KDELR2 as a diagnostic and prognostic biomarker of bladder urothelial carcinoma and its correlation with immune infiltration

Ma, Sai; Sa, Longqi; Zhang, Jitao; Jiang, Kuo; Mi, Baoguo; Shan, Lequn

doi:10.1590/1678-4685-GMB-2023-0002

Sai Ma

conducted the experiments (gene and protein expression assays)

wrote the manuscript

read and approved the final version

Air Force Medical University, School of Stomatology, National Clinical Research Centre for Oral Disease, State Key Laboratory of Military Stomatology, Department of Prosthodontics, Shaanxi Key Laboratory of Stomatology, Xi’an, Shaanxi, China.

* These authors contributed equally to this study.

Longqi Sa

conceived and designed the study

read and approved the final version

Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi’an, Shaanxi, China.

* These authors contributed equally to this study.

Jitao Zhang

conducted the experiments (wound healing assay, transwell migration and macrophage recruitment assay)

read and approved the final version

Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi’an, Shaanxi, China.

Kuo Jiang

conducted the experiment (cell culture and transfection)

read and approved the final version

Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi’an, Shaanxi, China.

Baoguo Mi

conducted data analysis and interpretation

read and approved the final version

Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi’an, Shaanxi, China.

Lequn Shan

conducted the experiments (bioinformatic analysis)

wrote the manuscript

read and approved the final version

Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi’an, Shaanxi, China.

https://orcid.org/0000-0001-7015-5436

Associate Editor:

Emmanuel Dias Neto

Send correspondence to Shan Lequn. Xi’an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Youyidong Road, No. 555, Xi’an 710054, Shaanxi, China. Email: drshanlq@fmmu.edu.cn

*
These authors contributed equally to this study.

Conflict of Interest

All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare.

Characteristics	Low expression of KDELR2	High expression of KDELR2	p
n	204	204
T stage, n (%)			0.044
T1	1 (0.3%)	2 (0.5%)
T2	70 (18.7%)	49 (13.1%)
T3	90 (24.1%)	104 (27.8%)
T4	23 (6.1%)	35 (9.4%)
N stage, n (%)			0.011
N0	131 (35.8%)	106 (29%)
N1	16 (4.4%)	30 (8.2%)
N2	31 (8.5%)	44 (12%)
N3	2 (0.5%)	6 (1.6%)
M stage, n (%)			0.534
M0	14 (55.1%)	82 (39.6%)
M1	5 (2.4%)	6 (2.9%)
Pathologic stage, n (%)			0.295
Stage I	1 (0.2%)	1 (0.2%)
Stage II	85 (20.9%)	45 (11.1%)
Stage III	66 (16.3%)	74 (18.2%)
Stage IV	51 (12.6%)	83 (20.4%)
Primary therapy outcome, n (%)			0.295
PD	31 (8.8%)	37 (10.5%)
SD	13 (3.7%)	16 (4.6%)
PR	9 (2.6%)	13 (3.7%)
CR	128 (36.5%)	104 (29.6%)
Gender, n (%)			0.115
Female	46 (11.3%)	61 (15%)
Male	158 (38.7%)	143 (35%)
Age, n (%)			0.194
<=70	122 (29.9%)	108 (26.5%)
>70	82 (20.1%)	96 (23.5%)
Histologic grade, n (%)			<0.001
High Grade	183 (45.2%)	201 (49.6%)
Low grade	20 (4.9%)	1 (0.2%)
Subtype, n (%)			0.002
Non-papillary	121 (30%)	150 (37.2%)
Papillary	81 (20.1%)	51 (12.7%)
Lymphovascular invasion, n (%)			0.040
No	72 (25.6%)	58 (20.6%)
Yes	64 (22.8%)	87 (31%)
Smoke, n (%)			0.008
No	67 (17%)	42 (10.6%)
Yes	131 (33.2%)	155 (39.2%)
Age, median (IQR)	67 (59.75, 75.25)	70 (61, 77)	0.126

