS. Mitochondrial defense mechanisms against ROS are also important for cell viability [10]. Increased oxidative damage to macromolecules and inactive antioxidant defense systems have been found in thyroid cancers [11]. Oxidative damage to macromolecules may be an early event in thyroid cancer that may affect disease progression. Additionally, whereas antioxidant defense activity increases in differentiated thyroid cancer, decreased expression of antioxidant enzymes was found in advanced thyroid cancer and anaplastic carcinoma.
The primary function of the thyroid gland is the production of thyroid hormone, a process that is regulated by multiple unique cell biological pathways [12]. Although many investigators suggest that oxidative stress and energy depletion might result in thyroid dysfunction, no clear evidence indicates that mitochondrial dysfunction is an immediate cause of thyroid dysfunction. We developed a mouse model of thyroid-specific mitochondrial dysfunction to investigate the role of oxidative function and to identify modifiers in thyroid failure. We showed that a severe mitochondrial OxPhos defect resulted in overt hypothyroidism, with morphological changes characterized by distortion of thyroid follicles (unpublished data).

ENERGY METABOLISM IN THYROID CANCER

Differentiated thyroid cancers (papillary, follicular, and medullary carcinoma) are slow-growing cancers with good prognoses. As previously described, the Warburg effect and aerobic glycolysis were not greatly elevated in slow-growing cancers, but were strongly associated with poorly differentiated fast-growing cancers. Activation of hypoxia-inducible factor 1 (HIF-1), a transcription factor that is stabilized in response to hypoxia, significantly contributes to the conversion of glucose to lactate [13]. The activation of certain oncogenes, such as epidermal growth factor receptor (EGFR) and Src, also stabilizes HIF-1 protein under normoxic conditions, resulting in inhibition of mitochondrial adenosine triphosphate (ATP) production and activation of aerobic glycolytic metabolism [14]. HIF-1 activation is associated with increased proliferation, which is potentially associated with more aggressive tumors and poor prognosis [15].
As well as differences in cancer cell metabolism between fast-growing and slow-growing thyroid cancers, there are also differences in survival rate and prognosis between differentiated and poorly differentiated thyroid cancers. A subgroup of patients with differentiated thyroid cancer showed higher expression of HIF-1, and its expression was associated with advanced stage and unfavorable clinical outcomes. These observations suggest that metabolic alterations, including biased activation of glycolysis, are a prerequisite determining aggressive tumor biology.
Cancer cells show suppression of mitochondrial OxPhos function, and increase aerobic glycolysis to create a more advantageous metabolic state for cancer cell survival. Normal and tumorous human thyroid tissues and human thyroid cancer cell lines are capable of a metabolic switch between aerobic glycolysis and OxPhos depending on the microenvironment [16]. This metabolic flexibility shows that interplay between glycolysis and OxPhos adapt the mechanisms of energy production to microenvironmental changes, as well as differences in tumor energy needs or biosynthetic activity. All these observations indicate the importance of maintaining proper mitochondrial function and active OxPhos metabolism in normal thyroid cancer cells [17].
Benign and well differentiated thyroid tumors retain fludeoxyglucose (FDG) poorly, whereas more malignant tumors appear to have a higher uptake of FDG. A recent series of the retrospective analyses showed the ability of FDG-positron emission tomography to identify thyroid cancer patients who may have a poor prognosis. It was hypothesized that patients with metastatic lesions that did not concentrate RAI but had high glucose uptake would have reduced survival. These clinical observations indicate that energy production via excessive glucose uptake and glycolysis, resulting from suppressed mitochondrial OxPhos function, is an important phenotypic change determining the clinical behavior of thyroid cancer.
Hürthle cell carcinoma is a relatively rare type of differentiated thyroid cancer. Excess mitochondria are the hallmark of Hürthle cells and oncocytic cells. Gene profiling of thyroid Hürthle cell tumors revealed up-regulation of genes coding for glycolytic, tricarboxylic acid cycle, and OxPhos enzymes, and underexpression of the lactate dehydrogenase A gene. This suggests that thyroid Hürthle cell tumors produce energy through an aerobic pathway because of defective OxPhos in mitochondria [18].

