Activation of IL-8 and its participation in cancer in schizophrenia patients: new evidence for the autoimmune hypothesis of schizophrenia

Figures & data

Table 1 General information about the deceased patients in this study

Groups	Sex	Age, years	Cause of death
Schizophrenia patients	Male	46	Accident
	Male	32	Accident
	Male	45	Accident
	Male	57	Suicide
	Female	43	Accident
	Female	55	Suicide
Normal controls	Male	35	Accident
	Male	43	Accident
	Male	41	Homicide
	Male	55	Accident
	Male	44	Accident
	Male	59	Accident

Note: This table shows the age, sex and cause of death of the deceased patients from whom brain samples were obtained.

Figure 1 Results of GSEA analysis. S1–S10 refers to the ten samples from schizophrenia patients and N1–N10 refers to the ten samples from controls.

Notes: (A) Data from ten schizophrenia patients and ten normal controls were extracted from the microarray dataset GSE27383 and analyzed using GSEA. Gene expression differences between the two groups are shown as heat maps of the top 50 DEGs. (B) mRNA expression of IL-8 in schizophrenia patients (S) and normal controls (N). Expression of IL-8 mRNA in peripheral blood of schizophrenia patients is significantly increased.
Abbreviations: DEGs, differentially expressed genes; GSEA, Gene Set Enrichment Analysis.

Figure 2 Results of enrichment analysis.

Notes: Gene expression differences between schizophrenia patients and normal controls were ranked according to the NES. In schizophrenia patients, both the cancer pathway (A) and the chemokine signaling pathway (B) were enriched around the increased expression of IL-8 (P<0.05).
Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; NES, normalized enrichment score.

Figure 3 Cancer-related genes and IL-8.

Table 2 Members of the gene set in the cancer pathway

Gene symbol	Gene location on chromosome	Rank in gene list	Rank metric score	Running ES	Core enrichment
PTGS2	1q31.1	1	0.563	0.0726	Yes
IL-8	4q13.3	4	0.528	0.1399	Yes
TPR	1q31.1	23	0.390	0.1763	Yes
JUN	1p32.1	29	0.378	0.2216	Yes
FGF13	Xq26.3-q27.1	55	0.343	0.2462	Yes
DAPK1	9q21.33	89	0.314	0.2606	Yes
PPARD	6p21.31	96	0.311	0.2963	Yes
FGF12	3q28-q29	124	0.299	0.3136	Yes
CBLC	19q13.32	177	0.282	0.3084	Yes
FGF18	5q35.1	201	0.275	0.3257	Yes
CREBBP	16p13.3	242	0.266	0.3281	Yes
EPAS1	2p21	266	0.261	0.3437	Yes
MMP9	20q13.12	287	0.257	0.3610	Yes
FGF22	19p13.3	510	0.224	0.2111	No
ARAF	Xp11.3	546	0.220	0.2115	No
IL-6	7p15.3	557	0.218	0.2319	No
MAPK10	4q21.3	558	0.217	0.2603	No
RET	10q11.21	586	0.214	0.2664	No
TCF7L2	10q25.2-q25.3	636	0.208	0.2541	No
SOS1	2p22.1	644	0.207	0.2754	No
NFKBIA	14q13.2	765	0.191	0.2035	No
CTNNA1	5q31.2	817	0.184	0.1864	No
AKT2	19q13.2	981	0.160	0.0757	No
MDM2	12q15	1,036	0.147	0.0513	No
FAS	10q23.31	1,045	0.145	0.0638	No
LAMA2	6q22.33	1,056	0.143	0.0744	No
CTNNB1	3p22.1	1,057	0.143	0.0931	No
ETS1	11q24.3	1,137	0.097	0.0420	No
MAP2K2	19p13.3	1,193	−0.151	0.0173	No
PAX8	2q14.1	1,263	−0.325	0.0040	No

Note: A “yes” in the last column (core enrichment) indicates core enrichment of the corresponding gene in the cancer pathway.

Abbreviation: ES, enrichment score.

Table 3 Members of the gene set in the chemokine signaling pathway

Gene symbol	Gene location on chromosome	Rank in gene list	Rank metric score	Running ES	Core enrichment
IL-8	4q13.3	4	0.528	0.1324	Yes
CXCL1	4q13.3	26	0.384	0.2143	Yes
CXCL5	4q13.3	40	0.360	0.2964	Yes
CXCL3	4q13.3	80	0.320	0.3475	Yes
PARD3	10p11.22-p11.21	135	0.296	0.3805	Yes
DOCK2	5q35.1	250	0.264	0.3573	Yes
CCR10	17q21.2	256	0.264	0.4211	Yes
SOS1	2p22.1	644	0.207	0.1653	No
NFKBIA	14q13.2	765	0.191	0.1186	No
VAV3	1p13.3	880	0.175	0.0726	No
AKT2	19q13.2	981	0.160	0.0339	No
JAK3	19p13.11	1,059	0.142	0.0090	No
CCR9	3p21.31	1,092	0.134	0.0179	No
CCR7	17q21.2	1,142	0.088	0.0014	No
ADRBK2	22q12.1	1,217	−0.185	−0.0101	No
CCL28	5p12	1,224	−0.195	0.0351	No

Note: A “yes” in the last column (core enrichment) indicates core enrichment of the corresponding gene in the chemokine signaling pathway.

Abbreviation: ES, enrichment score.

