Prognostic value of LAMP3 and TP53 overexpression in benign and malignant gastrointestinal tissues

Abstract

Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical and breast cancers. However, little is known of LAMP3 protein expression in gastrointestinal cancer and its prognostic value. We determined protein expression of LAMP3 and TP53 in both gastric (n=750) and colorectal (n=479) tissues by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients' clinical parameters. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to normal and benign tissues. In both gastric and colorectal cancers, high LAMP3 protein expression (LAMP3+) was significantly associated with tumor stage (P=0.014 and P<0.001). No correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 expression but not high TP53 expression had a poor overall survival (for gastric cancer P<0.001, CI: 1.762-4.567; for colorectal cancer P=0.036, CI: 1.062-5.980). Our data suggest that epithelial LAMP3 expression is an independent prognostic marker for gastrointestinal cancer.

Figure 1. Representation of LAMP3 and TP53 protein expression in gastric benign and malignant tissues on TMA sections

Column A: normal surgical margin of gastric cancer with low LAMP3 expression (IHC score, 80) and low TP53 expression (IHC score, 30); column B: chronic gastritis with no LAMP3 expression (IHC score, 0) and negative TP53 expression(IHC score, 0); column C: intestinal metaplasia with low LAMP3 expression (IHC score, 30) and no TP53 expression(IHC score, 0); column D: low-grade intraepithelial neoplasia with low LAMP3 expression (IHC score, 60) and high TP53 expression (IHC score, 180); column E: high-grade intraepithelial neoplasia with low LAMP3 expression (IHC score, 40) and no TP53 expression (IHC score, 0); column F: well differentiated gastric cancer with high LAMP3 expression (IHC score, 200) and high TP53 expression (IHC score, 210); column G: poorly differentiated gastric cancer with high LAMP3 expression (IHC score, 270)and no TP53 expression (IHC score, 0). Row 1 and 2 are LAMP3 staining with x40 (bar=500 μm) and x400 (bar=50 μm) magnification respectively, and row 3 and 4 are TP53 staining with with x40 (bar=500 μm) and x400 (bar=50 μm) magnification respectively.

Figure 2. Representation of LAMP3 and TP53 protein expression in colorectal benign and malignant tissues on TMA sections

Column A: normal surgical margin of colorectal cancer with low LAMP3 expression (IHC score, 60) and no TP53 expression (IHC score, 0); column B: chronic colitis with no LAMP3 expression (IHC score, 0) and TP53 expression (IHC score, 0); column C: intestinal metaplasia with low LAMP3 expression (IHC score, 40) and TP53 expression (IHC score, 40); column D: low-grade intraepithelial neoplasia with low LAMP3 expression (IHC score, 100) and high TP53 expression (IHC score, 300); column E: high-grade intraepithelial neoplasia with low LAMP3 expression (IHC score, 120) and no P53 expression (IHC score, 0); column F: low-grade colorectal cancer with high LAMP3 expression (IHC score, 180) and no TP53 expression (IHC score, 0); column G: high grade colorectal cancer with low LAMP3 expression (IHC score, 100) and high TP53 expression (IHC score, 270). Row 1 and 2 are LAMP3 staining with x40 (bar=500 μm) and x400 (bar=50 μm) magnification respectively, and row 3 and 4 are TP53 staining with with x40 (bar=500 μm) and x400 (bar=50 μm) magnification respectively.

Figure 3. Survival curves of gastric cancer by the Kaplan-Meier method and the log-rank test

A: overall survival curves of LAMP3+ (green line, 1) and LAMP3- (blue line, 0); B: overall survival curves of TP53+ (green line, 1) and TP53- (blue line, 0); C: overall survival curves of LAMP3+/TP53+ (blue line, 1), LAMP3+/TP53- (green line, 2), LAMP3-/TP53+ (yellow line, 3), and LAMP3-/TP53- (purple line, 4); D: overall survival curves by stage, TNM IIIc and IV (gray line, 7), TNM IIIb (lightblue line, 6), TNM IIIa (red line, 5), TNM IIb (yellow line, 4), TNM IIa (purple line, 3), TNM Ib (lightyellow line, 2), TNM Ia (green line, 1) and TNM 0 (blue line, 0); E: overall survival curves by preoperative CEA, high (green line, 1) and low (blue line, 0); F: overall survival curves by preoperative CA19-9 level, high (green line, 1) and low (blue line, 0).

Figure 4. Survival curves of colorectal cancer by the Kaplan-Meier method and the log-rank test

A: overall survival curves of LAMP3+ (green line, 1) and LAMP3- (blue line, 0); B: overall survival curves of TP53+ (green line, 1) and TP53- (blue line, 0); C: overall survival curves of LAMP3+/TP53+ (blue line, 1), LAMP3+/TP53- (green line, 2), LAMP3-/TP53+ (yellow line, 3), and LAMP3-/TP53- (purple line, 4); D: overall survival curves by stage, TNM III and IV (yellow line, 3), TNM II (green line, 2), and TNM 1 and 0 (blue line, 1); E: overall survival curves by differentiation, poor differentiation (green line, 1), well and middle differentiation (blue line, 0).