Adiponectin receptor-1 expression is associated with good prognosis in gastric cancer

Abstract

Background: Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression.

Methods: In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining.

Results: MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 μg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, p = 0.013 and 9/32, p = 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (p = 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (p = 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer.

Conclusions: In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.

Figure 1

The expression of AdipoR1 and AdipoR2 in human gastric cancer cell lines. (A) Western blotting analysis for AdipoR1 (42 kD), AdipoR2 (35 kD), and β-actin (42 kD) in human gastric cancer cell lines. (B) Densitometric analysis were performed. The results are mean ± SE values of 3 different experiments.

Figure 2

The effect of adiponectin on cell proliferation. Cell viability was assessed after 48-h exposure to a single dose of adiponectin (0, 0.1, 1, 5, or 10 μg/ml) in serum-free medium. The results are mean ± SE values of 3 different experiments.

Figure 3

Correlation between serum adiponectin level and body mass index or tumor stages. Correlation between serum adiponectin level and body mass index (A) or tumor stages (B) in gastric cancer. Box plots show interquartile range (box), median (thick line), and range (thin line).

Figure 4

Representative photomicrographs. Representative photomicrographs of immunohistochemical staining of AdipoR1 (A, normal mucosa; B, cancer tissue) and AdipoR2 (C, normal mucosa; D, cancer tissue). AdipoR1 and AdipoR2 were expressed in normal gastric mucosa in the cytoplasm as well as in the cell membrane. In gastric cancer tissues, higher intensity of immunostaining compared to normal mucosa was considered positive. Original magnification, ×100.

Figure 5

Survival curves for 100 patients with gastric cancer after surgery, according to serum adiponectin level. There was no significant difference between the high serum adiponectin level group (n = 61) and the low serum adiponectin level group (n = 39).

Figure 6

Survival curves for 100 patients with gastric cancer after surgery, according to AdipoR1 expression. The survival rate of patients with gastric cancer positive for AdipoR1 expression (n = 68) was significantly greater than that of patients negative for AdipoR1 (n = 32).

Figure 7

Survival curves for 100 patients with gastric cancer after surgery, according to AdipoR2 expression. There was no significant difference between the AdipoR2-positive group (n = 72) and the AdipoR2-negative group (n = 28).