ROLE OF MITOCHONDRIA IN ONCOGENE ACTION IN THYUROID CANCER

Many genetic alterations activating several signal transduction pathways have been identified in thyroid cancers. Activating mutations in the BRAF gene are found at high frequency in various human cancers. BRAFV600E is the most common of these activating mutations, especially in papillary thyroid cancer, where its frequency is 40% to 70%. In BRAFV600E-positive thyroid cancer cell lines and BRAFV600E-transgenic mice, this mutation is responsible for tumor initiation, transformation, growth, proliferation, and dedifferentiation. Research into the molecular mechanisms of BRAFV600E-positive tumors has revealed that the missense valine to glutamic acid mutation increases kinase activity, promoting the constitutive activation of mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling and increasing ERK-dependent transcriptional output. However, signaling pathways other than the MEK-ERK pathways that are regulated in BRAFV600E-positive tumors are not fully characterized. Moreover, tumor suppressor systems that may be controlled by BRAFV600E in thyroid cancer remain to be identified.
Recently, we explored oncogenic actions of BRAFV600E related to crosstalk with Hippo signaling pathways and mitochondria. We identified novel crosstalk between BRAFV600E and MST1, thereby demonstrating functional activity of the RASSF1A-MST1-FoxO3 tumor suppressor system. In addition, we found that BRAFV600E interacts with mitochondria in a mutation-specific fashion. The mitochondrial localization of BRAFV600E induced anti-apoptotic effects and metabolic changes characterized by decreased O2 consumption and an increased rate of glucose uptake, suggesting reduced mitochondrial OxPhos. Surprisingly, a well known and clinically used RAF inhibitor had no effect on the crosstalk with Hippo pathways and mitochondrial interactions. These new insights into the mutation-specific roles of BRAFV600E may be important for the development of future therapeutics.
The receptor tyrosine kinase (RTK) genes EGFR, PDGFRα, PDGFRβ, VEGFR1, VEGFR2, c-MET, and c-KIT encode cell surface receptors for polypeptide growth factors, cytokines, and hormones. RTKs are frequently overexpressed or aberrantly activated in follicular and anaplastic thyroid carcinomas [19]. Recently, RTKs were shown to directly modulate mitochondrial function. EGF stimulation leads to EGFR and c-Src activation. EGFR and c-Src translocate to the mitochondria, and then phosphorylate respiratory chain complex II. These processes lead to the inactivation of respiratory chain complexes, reduced oxidative ATP and free radical production, and an increase in cell viability [20].
The Ras-Raf-MEK-ERK/mitogen-activated protein kinase (MAPK) cascade is initiated by ligation of a RTK. Oncogenic BRAF mutations in the Ras-Raf-MEK-ERK/MAPK pathway occur preferentially in papillary thyroid cancer. Recently, our group demonstrated that BRAFV600E is localized to the outer mitochondrial membrane in thyroid cancer [21].
In cancer cell lines, ERK1 was shown to translocate to mitochondria, where it inhibits apoptosis by binding to several mitochondrial proteins, such as voltage-dependent anion channel [22], and by desensitizing the permeability transition pore (PTP) through inhibition of a signaling axis that involves glycogen synthase kinase-3 (GSK3) and the PTP regulator cyclophilin D [23]. Previous studies performed on BRAFV600E-positive melanoma cell lines showed that its anti-apoptotic effects were linked to constitutive MEK-ERK activation. Inhibition of MEK signaling pathways accelerated death in these cells. However, we demonstrated that ERK activation by BRAFV600E may not be a critical factor determining the apoptotic response. Therefore, the anti-apoptotic effects of BRAFV600E are not solely dependent on MEK/ERK activities in thyroid cells [21].
Ras mutations are also common in thyroid tumors, particularly in follicular carcinoma [24], follicular variants of papillary carcinoma [25], and poorly differentiated carcinomas [26]. By cont t, Ras mutations rarely occur in papillary carcinoma [27]. RAS mutations constitutively activate the PI3K-Akt pathway in thyroid cancers [28,29,30]. PI3K stimulation induces rapid accumulation of Akt in mitochondria. Within the mitochondria, Akt phosphorylates the β-subunit of ATP synthase, GSK3β, thereby inactivating it. Phospho-inactivation of GSK3β inhibits apoptosis and serves to promote cell survival [30].
The oncogenic function of Ras requires the activation and subsequent translocation to mitochondria of the transcription factor STAT3 [31]. Mitochondrial STAT3 has been suggested to be a modulator of cellular metabolism, including glycolysis and mitochondrial respiration. Recent studies indicate that phospho-S727 STAT3 localizes to mitochondria, where it regulates the activity of complex I/II in OxPhos and ROS production [32,33].
The Wnt-β-catenin signaling pathway regulates cell development. However, its dysregulated activation has emerged as an important player in cancer formation [34]. In thyroid cancer, PI3K/Akt signaling affected Wnt-β-catenin signaling by activating GSK3β, resulting in cytoplasmic retention of β-catenin and reduced expression of its target genes (cyclins). Downstream effectors of Wnt signaling, such as β-catenin and GSK3β, regulate mitochondria-dependent apoptosis and mitochondrial function. These data emphasize the fact that Wnt may regulate mitochondrial function.
The types of mitochondrial dysfunction in cancerous thyroid follicular cells can be classified as follows: (1) defective OxPhos arising from somatic alterations in mitochondrial DNA in Hürthle cell thyroid carcinoma [35] and papillary thyroid carcinoma [36]; (2) mitophagy defects in Hürthle thyroid carcinoma; and (3) increased cytochrome b and cytochrome c oxidase I in papillary thyroid carcinoma [37].

