Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma

Yea Eun Kang; Minho Shong; Jin Man Kim; Bon Seok Koo

doi:10.11106/ijt.2018.11.2.143

Journal List > Int J Thyroidol > v.11(2) > 1109112

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Kang, Shong, Kim, and Koo: Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma

Original Article

Int J Thyroidol 2018;11(2):143-151.

Published online: 5 November 2018

DOI: https://doi.org/10.11106/ijt.2018.11.2.143

Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma

Yea Eun Kang¹, Minho Shong¹, Jin Man Kim², Bon Seok Koo³

¹Departments of Endocrinology and Metabolism, College of Medicine, Chungnam National University, Daejeon, Korea

²Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea

³Departments of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Korea

Correspondence: Jin Man Kim, MD, PhD, Department of Pathology, College of Medicine, Chungnam National University, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: 82-42-280-7690, Fax: 82-42-253-4059, E-mail: jinmank@cnu.ac.kr

Correspondence: Bon Seok Koo, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: 82-42-280-7690, Fax: 82-42-253-4059, E-mail: bskoo515@cnuh.co.kr

Received 14 August 201812 September 2018 Accepted 13 September 2018

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creative-commons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

초록

Background and Objectives

Sirtuins (SIRTs) play important roles in cellular and organismal homeostasis. They have distinct gene expression patterns in various cancers; however, the relationship between SIRT expression and the progression of thyroid cancer is unclear. We investigated the expression of SIRTs in patients with papillary thyroid carcinoma (PTC) and their role as biomarkers for predicting the aggressiveness of this disease.

Materials and Methods

We used immunohistochemical staining to evaluate the expression of SIRT1 and SIRT3 in tumor specimens from 270 patients with PTC. We also evaluated the potential association between SIRT expression and diverse clinicopathological features.

Results

High SIRT1 expression was negatively correlated with lymphovascular invasion, central lymph node metastasis, and lateral lymph node metastasis. Multivariate analyses revealed that high SIRT1 expression was a negative independent risk factor for lateral lymph node metastasis. By contrast, high SIRT3 expression was positively correlated with locoregional recurrence. Interes-tingly, when patients were grouped by tumor SIRT expression patterns, the group with low SIRT1 expression and high SIRT3 expression was correlated with more aggressive cancer phenotypes including central lymph node metastasis and lateral lymph node metastasis.

Conclusion

Our results suggest that SIRTs play dual roles in tumor progression, and the combination of decreased SIRT1 expression and increased SIRT3 expression is significantly associated with a poor prognosis in patients with PTC.

Keywords: Papillary thyroid carcinoma, SIRT1, SIRT3, Sirtuin, Tumor progression

REFERENCES

1). Guarente L. Franklin H. Epstein lecture: sirtuins, aging, and medicine. N Engl J Med. 2011; 364(23):2235–44.

2). Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000; 273(2):793–8.

3). Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012; 21(3):297–308.

4). Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015; 15(10):608–24.

5). Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646–74.

6). Mirebeau-Prunier D, Le Pennec S, Jacques C, Fontaine JF, Gueguen N, Boutet-Bouzamondo N, et al. Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One. 2013; 8(3):e58683.

7). Lee MH, Lee SE, Kim DW, Ryu MJ, Kim SJ, Kim SJ, et al. 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(1):E19–30.

8). Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M, et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene. 2013; 32(34):4052–6.

9). Kweon KH, Lee CR, Jung SJ, Ban EJ, Kang SW, Jeong JJ, et al. Sirt1 induction confers resistance to etoposide-induced genotoxic apoptosis in thyroid cancers. Int J Oncol. 2014; 45(5):2065–75.

10). Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009; 460(7255):587–91.

11). Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008; 105(28):9793–8.

12). Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome- associated cancer. Nat Commun. 2010; 1:3.

13). Fang Y, Nicholl MB. Sirtuin 1 in malignant transformation: friend or foe? Cancer Lett. 2011; 306(1):10–4.

14). Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci. 2009; 5(2):147–52.

15). Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007; 67(14):6612–8.

16). Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005; 19(10):1751–9.

17). Lim CS. SIRT1: tumor promoter or tumor suppressor? Med Hypotheses. 2006; 67(2):341–4.

18). Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008; 8(4):333–41.

19). Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 2008; 3(4):e2020.

20). Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C, et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem. 2009; 284(27):18210–7.

21). Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell. 2008; 32(1):11–20.

22). Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007; 27(24):8807–14.

23). Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010; 464(7285):121–5.

24). Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009; 119(9):2758–71.

25). Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One. 2010; 5(5):e10486.

26). Ashraf N, Zino S, Macintyre A, Kingsmore D, Payne AP, George WD, et al. Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer. 2006; 95(8):1056–61.

27). Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle. 2007; 6(21):2669–77.

28). Ford J, Jiang M, Milner J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 2005; 65(22):10457–63.

29). Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress. Mol Cell. 2011; 42(5):561–8.

30). Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell. 2011; 41(2):139–49.

31). Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008; 14(4):312–23.

32). Jang KY, Noh SJ, Lehwald N, Tao GZ, Bellovin DI, Park HS, et al. SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas. PLoS One. 2012; 7(9):e45119.

Fig. 1.

Immunohistochemical evaluation of sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) expression in papillary thyroid carcinoma (PTC) tissue. (A) Representative immunohistochemical images of SIRT1. (B) Representative immunohistochemical images of SIRT3. 0: no staining intensity, +1: weak staining intensity, +2: moderate staining intensity, +3: strong staining intensity (magnification ×100)

Table 1.

