Associations of sirtuins with clinicopathological parameters and prognosis in non–small cell lung cancer

Figures & data

Table 1 Correlations of sirtuins and clinicopathological parameters in patients with NSCLC

Parameters	N	SIRT1			SIRT2			SIRT3			SIRT4			SIRT5			SIRT6			SIRT7
		Low	High	P-value	Low	High	P-value	Low	High	P-value	Low	High	P-value	Low	High	P-value	Low	High	P-value	Low	High	P-value
Histology
ADC	515	109 (21.17%)	406 (78.83%)	0.000	237 (46.02%)	278 (53.98%)	0.000	293 (56.89%)	222 (43.11%)	0.000	308 (59.81%)	207 (40.19%)	0.000	331 (64.27%)	184 (35.73%)	0.000	361 (70.1%)	154 (29.9%)	0.788	202 (39.22%)	313 (60.78%)	0.046
SCC	502	313 (62.35%)	189 (37.65%)		127 (25.30%)	375 (74.70%)		417 (83.07%)	85 (16.93%)		445 (88.65%)	57 (11.35%)		196 (39.04%)	306 (60.96%)		348 (69.32%)	154 (30.68%)		228 (45.42%)	274 (54.58%)
Gender
Female	402	133 (33.08%)	269 (66.92%)	0.000	138 (34.33%)	264 (65.67%)	0.409	258 (64.18%)	144 (35.82%)	0.001	272 (67.66%)	130 (32.34%)	0.000	243 (60.45%)	159 (39.55%)	0.000	280 (69.65%)	122 (30.35%)	0.924	170 (42.29%)	232 (57.71%)	0.976
Male	602	280 (46.51%)	322 (53.49%)		222 (36.88%)	380 (63.12%)		445 (73.92%)	157 (26.08%)		472 (78.41%)	130 (21.59%)		280 (46.51%)	322 (53.49%)		421 (69.93%)	181 (30.07%)		254 (42.19%)	348 (57.81%)
Age
<70 years	627	258 (41.15%)	369 (58.85%)	0.999	234 (37.32%)	393 (62.68%)	0.192	444 (70.81%)	183 (29.19%)	0.522	454 (72.41%)	173 (27.59%)	0.155	314 (50.08%)	313 (49.92%)	0.178	433 (69.06%)	194 (30.94%)	0.831	244 (38.92%)	383 (61.08%)	0.012
≥70 years	350	144 (41.14%)	206 (58.86%)		116 (33.14%)	234 (66.86%)		241 (68.86%)	109 (31.14%)		268 (76.57%)	82 (23.43%)		191 (54.57%)	159 (45.43%)		244 (69.71%)	106 (30.29%)		165 (47.14%)	185 (52.86%)
M stage
M0	747	327 (43.78%)	420 (56.22%)	0.014	252 (33.73%)	495 (66.27%)	0.125	535 (71.62%)	212 (28.38%)	0.463	551 (73.76%)	196 (26.24%)	0.876	375 (50.20%)	372 (49.80%)	0.715	529 (70.82%)	218 (29.18%)	0.202	320 (42.84%)	427 (57.16%)	0.343
M1	32	7 (21.88%)	25 (78.13%)		15 (46.88%)	17 (53.13%)		21 (65.63%)	11 (34.38%)		24 (75.00%)	8 (25.00%)		15 (46.88%)	17 (53.13%)		26 (81.25%)	6 (18.75%)		11 (34.38%)	21 (65.63%)
N stage
N0	642	258 (40.19%)	384 (59.81%)	0.299	225 (35.05%)	417 (64.95%)	0.444	452 (70.4%)	190 (29.6%)	0.910	469 (73.05%)	173 (26.95%)	0.142	326 (50.78%)	316 (49.22%)	0.246	455 (70.87%)	187 (29.13%)	0.353	273 (42.52%)	369 (57.48%)	0.521
N1–3	344	150 (43.6%)	194 (56.4%)		129 (37.5%)	215 (62.5%)		241 (70.06%)	103 (29.94%)		266 (77.33%)	78 (22.67%)		188 (54.65%)	156 (45.35%)		234 (68.02%)	110 (31.98%)		139 (40.41%)	205 (59.59%)
T stage
T1	280	95 (33.93%)	185 (66.07%)	0.003	96 (34.29%)	184 (65.71%)	0.516	188 (67.14%)	92 (32.86%)	0.214	195 (69.64%)	85 (30.36%)	0.039	148 (52.86%)	132 (47.14%)	0.780	203 (72.50%)	77 (27.50%)	0.235	115 (41.07%)	165 (58.93%)	0.665
T2–4	721	318 (44.11%)	403 (55.89%)		263 (36.48%)	458 (63.52%)		513 (71.15%)	208 (28.85%)		548 (76.01%)	173 (23.99%)		374 (51.87%)	347 (48.13%)		495 (68.65%)	226 (31.35%)		307 (42.58%)	414 (57.42%)
Stage
I–II	518	207 (39.96%)	311 (60.04%)	0.448	174 (33.59%)	344 (66.41%)	0.131	352 (67.95%)	166 (32.05%)	0.143	368 (71.04%)	150 (28.96%)	0.022	259 (50.00%)	259 (50.00%)	0.131	373 (72.01%)	145 (27.99%)	0.132	228 (44.02%)	290 (55.98%)	0.228
III–IV	482	204 (42.32%)	278 (57.68%)		184 (38.17%)	298 (61.83%)		348 (72.2%)	134 (27.8%)		373 (77.39%)	109 (22.61%)		264 (54.77%)	218 (45.23%)		326 (67.63%)	156 (32.37%)		194 (40.25%)	288 (59.75%)
Smoking status
Yes	890	381 (42.81%)	509 (57.19%)	0.001	314 (35.28%)	576 (64.72%)	0.388	631 (70.90%)	259 (29.10%)	0.054	672 (75.51%)	218 (24.49%)	0.006	447 (50.22%)	443 (49.78%)	0.009	624 (70.11%)	266 (29.89%)	0.698	369 (41.46%)	521 (58.54%)	0.059
No	93	23 (24.73%)	70 (75.27%)		37 (39.78%)	56 (60.22%)		57 (61.29%)	36 (38.71%)		58 (62.37%)	35 (37.63%)		60 (64.52%)	33 (35.48%)		67 (72.04%)	26 (27.96%)		48 (51.61%)	45 (48.39%)

