In our cohort study of cases of gastric adenocarcinoma, we observed frequent overexpression of AMACR in gastric adenocarcinomas. Specifically, sixty-four percent (141/220) of gastric tumor samples displayed elevated expression of AMACR. By contrast, no expression of AMACR in normal gastric tissue was identified. The differential expression of AMACR in gastric cancer samples and non-neoplastic gastric tissue was statistically significant (p<0.05). The striking differential expression of AMACR in gastric cancer as compared to non-neoplastic gastric tissue has also been documented at mRNA level. For example, a recent study using quantitative real-time polymerase chain reaction analysis demonstrated robust AMACR mRNA expression in gastric carcinomas but very low to undetectable levels of AMACR mRNA expression in normal gastric mucosa [20
]. These observations suggest a potentially important function of AMACR in gastric adenoma/carcinoma tumorigenesis. The significant overexpression of AMACR in human gastric adenocarcinomas in our study further supports the role of upregulation of AMACR expression in gastric cancer development and progression.
In an independent study of AMACR in gastric cancer, Lee et al
reported that AMACR was expressed in 52% (34/66) of cases of gastric carcinoma, 83% (40/48) of cases of gastric dysplasia, and 5% (2/44) of cases of nonneoplastic epithelium [13
]. It is not clear why a minor subset of nonneoplastic gastric epithelium in their study displayed AMACR expression. One possible explanation is nonspecific protein binding in gastric tissue, a known phenomenon due to its abundant endogenous enzymes. In addition, the authors used an AMACR antibody produced by a different biocompany, suggesting possible differences in epitope recognition or specificity. Our findings are more in agreement with those reported by Cho et al
]. In their study, AMACR expression was identified in 63% (83/132) of cases of gastric adenocarcinoma, 79% (23/29) of cases of gastric adenoma, 8% (2/26) of cases of intestinal metaplasia, and 0% (0/32) of cases of normal gastric mucosa. Overall, we believe our data is fairly representative as it reflects a well-defined larger group of primary gastric adenocarcinoma that was tested in a uniform manner, namely, we simultaneously subjected all of our samples to the same sectioning, tissue microarray construction, and staining conditions, thus minimizing the preanalytical variables in the processes of the experiments. Nevertheless, additional validations of this finding, preferably among multiple institutions, will be needed to confirm the expression of AMACR in gastric adenocarcinoma and to evaluate its clinical significance. Of note, we observed significantly higher expression of AMACR in intestinal than in signet ring cell adenocarcinoma (p<0.05). This significant finding may indicate a role of AMACR in gastric tumor differentiation.
Gastric cancer is the second most common cause of cancer-associated deaths worldwide. The majority of patients with gastric cancer have advance-stage disease at the time of diagnosis. Radical surgical resection has been the main treatment modality for resectable disease [15
]. However, up to 70% of patients with advance-stage gastric cancer have a relapse and die within 5 years after resection despite recent improvements in surgical treatment [15
]. Recently, use of adjuvant chemotherapy and radiotherapy has led to reduced locoregional relapse rates, thus improving prognoses for gastric cancers. However, further improvements in local tumor control, reduction of metastasis, and minimization of therapy-related toxicity are still needed to increase the survival rates in patients with gastric cancer. Therefore, finding more specific targets for neoadjuvant therapy for gastric cancer is essential.
AMACR may be such a target. Emerging evidence suggests that more specific targets for combating gastric cancer are needed. Currently, AMACR's potential role as a target for treating gastric cancer seems to be promising. However, confirming this role requires a more thorough understanding of the function of AMACR in gastric tumorigenesis as well as its use as a therapeutic target. One possible function of AMACR in gastric cancer is via its ability to act as an activator of peroxisome proliferator-activated receptor (PPAR)-γ, an enzyme that is predominantly expressed in adipose tissue and has an important function in triggering adipocyte differentiation. Studies have shown that PPAR-y is expressed in various human cancer cells, including colon, prostate, breast, and gastric cancer cells. Sato et al
] reported strong expression of PPAR-γ in gastric carcinomas regardless of the tumor differentiation as well as PPAR-γ expression in gastric antral mucosa with intestinal metaplasia. Thus, AMACR may play a role in the promotion of gastric cancer cell growth through PPAR-γ activation [4