Clinicopathologic parameters of patients (n=270)

Variables		Mean±SD or number of patients (%)
Age, years		48.3±12.4
Gender	Male	47 (17.4)
	Female	223 (82.6)
Tumor size	≤1 cm	110 (40.7)
	＞1 cm	160 (59.3)
Multicentricity	No	158 (58.5)
	Yes	112 (41.5)
Microscopic capsular	No	71 (26.3)
invasion	Yes	199 (73.7)
Extrathryoid extension	No	88 (32.6)
	Yes	182 (67.4)
Lymphovascular invasion	No	63 (23.3)
	Yes	207 (76.7)
Lymph node metastasis	No	116 (43.0)
	Yes	154 (57.0)
Central lymph node	No	116 (43.0)
metastasis	Yes	154 (57.0)
Lateral lymph node	No	222 (82.2)
metastasis	Yes	48 (17.8)
Locoregional recurrence	No	233 (86.3)
	Yes	37 (13.7)
Follow-up period (months)		106.6±22.5

SD: standard deviation

Table 2.

Relationships between intensity of sirtuin 1 (SIRT1) staining and clinicopathological factors in 270 patients

Variables		No. of patients	SIRT1
Variables		No. of patients	Low (Grade 1 and 2)	High (Grade 3 and 4)	p value
Age, years	＜45	104	66	38	0.411
	≥45	166	97	69
Gender	Male	47	31	16	0.389
	Female	223	132	91
Tumor size	≤1 cm	110	61	49	0.171
	＞1 cm	160	102	58
Multicentricity	No	158	96	62	0.877
	Yes	112	67	45
Microscopic capsular invasion	No	71	37	34	0.098
	Yes	199	126	73
Extrathyroid extension	No	88	48	40	0.174
	Yes	182	115	67
Lymphovascular invasion	No	63	31	32	0.039∗
	Yes	207	132	75
Lymph node metastasis	No	116	58	58	0.002∗
	Yes	154	105	49
Central lymph node metastasis	No	116	58	58	0.002∗
	Yes	154	105	49
Lateral lymph node metastasis	No	222	122	100	＜0.001∗
	Yes	48	41	7
Locoregional recurrence	No	233	139	94	0.547
	Yes	37	24	13

^∗ p＜0.05 between the two categories for a given variable

Table 3.

Multivariate analysis of the relationship between SIRT1 staining and clinicopathologic factors

Factors	Exp (β)	SE	95.0% CI	p value
Lymphovascular invasion	0.645	0.309	(0.352, 1.182)	0.156
Lateral lymph node metastasis	0.233	0.443	(0.097. 0.555)	0.001∗
Central lymph node metastasis	0.681	0.275	(0.345, 0.849)	0.162

Data analyzed using a stepwise logistic

CI: confidence interval, Exp (β): odds ratio, SE: standard error

^∗ value＜0.05

Table 4.

Relationships between intensity of sirtuin 3 (SIRT3) staining and clinicopathological factors in 270 patients

Variables		No. of patients	SIRT3
Variables		No. of patients	Low (Grade 1 and 2)	High (Grade 3 and 4)	p value
Age, years	＜45	104	52	52	0.175
	≥45	166	69	97
Gender	Male	47	27	20	0.055
	Female	223	94	129
Tumor size	≤1 cm	110	54	56	0.241
	＞1 cm	160	67	93
Multicentricity	No	158	66	92	0.232
	Yes	112	55	57
Microscopic capsular invasion	No	71	34	37	0.544
	Yes	199	87	112
Extrathryoid extension	No	88	43	45	0.352
	Yes	182	78	104
Lymphovascular invasion	No	63	26	37	0.518
	Yes	207	95	112
Lymph node metastasis	No	116	48	68	0.325
	Yes	154	73	81
Central lymph node metastasis	No	116	48	68	0.325
	Yes	154	73	81
Lateral lymph node metastasis	No	222	95	127	0.151
	Yes	48	26	22
Locoregional recurrence	No	233	111	122	0.019∗
	Yes	37	10	27

^∗ means p value ＜0.05

Table 5.

Relationships between patterns of sirtuin staining intensity and clinicopathological factors

Variables		SIRT1 low SIRT3 low (n=88)	SIRT1 low SIRT3 high (n=75)	SIRT1 high SIRT3 low (n=33)	SIRT1 high SIRT3 high (n=74)	p value
Age, years	＜45	40	26	12	26	0.444
	≥45	48	49	21	48
Gender	Male	12	14	11	10	0.368
	Female	76	43	40	64
Tumor size	≤1 cm	35	26	19	30	0.168
	＞1 cm	53	49	14	44
Multicentricity	No	49	47	17	45	0.648
	Yes	39	28	16	29
Microscopic capsular invasion	No	23	14	11	23	0.265
	Yes	65	61	22	51
Extrathryoid extension	No	28	20	15	25	0.289
	Yes	60	55	18	49
Lymphovascular invasion	No	17	14	9	23	0.214
	Yes	71	61	24	51
Lymph node metastasis	No	30	28	18	40	0.025∗
	Yes	58	47	15	34
Central lymph node metastasis	No	30	28	18	40	0.025∗
	Yes	58	47	15	34
Lateral lymph node metastasis	No	64	58	31	69	0.001∗
	Yes	24	17	2	5
Locoregional recurrence	No	79	60	32	62	0.072
	Yes	9	15	1	12

^∗ means p value ＜0.05

TOOLS

Similar articles