Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.

Hongpan Xu,Nongyue He,Lijun Peng,Yanyan Xia,Mengjiao Shen,Zhiyang Li

doi:10.1111/cpr.12607

Abstract

Tumour-targeted gene therapy is a promising approach for effective control of gastric cancer cell proliferation. Our study aims to develop a cancer therapy which combines tumour-targeting promoters with cytotoxins. The expression of globotriaosylceramide (Gb3), which is a Shiga-like toxin I (Stx1) receptor, was verified in gastric cancer compared with normal stomach tissues as assessed by flow cytometry and immunohistochemical analysis. We therefore constructed the recombinant pFZD7-Stx1 plasmid vectors with tumour-preferential Frizzled-7 promoter and Stx1. pFZD7-Stx1 was used to treat gastric cancer in vitro and in vivo. The gastric cancer cell proliferation and tumour growth were identified after the transfection with the pFZD7-Stx1. Globotriaosylceramide was obviously increased in gastric cancer compared with normal stomach. The gastric cancer cell proliferation and tumour growth decreased significantly after the transfection with the pFZD7-Stx1. Frizzled-7 promoter is preferentially active, and Gb3 is abundant in gastric cancer cells. Frizzled-7 promoter and Stx1 may be used to determine a novel and relatively specific and potent gastric cancer therapeutic strategy.

Highlights

Tumour‐targeted gene therapy may be a complementary treatment for gastric cancer
There was no significant difference in apoptotic rates among the control group, pFZD7‐ and Mut pFZD7‐Stx1‐transfected SGC7901 cell groups or between normal GES‐1 cells
We proved overexpression of Gb3 in gastric cancer and firstly reported that the Stx[1] can and significantly suppress the gastric cancer cell proliferation and tumour growth when driven by the Frizzled‐7 promoter

Summary

| INTRODUCTION

The incidence of gastric cancer is still very high worldwide and is associated with poor prognosis.[1]. In order to improve the targeting by gene therapy, there is still a long way to go to find cancer‐specific genes To achieve this goal, a range of tumour‐targeting promoters and cytotoxins have been discovered and used in cancer therapy.[4-6]. The expression level of Frizzled protein‐7 in gastric cancer cell lines is higher than that in human oesophageal cancer.[11]. The Gb3 expression level in gastric cancer is still controversial and the use of Stx[1] has high potential but needs to be further identified in gastric cancer therapy. The apop‐ tosis‐necrosis rate and cleaved caspase 3 expression for gastric cancer cells transfected with pFZD7‐Stx[1] were significantly higher than that of normal stomach cells. Our tumour‐specific targeting promoters combined with cytotoxins demonstrated this new specific and effective gene therapy for gastric cancer in vitro and in vivo

| MATERIALS AND METHODS

| DISCUSSION

Findings

| CONCLUSIONS