Characteristics	Total (n)	Univariate analysis		Multivariate analysis
Characteristics	Total (n)	HR (95% CI)	P	HR (95% CI)	P
Gender (male vs. female)	413	0.849 (0.616-1.169)	0.316
Age (>70 vs. <=70)	413	1.421 (1.063-1.901)	0.018	1.117 (0.594-2.102)	0.730
T stage (T3/T4 vs. T1/T23)	379	2.199 (1.515-3.193)	<0.001	1.335 (0.281-6.347)	0.716
N stage (N1/N2/N3 vs. N0)	369	2.289 (1.678-3.122)	<0.001	0.875 (0.371-2.064)	0.760
M stage (M1 vs. M0)	213	3.136 (1.503-6.544)	0.002	0.732 (0.209-2.565)	0.626
Pathologic stage (stage III/IV vs. Stage I/II)	411	2.310 (1.596-3.342)	<0.001	1.484 (0.231-9.540)	0.678
Primary therapy outcome (PD/SD vs. PR/CR)	357	0.226 (0.162-0.315)	<0.001	0.306 (0.144-0.652)	0.002
Smoker (yes vs. no)	400	1.305 (0.922-1.847)	0.133
Histologic grade (high grade vs. low grade)	410	2.972 (0.735-12.008)	0.126
Lymphovascular invasion (yes vs. no)	282	2.294 (1.580-3.328)	<0.001	1.952 (0.853-4.463)	0.113
KDELR2 (high vs. low413)	413	1.567 (1.163-2.112)	0.003	2.901 (1.475-5.705)	0.002

