Bile salt receptor TGR5 is highly expressed in esophageal adenocarcinoma and precancerous lesions with significantly worse overall survival and gender differences

Figures & data

Figure 1 Immunohistochemical score of TGR5 in EAC.

Notes: TGR5 expression is located in the cell membrane and cytoplasm. (A) No TGR5 expression in EAC glands (score 0); (B) TGR5 weakly positive cells evenly distributed in EAC glands (score 1+); (C) TGR5 moderately positive cells evenly distributed in EAC glands (score 2+); and (D) TGR5 strongly positive cells evenly distributed in the membrane and cytoplasm of EAC glands (score 3+). Magnification 400×.
Abbreviations: EAC, esophageal adenocarcinoma; TGR5, the G-protein coupled bile acid receptor.

Figure 2 High expression of TGR5 in various histologic subtypes assessed via immunohistochemical studies.

Notes: (A) TGR5 positive cells (score 2+ in most cells) predominately distributed in the basal layer of normal esophageal squamous epithelium; (B) TGR5 strongly positive cells evenly distributed in the glands of columnar cell metaplasia; (C) TGR5 strongly positive cells evenly distributed in the glands of Barrett’s esophagus; (D) TGR5 strongly positive cells evenly distributed in low-grade dysplasia glands; (E) TGR5 strongly positive cells evenly distributed in high-grade dysplasia glands; (F) TGR5 strongly positive cells evenly distributed in EAC glands. Magnification (A) 200× and (B–F) 400×.

Abbreviations: EAC, esophageal adenocarcinoma; TGR5, the G-protein coupled bile acid receptor.

Table 1 Rates of TGR5 high expression in EAC and precancerous lesions

Histological type	Total (n)	High expression (%)	Nonhigh expression (%)
Adenocarcinoma	106	75 (71)	31 (29)
High-grade dysplasia	11	11 (100)	0 (0)
Low-grade dysplasia	18	13 (72)	5 (28)
Barrett’s esophagus	35	23 (66)	12 (34)
Columnar cell metaplasia	62	52 (84)	10 (16)
Squamous epithelium	83	30 (36)	53 (64)

Abbreviations: EAC, esophageal adenocarcinoma; TGR5, the G-protein coupled bile acid receptor.

Table 2 Comparison of TGR5 high-expression rates between various esophageal lesions

Comparison	p-Value
Adenocarcinoma vs.
Barrett’s esophagus	0.5748
Columnar cell metaplasia	0.0595
High-grade dysplasia	0.9725
Low-grade dysplasia	0.8991
Squamous epithelium	<0.0001**
Barrett’s esophagus vs.
Columnar cell metaplasia	0.0442*
High-grade dysplasia	0.9720
Low-grade dysplasia	0.6313
Squamous epithelium	0.0039*
Columnar cell metaplasia vs.
High-grade dysplasia	0.9740
Low-grade dysplasia	0.2708
Squamous epithelium	<0.0001**
High-grade dysplasia vs.
Low-grade dysplasia	0.9726
Squamous epithelium	0.9695
Low-grade dysplasia vs.
Squamous epithelium	0.0079*

Notes:

* Significant difference without using the Bonferroni correction;

** significant difference using the Bonferroni correction with α=0.05/15=0.0033.

Abbreviation: TGR5, the G-protein coupled bile acid receptor.

Figure 3 Association between TGR5 high expression and overall survival of esophageal adenocarcinoma patients.

Notes: TGR5 high-expression patients (mean survival: 36 months) exhibited a worse prognosis compared to patients with TGR5 low or no expression (mean survival: 48 months) (p=0.432).
Abbreviations: EAC, esophageal adenocarcinoma; TGR5, the G-protein coupled bile acid receptor.

Table 3 Examination of the relationship between TGR5 high expression and clinicopathologic characteristics in esophageal adenocarcinoma

Covariate	High expression	Nonhigh expression	p-Value
Age
Mean (SD)	64.5 (10.8)	65.9 (10.3)	0.5445
Range	34–83	43–85
Gender
Male	69	27	0.3254
Female	6	4
Lymph node metastasis
# (+) nodes	3.8 (4.7)	3.0 (4.2)	0.3854
Survival time
	37.6 (4.49)	46.3 (5.87)	0.0432
Tumor location
Esophagus	17	4	0.3202
GEJ	58	27
Stage
1	10	5	0.8782
2	20	9
3	45	17
T
1	12	7	0.4446
2	17	4
3	46	20
N stage
0	20	11	0.3893
1	34	16
2	13	2
3	8	2
Differentiation
Poor	44	19	0.8938
Moderate	25	9
Well	6	3

Abbreviations: SD, standard deviation; GEJ, gastroesophageal junction; TGR5, the G-protein coupled bile acid receptor.

Table 4 Overall association between high TGR5 expression and high VDR expression in esophageal adenocarcinoma and precancerous lesions

TGR5 high expression	TGR5 nonhigh expression	Pearson’s correlation	p-Value
VDR high expression
130	47	0.2299 (SE=0.0585)	<0.0001
VDR nonhigh expression
57	55

Abbreviations: SE, standard error; TGR5, the G-protein coupled bile acid receptor; VDR, vitamin D receptor.

Figure 4 TGR5 amplification and overall survival.

Notes: (A) Frequency histogram indicates amplification of the TGR5 locus at chromosome 2q35 in 116 esophageal adenocarcinoma samples, using high density copy number DNA microarrays. This locus is amplified in 14/116 (12.7%) cases in this patient cohort. (B) There is no significant association between TGR5 amplification and overall survival (p=0.33).

Abbreviation: TGR5, the G-protein coupled bile acid receptor.