Note: Bold: P<0.05 demonstrated by chi-square test.

Abbreviations: NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; ADC, adenocarcinoma; SCC, squamous cell carcinoma.

Table 2 Cox proportional regression analysis to investigate the correlations of sirtuins and overall survival in patients with NSCLC

SIRTs	Univariate analysis				Multivariate analysis*
	P-value	HR	95% CI		P-value	HR	95% CI
SIRT1	0.352	0.902	0.725	1.121	0.956	1.007	0.787	1.288
SIRT2	0.007	0.736	0.588	0.920	0.005	0.697	0.543	0.894
SIRT3	0.244	0.865	0.677	1.104	0.568	0.922	0.696	1.220
SIRT4	0.043	0.761	0.584	0.992	0.255	0.842	0.626	1.132
SIRT5	0.109	0.837	0.673	1.040	0.128	0.828	0.650	1.056
SIRT6	0.044	0.780	0.612	0.994	0.009	0.684	0.514	0.911
SIRT7	0.253	0.881	0.708	1.095	0.305	0.878	0.686	1.125

Note:

* The potential confounding factors were age, M, N, and T stage. Bold font: P<0.05 demonstrated by Cox proportional regression analysis.

Abbreviation: TCGA, The Cancer Genome Atlas; NSCLC, non-small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; HR, hazard ratio; CI, confidence interval.

Table 3 Cox proportional regression analysis to investigate the correlations of sirtuins and recurrence-free survival in patients with NSCLC

SIRTs	Univariate analysis				Multivariate analysis*
	P-value	HR	95% CI		P-value	HR	95% CI
SIRT1	0.000	1.899	1.366	2.639	0.001	1.852	1.294	2.650
SIRT2	0.000	0.531	0.394	0.717	0.001	0.588	0.432	0.800
SIRT3	0.034	1.410	1.026	1.938	0.107	1.316	0.943	1.837
SIRT4	0.099	1.284	0.954	1.730	0.416	1.144	0.827	1.583
SIRT5	0.000	0.565	0.415	0.769	0.007	0.636	0.459	0.883
SIRT6	0.028	0.687	0.492	0.961	0.004	0.606	0.431	0.852
SIRT7	0.013	0.625	0.432	0.906	0.005	0.585	0.403	0.848

Note:

* The potential confounding factors were histology, N, and T stage. Bold font: P<0.05 demonstrated by Cox proportional regression analysis.

Abbreviation: TCGA, The Cancer Genome Atlas; NSCLC, non-small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; HR, hazard ratio; CI, confidence interval.

Figure 1 Overall survival in TCGA NSCLC patients with high and low sirtuin expression (SIRT1–7) were compared with Kaplan–Meier plot curves.

Abbreviations: TCGA, The Cancer Genome Atlas; NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7.