Cell Type	Gene Marker	None Cor	P	Purity Cor	p	Tumor R	p	Normal R	P
B cell	CD19	0.132	**	0.083	0.111	0.16	**	0.038	0.69
	CD20 (KRT20)	0.128	*	0.177	**	0.083	0.096	-0.055	0.56
	CD38	0.142	**	0.095	0.068	0.21	***	0.23	*
CD8⁺ T cell	CD8A	0.102	*	0.038	0.469	0.14	**	-0.019	0.84
CD8⁺ T cell	CD8B	0.07	0.157	0.026	0.616	0.1	*	-0.14	0.14
Tfh	BCL6	0.003	0.952	-0.003	0.947	0.071	0.15	-0.15	0.13
	ICOS	0.126	*	0.067	0.199	0.16	***	0.19	*
	CXCR5	0.134	**	0.073	0.164	0.092	0.065	0.089	0.35
Th1	T-bet (TBX21)	0.098	*	0.035	0.498	0.13	**	0.29	0.23
Th1	STAT4	0.046	0.344	-0.027	0.604	0.13	**	0.27	0.27
Th1	IL12RB2	0.135	**	0.106	*	0.2	***	0.26	0.28
	WSX1 (IL27RA)	0.225	***	0.198	***	0.27	***	0.21	0.38
	STAT1	0.214	***	0.178	***	0.29	***	0.4	0.091
	IFN-γ (IFNG)	0.069	0.165	0.018	0.733	0.11	*	0.19	0.43
	TNF-a (TNF)	0.126	*	0.107	*	0.2	***	-0.25	0.29
Th2	GATA3	0.049	0.624	0.096	0.067	0.032	0.52	0.37	0.12
	CCR3	0.196	***	0.202	***	0.25	***	0.37	0.12
	STAT6	-0.073	0.143	-0.046	0.378	0.025	0.62	0.15	0.54
	STAT5A	0.182	***	0.159	**	0.24	***	-0.14	0.57
Th9	TGFBR2	0.28	***	0.159	**	0.24	***	-0.14	0.11
	IRF4	0.119	*	0.042	0.425	0.14	**	0.19	0.43
	PU.1 (SPL1)	0.166	***	0.108	*	0.2	***	0.086	0.73
Th17	STAT3	0.229	***	0.195	***	0.32	***	0.29	0.23
	IL-21R	0.164	***	0.112	*	0.2	***	0.2	0.41
	IL-23R	-0.019	0.698	-0.032	0.545	0.022	0.66	0.21	0.38
	IL-17A	-0.092	0.064	-0.093	0.075	-0.061	0.22	-0.22	0.38
Th22	CCR10	0.106	*	0.089	0.086	0.14	**	0.061	0.81
Th22	AHR	0.175	***	0.215	***	0.2	***	0.27	**
Treg	FOXP3	0.164	***	0.128	*	0.2	***	0.17	0.5
	CD25 (IL2RA)	0.214	***	0.178	***	0.26	***	-0.023	0.93
	CCR8	0.281	***	0.266	***	0.3	***	0.44	0.057
T cell exhaustion	PD1 (PDCD-1)	0.086	0.082	0.017	0.749	0.13	**	0.14	0.57
	CTLA4	0.088	0.078	0.02	0.698	0.14	**	0.088	0.72
	LAG3	0.096	0.053	0.04	0.448	0.13	**	0.24	0.31
	TIM-3 (HAVCR2)	0.236	***	0.205	***	0.28	***	0.046	0.85
Macrophage	CD68	0.084	0.091	0.02	0.702	0.19	***	0.22	0.37
Macrophage	CD11b (ITGAM)	0.292	***	0.277	***	0.33	***	0	1
M1	INOS (NOS2)	0.06	0.23	0.056	0.286	0.11	*	0.21	0.39
	IRF5	0.153	**	0.151	**	0.14	**	0.11	0.65
	COX2 (PTGS2)	0.254	***	0.231	***	0.28	***	0.15	0.55
M2	CD16	0.292	***	0.27	***	0.33	***	0.033	0.89
	ARG1	0.009	0.857	0.029	0.579	-0.054	0.28	-0.17	0.48
	MRC1	0.296	***	0.283	***	0.34	***	0.16	0.51
	MS4A4A	0.261	***	0.23	***	0.29	***	0.074	0.76
TAM	CCL2	0.272	***	0.251	***	0.29	***	0.028	0.91
	CD80	0.188	***	0.151	**	0.25	***	0.13	0.6
	CD86	0.189	***	0.138	**	0.25	***	0.18	0.45
	CCR5	0.197	***	0.148	**	0.23	***	0.42	0.075
Monocyte	CD14	0.193	***	0.146	**	0.24	***	-0.021	0.93
	CD16 (FCGR3B)	0.187	***	0.174	***	0.33	***	-0.14	0.58
	CD115 (CSF1R)	0.215	***	0.168	**	0.27	***	0.17	0.48
Neutrophil	CD66b (CEACAM8)	0.115	*	0.132	*	0.091	0.068	-0.032	0.9
	CD15 (FUT4)	0.333	***	0.295	***	0.35	***	0.23	0.33
	CD11b (ITGAM)	0.292	***	0.277	***	0.33	***	0	1
Natural killer cell	XCL1	-0.034	0.489	-0.034	0.512	-0.035	0.48	0.47	*
	CD7	0.088	0.077	0.016	0.765	0.12	*	0.19	0.42
	KIR3DL1	0.047	0.347	0.018	0.724	0.074	0.14	0.4	0.09
Dendritic cell	CD1C (BDCA-1)	-0.017	0.734	-0.088	0.093	0.006	0.91	0.27	0.27
	CD141 (THBD)	-0.015	0.766	-0.046	0.379	0.086	0.085	-0.014	0.96
	CD11C (ITGAX)	0.233	***	0.209	0.055	0.27	***	-0.028	0.91

[1] Associate Editor:

Emmanuel Dias Neto

Brazil

Brazil

KDELR2 as a diagnostic and prognostic biomarker of bladder urothelial carcinoma and its correlation with immune infiltration

Abstract