AUTOPHAGY AND MITOPHAGY IN THYROID CANCER

Cargo-specific autophagy is a critical cellular catabolic pathway that performs quality control of cellular organelles, including mitochondria, by recycling dysfunctional cellular components through the autophagosome-lysosome machinery [38]. Autophagy can be considered a double-edged sword in tumorigenesis: it is a context-dependent tumor-suppressing mechanism that can also promote tumor cell survival under certain adverse conditions [39]. Mitophagy serves to degrade damaged or dysfunctional mitochondria to match the metabolic demand and orchestrate mitochondrial quality and quantity control in cellular homeostasis. Recent studies demonstrated that mitophagy also plays a double-faceted role in tumorigenesis. While it serves to remove dysfunctional mitochondria to mitigate oxidative stress and prevent carcinogenesis, it can protect cells from apoptosis or necrosis and promote tumor cell survival under poor nutrient supply and hypoxic stress [40]. Mutation of the PARK2 gene, which is involved in PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy, is the most common cause of early-onset Parkinson's disease. In human cancers, PARK2 mutation-associated mitophagy may contribute to oncogenesis when it is altered in non-neuronal somatic cells [41]. Although autophagy defects are indeed associated with thyroid cancers [42], the relationship between mitophagy defects and thyroid cancer is yet to be established. In one study, we observed a Parkin-associated mitophagy defect in Hürthle cell thyroid tumors that affected tumor pathogenesis (unpublished data).

CONCLUSIONS

Advanced thyroid cancer that is refractory to radioactive iodine is usually intractable to current chemotherapy and conventional radiotherapy. The changes in metabolic phenotypes during tumor progression determine the biological and clinical behavior. Elucidation of the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.

ACKNOWLEDGMENTS

This work was supported by NRF grant 2012R1A2A1A03002833 from the National Research Foundation, Ministry of Science, ICT and Future Planning, Korea.

