REG Iα is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer

Abstract

Background: The regenerating gene Iα (REG Iα) is involved in gastric carcinogenesis as an antiapoptotic factor. Therefore, we investigated whether REG Iα confers resistance to chemotherapeutic drugs in gastric cancer (GC) cells and whether REG Iα expression is useful for predicting the response to chemotherapy and outcome in patients with GC.

Methods: A total of 70 patients with unresectable stage IV GC received first-line chemotherapy with S-1 and cisplatin (S-1/CDDP). The expression of REG Iα was evaluated immunohistochemically using biopsy samples obtained before chemotherapy, and its relationship to clinicopathological parameters was analysed statistically. The effects of REG Iα gene induction on resistance to 5-FU or CDDP treatment were examined by cell survival assay and flow cytometry.

Results: Of the 70 patients with unresectable stage IV GC, 19 (27%) were positive for REG Iα expression. The expression of REG Iα was independently predictive of poorer progression-free and overall survival in such patients (hazard ratio (HR) 2.46; P=0.002 and HR 1.89; P=0.037, respectively). The gene induction of REG Iα conferred resistance to cell death induced by 5-FU or CDDP in GC cells.

Conclusion: In patients with stage IV GC, REG Iα, which confers resistance to chemotherapeutic drugs in GC cells, is a potential biomarker for predicting resistance to S-1/CDDP treatment.

Figure 1

Immunostaining of REG Iα in biopsy samples obtained from gastric cancer tissues. The biopsy samples were obtained before chemotherapy (A, B, and D) and after disease progression (C). (A) The REG Iα-negative gastric cancer (diffuse type). (B) The REG Iα-positive gastric cancer (intestinal type). (C) The REG Iα-positive gastric cancer (diffuse type). This sample was obtained from the same patient as that in (A) when he developed disease progression after S-1/CDDP treatment. (D) The REG Iα-positive signet-ring cell carcinoma (diffuse type).

Figure 2

(A) Progression-free survival (PFS) and (B) overall survival (OS) according to REG Iα expression in patients with unresectable stage IV GC who received first-line treatment with S-1/CDDP. Kaplan–Meier curves were constructed and pairwise differences were analysed by log-rank test.

Figure 3

Effects of REG Iα gene induction on resistance to anticancer drugs in gastric cancer cells. Human gastric cancer AGS cells stably transfected with pIRES2-hREG Iα (AGS-REG Iα) or pIRES2-EGFP (AGS-EGFP; control) plasmid were treated with 5-FU (A, 0.2–20 mℳ) or CDDP (B, 1–100 μℳ) for 30 h. The percentage of viable cells was then evaluated, as described in Materials and Methods. All results are expressed as the means±s.e.m. of four samples. *P<0.001 vs AGS-EGFP at the same dose point.

Figure 4

Effects of REG Iα gene induction on cell death induced by anticancer drugs in gastric cancer cells. The AGS-REG Iα or AGS-EGFP cells were treated with 5-FU (A and B, 20 mℳ) or CDDP (C and D, 100 μℳ) for 24 h. The cells were then stained using propidium iodide and analysed by flow cytometry to evaluate the percentage of dead cells, as described in Materials and Methods. All results are expressed as the means±s.e.m. of four samples.