Figure 2 Recurrence-free survival in TCGA NSCLC patients stratified by high and low sirtuin expression (SIRT1–7) or a combination of SIRT1 and SIRT2 were compared with Kaplan–Meier plot curves. (A) SIRT1, (B) SIRT2, (C) SIRT3, (D) SIRT4, (E) SIRT5, (F) SIRT6, (G) SIRT7, and (H) Combination of SIRT1 and SIRT2.

Abbreviations: TCGA, The Cancer Genome Atlas; NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; +, high expression; –, low expression.

Table 4 Cox proportional regression analysis to investigate the correlations of the combination of SIRT1 and SIRT2 with recurrence-free survival in patients with NSCLC

SIRTs	Univariate analysis				Multivariate analysis*
	P-value	HR	95% CI		P-value	HR	95% CI
SIRT1−/SIRT2+	Reference
SIRT1−/SIRT2− or SIRT1+/SIRT2+	0.007	1.758	1.167	2.648	0.010	1.746	1.144	2.665
SIRT1+/SIRT2−	0.000	3.134	2.037	4.820	0.000	3.021	1.883	4.849

Note:

* The potential confounding factors were histology, N, and T stage. Bold font: P<0.05 demonstrated by Cox proportional regression analysis.

Abbreviations: TCGA, The Cancer Genome Atlas; NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; HR, hazard ratio; CI, confidence interval; +, high expression; –, low expression.

Figure 3 Forest plot for the correlations of sirtuins (SIRT1–7) and recurrence-free survival in patients with NSCLC by pooling the results of the datasets from TCGA and Kaplan–Meier plotter databases.

Abbreviations: TCGA, The Cancer Genome Atlas; NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7.

Table 5 Associations of high sirtuins expressions with overall survival in NSCLC in previous reports

Study	Sirtuins	HR	P value	Sample size	Detection method
Noh et al^Citation28	SIRT1	NS		144	IHC
Zhang et al^Citation29	SIRT1	HR>1	0.003	295	IHC
Grbesa et al^Citation30	SIRT1	NS		105	IHC
Li et al^Citation31	SIRT1	HR>1	0.009	75	IHC
Gharabaghi^Citation32	SIRT1	HR>1	0.001	40	IHC
Lin and Peng^Citation33	SIRT1	NS		260	IHC
Wang and Wang^Citation34	SIRT1	HR>1	<0.01	60	IHC
Grbesa et al^Citation30	SIRT2	NS		105	IHC
Li et al^Citation36	SIRT2	HR<1	<0.01	28	PCR
Yang et al^Citation37	SIRT3	HR>1	0.001	131	IHC
Xiong et al^Citation38	SIRT3	HR>1	0.028	70	IHC
Lu et al^Citation39	SIRT5	HR>1	0.03	39	PCR
Azuma et al^Citation40	SIRT6	HR>1	0.022	98	IHC
Bai et al^Citation41	SIRT6	HR>1	0.034	174	IHC
Chen et al^Citation42	SIRT6	HR>1	<0.01	122	IHC

Abbreviations: NSCLC, non–small cell lung cancer; NS, not significant; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT5, sirtuin 5; SIRT6, sirtuin 6; HR, hazard ratio; IHC, immunohistochemistry; PCR, polymerase chain reaction.

Figure 4 Biological processes regulated by SIRT1, SIRT2, and SIRT7 in TCGA NSCLC patients: (A) SIRT1, (B) SIRT2, and (C). SIRT7.

Abbreviations: TCGA, The Cancer Genome Atlas; NSCLC, non–small cell lung cancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT7, sirtuin 7.

Figure 5 Expression correlations of SIRT1, SIRT2, and SIRT7 with BAD, BAX, BID, BCL2, and ZEB1 in TCGA NSCLC patients. (A–C). Correlations of SIRT1 with BAD (A), BAX (B), and BID (C). (D) Correlation of SIRT2 with BAD. (E–H) Correlations of SIRT7 with BAD (E), BAX (F), BCL2 (G), and ZEB1 (H).

Abbreviations: SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT7, sirtuin 7; BAX, Bcl-2 associated X; BAD, Bcl-2 associated agonist of cell death; BID, BH3 interacting domain death agonist; ZEB1, zinc finger E-box binding homeobox 1; TCGA, The Cancer Genome Atlas; NSCLC, non-small cell lung cancer.