NOTES

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Lee JU, Huang S, Lee MH, Lee SE, Ryu MJ, Kim SJ, Kim YK, Kim SY, Joung KH, Kim JM, Shong M, Jo YS. Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer. Eur J Endocrinol 2012;167:93-101.
[CROSSREF]  [PUBMED] 
2. Lee SJ, Lee MH, Kim DW, Lee S, Huang S, Ryu MJ, Kim YK, Kim SJ, Kim SJ, Hwang JH, Oh S, Cho H, Kim JM, Lim DS, Jo YS, Shong M. Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma. PLoS One 2011;6:e16180
[CROSSREF]  [PUBMED]  [PMC] 
3. Kim YR, Byun HS, Won M, Park KA, Kim JM, Choi BL, Lee H, Hong JH, Park J, Seok JH, Kim DW, Shong M, Park SK, Hur GM. Modulatory role of phospholipase D in the activation of signal transducer and activator of transcription (STAT)-3 by thyroid oncogenic kinase RET/PTC. BMC Cancer 2008;8:144
[CROSSREF]  [PUBMED]  [PMC]  [PDF]
4. Kim DW, Chung HK, Park KC, Hwang JH, Jo YS, Chung J, Kalvakolanu DV, Resta N, Shong M. Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC). Mol Endocrinol 2007;21:3039-3049.
[CROSSREF]  [PUBMED]  [PDF]
5. Jo YS, Lee JC, Li S, Choi YS, Bai YS, Kim YJ, Lee IS, Rha SY, Ro HK, Kim JM, Shong M. Significance of the expression of major histocompatibility complex class II antigen, HLA-DR and -DQ, with recurrence of papillary thyroid cancer. Int J Cancer 2008;122:785-790.
[CROSSREF]  [PUBMED] 
6. Kim KS, Min JK, Liang ZL, Lee K, Lee JU, Bae KH, Lee MH, Lee SE, Ryu MJ, Kim SJ, Kim YK, Choi MJ, Jo YS, Kim JM, Shong M. Aberrant l1 cell adhesion molecule affects tumor behavior and chemosensitivity in anaplastic thyroid carcinoma. Clin Cancer Res 2012;18:3071-3078.
[CROSSREF]  [PUBMED] 
7. Kim SJ, Kwon MC, Ryu MJ, Chung HK, Tadi S, Kim YK, Kim JM, Lee SH, Park JH, Kweon GR, Ryu SW, Jo YS, Lee CH, Hatakeyama H, Goto Y, Yim YH, Chung J, Kong YY, Shong M. CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane. Cell Metab 2012;16:274-283.
[CROSSREF]  [PUBMED] 
8. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004;287:C817-C833.
[CROSSREF]  [PUBMED] 
9. Rustin P. Mitochondria, from cell death to proliferation. Nat Genet 2002;30:352-353.
[CROSSREF]  [PUBMED]  [PDF]
10. Cox AG, Winterbourn CC, Hampton MB. Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling. Biochem J 2009;425:313-325.
[CROSSREF]  [PUBMED]  [PDF]
11. Karbownik-Lewinska M, Kokoszko-Bilska A. Oxidative damage to macromolecules in the thyroid: experimental evidence. Thyroid Res 2012;5:25
[CROSSREF]  [PUBMED]  [PMC] 
12. Suh JM, Song JH, Kim DW, Kim H, Chung HK, Hwang JH, Kim JM, Hwang ES, Chung J, Han JH, Cho BY, Ro HK, Shong M. Regulation of the phosphatidylinositol 3-kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland. J Biol Chem 2003;278:21960-21971.
[CROSSREF]  [PUBMED] 
13. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995;92:5510-5514.
[CROSSREF]  [PUBMED]  [PMC] 
14. Tan C, de Noronha RG, Roecker AJ, Pyrzynska B, Khwaja F, Zhang Z, Zhang H, Teng Q, Nicholson AC, Giannakakou P, Zhou W, Olson JJ, Pereira MM, Nicolaou KC, Van Meir EG. Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res 2005;65:605-612.
[PUBMED] 
15. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001;93:309-314.
[CROSSREF]  [PUBMED] 
16. Mirebeau-Prunier D, Le Pennec S, Jacques C, Fontaine JF, Gueguen N, Boutet-Bouzamondo N, Donnart A, Malthiery Y, Savagner F. Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One 2013;8:e58683
[CROSSREF]  [PUBMED]  [PMC] 
17. Jose C, Bellance N, Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim Biophys Acta 2011;1807:552-561.
[CROSSREF]  [PUBMED] 
18. Baris O, Savagner F, Nasser V, Loriod B, Granjeaud S, Guyetant S, Franc B, Rodien P, Rohmer V, Bertucci F, Birnbaum D, Malthiery Y, Reynier P, Houlgatte R. Transcriptional profiling reveals coordinated up-regulation of oxidative metabolism genes in thyroid oncocytic tumors. J Clin Endocrinol Metab 2004;89:994-1005.
[CROSSREF]  [PUBMED] 
19. Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJ, Herrero A, Fusco A, Cameselle-Teijeiro J, Santoro M. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res 2005;65:10199-10207.
[CROSSREF]  [PUBMED] 
20. Demory ML, Boerner JL, Davidson R, Faust W, Miyake T, Lee I, Huttemann M, Douglas R, Haddad G, Parsons SJ. Epidermal growth factor receptor translocation to the mitochondria: regulation and effect. J Biol Chem 2009;284:36592-36604.
[CROSSREF] 