Table 4 P-values and FWER P-values for gene sets

Pathway	P-value	FWER P-value
Chemokine signaling pathway	0.030	0.387
Cancer pathway	0.043	0.498

Notes: P-values were adjusted using the Bonferroni correction to yield the FWER P-value. FWER P-values >0.05 indicate nonsignificant effects. According to the user guide of GSEA software, the software development team suggest the use of FDR and NES, instead of FWER, for evaluate the results of GSEA.

Abbreviations: FWER, family-wise error rate; GSEA, Gene Set Enrichment Analysis.

Notes: (A–G) GSEA results showed that the expression levels of several cancer-related genes, including PTGS2, TPR, JUN, CXCL1, CXCL3, CXCL5 and PARD3, were significantly increased in schizophrenia patients and that the increased expression of each was correlated with the increased expression of IL-8.
Abbreviation: GSEA, Gene Set Enrichment Analysis.

Table 2 Members of the gene set in the cancer pathway

Gene symbol	Gene location on chromosome	Rank in gene list	Rank metric score	Running ES	Core enrichment
PTGS2	1q31.1	1	0.563	0.0726	Yes
IL-8	4q13.3	4	0.528	0.1399	Yes
TPR	1q31.1	23	0.390	0.1763	Yes
JUN	1p32.1	29	0.378	0.2216	Yes
FGF13	Xq26.3-q27.1	55	0.343	0.2462	Yes
DAPK1	9q21.33	89	0.314	0.2606	Yes
PPARD	6p21.31	96	0.311	0.2963	Yes
FGF12	3q28-q29	124	0.299	0.3136	Yes
CBLC	19q13.32	177	0.282	0.3084	Yes
FGF18	5q35.1	201	0.275	0.3257	Yes
CREBBP	16p13.3	242	0.266	0.3281	Yes
EPAS1	2p21	266	0.261	0.3437	Yes
MMP9	20q13.12	287	0.257	0.3610	Yes
FGF22	19p13.3	510	0.224	0.2111	No
ARAF	Xp11.3	546	0.220	0.2115	No
IL-6	7p15.3	557	0.218	0.2319	No
MAPK10	4q21.3	558	0.217	0.2603	No
RET	10q11.21	586	0.214	0.2664	No
TCF7L2	10q25.2-q25.3	636	0.208	0.2541	No
SOS1	2p22.1	644	0.207	0.2754	No
NFKBIA	14q13.2	765	0.191	0.2035	No
CTNNA1	5q31.2	817	0.184	0.1864	No
AKT2	19q13.2	981	0.160	0.0757	No
MDM2	12q15	1,036	0.147	0.0513	No
FAS	10q23.31	1,045	0.145	0.0638	No
LAMA2	6q22.33	1,056	0.143	0.0744	No
CTNNB1	3p22.1	1,057	0.143	0.0931	No
ETS1	11q24.3	1,137	0.097	0.0420	No
MAP2K2	19p13.3	1,193	−0.151	0.0173	No
PAX8	2q14.1	1,263	−0.325	0.0040	No

Note: A “yes” in the last column (core enrichment) indicates core enrichment of the corresponding gene in the cancer pathway.

Abbreviation: ES, enrichment score.

Table 3 Members of the gene set in the chemokine signaling pathway

Gene symbol	Gene location on chromosome	Rank in gene list	Rank metric score	Running ES	Core enrichment
IL-8	4q13.3	4	0.528	0.1324	Yes
CXCL1	4q13.3	26	0.384	0.2143	Yes
CXCL5	4q13.3	40	0.360	0.2964	Yes
CXCL3	4q13.3	80	0.320	0.3475	Yes
PARD3	10p11.22-p11.21	135	0.296	0.3805	Yes
DOCK2	5q35.1	250	0.264	0.3573	Yes
CCR10	17q21.2	256	0.264	0.4211	Yes
SOS1	2p22.1	644	0.207	0.1653	No
NFKBIA	14q13.2	765	0.191	0.1186	No
VAV3	1p13.3	880	0.175	0.0726	No
AKT2	19q13.2	981	0.160	0.0339	No
JAK3	19p13.11	1,059	0.142	0.0090	No
CCR9	3p21.31	1,092	0.134	0.0179	No
CCR7	17q21.2	1,142	0.088	0.0014	No
ADRBK2	22q12.1	1,217	−0.185	−0.0101	No
CCL28	5p12	1,224	−0.195	0.0351	No

Note: A “yes” in the last column (core enrichment) indicates core enrichment of the corresponding gene in the chemokine signaling pathway.

Abbreviation: ES, enrichment score.

Table 4 P-values and FWER P-values for gene sets

Pathway	P-value	FWER P-value
Chemokine signaling pathway	0.030	0.387
Cancer pathway	0.043	0.498

Notes: P-values were adjusted using the Bonferroni correction to yield the FWER P-value. FWER P-values >0.05 indicate nonsignificant effects. According to the user guide of GSEA software, the software development team suggest the use of FDR and NES, instead of FWER, for evaluate the results of GSEA.

Abbreviations: FWER, family-wise error rate; GSEA, Gene Set Enrichment Analysis.

Figure 4 Increased expression of IL-8 among schizophrenia patients.

Notes: “S” means schizophrenia patients and “N” means normal control. IL-8 was found to be significantly increased in the prefrontal cortex of schizophrenia patients according to results from PCR; the X axis represents different groups and the Y axis represents the relative percentage of GAPDH (A), Western blotting (B), and immunohistochemistry (C).
Abbreviation: GAPDH, glyceraldehyde-phosphate dehydrogenase.