Figure 6 Concordance of SIRT2 mRNA and protein expressions in NSCLC. (A). SIRT2 immunohistochemical staining results in normal lung tissues (n=3) and lung cancer tissues (n=12). The images were obtained from the Human Protein Atlas.⁴³ (B). SIRT2 mRNA expression in normal lung tissues (n=110) and lung cancer tissues (n=1017) in the TCGA NSCLC cohort. (C–E). SIRT2 mRNA expression detected by qRT-PCR (C) and protein expression detected by Western blotting (D) in seven lung cancers and paired adjacent normal tissues (n=7); consistency of SIRT2 mRNA and protein expression were explored by Pearson’s correlation analysis (E). These were re-analyses results of Li et al’s report.⁴⁴ (F). Associations of SIRT2 mRNA with protein expressions in lung cancers. SIRT2 protein expression and mRNA expression data were extracted from proteomics and gene microarray profiles, respectively, which was reported by Stewart et al.⁴⁶

Abbreviations: SIRT2, sirtuin 2; N, normal; T, tumor; qRT-PCR, quantitative real-time polymerase chain reaction.

Table S1 Underlying mechanism of sirtuins in NSCLC in the previous reports

Study	Sirtuins	Mechanisms
Xie et al^Citation47	SIRT1	SIRT1 promote lung tumor growth through downregulation of DLL4/Notch signaling and deacetylation of N1IC
Zhang et al^Citation29	SIRT1	High SIRT1 was associated with chemotherapy resistance
Han et al^Citation54	SIRT1	SIRT1 promotes cell migration
Zhu et al^Citation48	SIRT1	SIRT1 inactivation evokes antitumor activities in NSCLC through the tumor suppressor p27
Grbesa et al^Citation30	SIRT1	Downregulation of SIRT1 decreased cell proliferation
Cheng et al^Citation55	SIRT1	K-Ras promotes the survival of non–small cell lung cancer cells by cooperating with sirtuin 1 and p27 under ROS stimulation
Lu et al^Citation49	SIRT1	SIRT1 is involved in Benzo[a]pyrene B[a]P-induced transformation associated with activation of the TNF-α/β-catenin axis
Li et al^Citation44	SIRT2	SIRT2 inhibits cell proliferation, induces apoptosis and cell-cycle arrest by increasing the ROS production and p27 levels, and is associated with increased chemotherapy sensitivity
Grbesa et al^Citation30	SIRT2	Downregulation of SIRT2 decreased cell proliferation
Xu et al^Citation51	SIRT2	SIRT2 inhibits cell proliferation and tumor growth via downregulating JMJD2A
Li et al^Citation36	SIRT2	Downregulation of SIRT2 increases the level of SKP2 acetylation, then increases p27 ubiquitination, and finally enhances tumor cell proliferation
Luo et al^Citation56	SIRT2	SPOP promotes SIRT2 degradation and suppresses non–small cell lung cancer cell growth
Xiao et al^Citation57	SIRT3	SIRT3 increased the bax/bcl-2 and bad/bcl-x/L ratios, and promoted AIF translocation to the nucleus. SIRT3 overexpression upregulated p53 and p21 protein levels, and decreased intracellular ROS levels
Li et al^Citation52	SIRT3	Low expression of SIRT3 significantly inhibited mitotic entry, growth, and proliferation of NSCLC cell lines and promoted apoptosis, which was related to energy metabolism involved in the interaction between SIRT3 and NMNAT2
Xiong et al^Citation38	SIRT3	SIRT3 increases Akt activation by post-transcriptional modification and, then, promotes NSCLC malignancy
Xiong et al^Citation58	SIRT3	SIRT3 deacetylates and promotes degradation of P53 in PTENdefective non–small cell lung cancer
Lu et al^Citation39	SIRT5	SIRT5 promotes cell proliferation and chemotherapy resistance by induction of Nrf2 expression
Azuma et al^Citation40	SIRT6	SIRT6 increases NFkappaB and Beclin1, and is associated with chemotherapy resistance
Han et al^Citation53	SIRT6	SIRT6 suppresses cell proliferation through inhibition of Twist1 expression
Kim and Juhnn^Citation59	SIRT6	Cyclic AMP signaling reduces SIRT6 expression in non–small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf–MEK–ERK pathway
Bai et al^Citation41	SIRT6	SIRT6 increases tumor migration and invasion via increasing ERK1/2 phosphorylation and MMP9 expression

Abbreviations: SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; NSCLC, non-small cell lung cancer; DLL4, Delta-like ligand 4; N1IC, Notch1 intracellular domain; JMJD2A, lysine demethylase 4A; Skp2, S-phase kinase associated protein 2; SPOP, speckle type BTB/POZ protein; BAX, Bcl-2 associated X; BAD, Bcl-2 associated agonist of cell death; Bcl-x/L, Bcl-2 like 1; AIF, apoptosis inducing factor; NMNAT2, nicotinamide nucleotide adenylyltransferase 2; PTEN, phosphatase and tensin homolog; Nrf2, nuclear factor erythroid 2 like 2; Twist1, twist family bHLH transcription factor 1; MMP9, matrix metallopeptidase 9.

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