21. Lee MH, Lee SE, Kim DW, Ryu MJ, Kim SJ, Kim SJ, Kim YK, Park JH, Kweon GR, Kim JM, Lee JU, De Falco V, Jo YS, Shong M. Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: a clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. J Clin Endocrinol Metab 2011;96:E19-E30.
[CROSSREF]  [PUBMED]  [PDF]
22. Galli S, Jahn O, Hitt R, Hesse D, Opitz L, Plessmann U, Urlaub H, Poderoso JJ, Jares-Erijman EA, Jovin TM. A new paradigm for MAPK: structural interactions of hERK1 with mitochondria in HeLa cells. PLoS One 2009;4:e7541
[CROSSREF]  [PUBMED]  [PMC] 
23. Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P. Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci U S A 2010;107:726-731.
[CROSSREF]  [PUBMED] 
24. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003;120:71-77.
[CROSSREF]  [PUBMED]  [PDF]
25. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab 2003;88:2745-2752.
[CROSSREF]  [PUBMED]  [PDF]
26. Volante M, Rapa I, Gandhi M, Bussolati G, Giachino D, Papotti M, Nikiforov YE. RAS mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab 2009;94:4735-4741.
[CROSSREF]  [PUBMED]  [PDF]
27. Cyniak-Magierska A, Brzezianska E, Januszkiewicz-Caulier J, Jarzab B, Lewinski A. Prevalence of RAS point mutations in papillary thyroid carcinoma; a novel mutation at codon 31 of K-RAS. Exp Clin Endocrinol Diabetes 2007;115:594-599.
[CROSSREF]  [PUBMED] 
28. Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, El-Naggar AK, Xing M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 2008;93:3106-3116.
[CROSSREF]  [PUBMED]  [PDF]
29. Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, Al-Nuaim A, Ahmed M, Amin T, Al-Fehaily M, Al-Sanea O, Al-Dayel F, Uddin S, Al-Kuraya KS. Clinicopathological analysis of papillary thyroid cancer with PIK-3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab 2008;93:611-618.
[CROSSREF]  [PUBMED]  [PDF]
30. Bijur GN, Jope RS. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem 2003;87:1427-1435.
[CROSSREF]  [PUBMED]  [PMC] 
31. Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, Alberghina L, Stephanopoulos G, Chiaradonna F. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 2011;7:523
[CROSSREF]  [PUBMED]  [PMC] 
32. Sosonkina N, Starenki D, Park JI. The role of STAT3 in thyroid cancer. Cancers (Basel) 2014;6:526-544.
[CROSSREF]  [PUBMED]  [PMC] 
33. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, Derecka M, Chen Q, Hu Y, Sisler J, Hamed H, Lesnefsky EJ, Valerie K, Dent P, Larner AC. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem 2013;288:31280-31288.
[CROSSREF]  [PUBMED]  [PMC] 
34. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012;149:1192-1205.
[CROSSREF]  [PUBMED] 
35. Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V, Baracca A, Tallini G, Martinuzzi A, Lenaz G, Rugolo M, Romeo G. Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res 2006;66:6087-6096.
[CROSSREF]  [PUBMED] 
36. Yeh JJ, Lunetta KL, van Orsouw NJ, Moore FD Jr, Mutter GL, Vijg J, Dahia PL, Eng C. Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours. Oncogene 2000;19:2060-2066.
[CROSSREF]  [PUBMED]  [PDF]
37. Haugen DR, Fluge O, Reigstad LJ, Varhaug JE, Lillehaug JR. Increased expression of genes encoding mitochondrial proteins in papillary thyroid carcinomas. Thyroid 2003;13:613-620.
[CROSSREF]  [PUBMED] 
38. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51-64.
[CROSSREF]  [PUBMED]  [PMC] 
39. Kubisch J, Turei D, Foldvari-Nagy L, Dunai ZA, Zsakai L, Varga M, Vellai T, Csermely P, Korcsmaros T. Complex regulation of autophagy in cancer: integrated approaches to discover the networks that hold a double-edged sword. Semin Cancer Biol 2013;23:252-261.
[CROSSREF]  [PUBMED] 
40. Azad MB, Chen Y, Gibson SB. Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal 2009;11:777-790.
[CROSSREF]  [PUBMED] 
41. Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 2010;42:77-82.
[CROSSREF]  [PUBMED]  [PDF]
42. Morani F, Titone R, Pagano L, Galetto A, Alabiso O, Aimaretti G, Isidoro C. Autophagy and thyroid carcinogenesis: genetic and epigenetic links. Endocr Relat Cancer 2014;21:R13-R29.
[CROSSREF]  [PUBMED] 


Editorial Office
101-2503, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea​
Tel: +82-2-716-2428    Fax: +82-2-714-5103    E-mail: journal@endocrinology.or.kr                

Copyright © 2020 by Korean Endocrine Society. All rights reserved.

Developed in M2community

Close layer
prev next