ABSTRACT: Trefoil factor family member 2 (Tff2) is significantly involved in intestinal tumor growth in ApcMin/+ mice, which can be used as a human colon cancer model. TFF2, which encodes TFF2 (spasmolytic protein 1) is highly expressed in human cancer tissues, including the pancreas, colon and bile ducts, as well as in normal gastric and duodenum tissues. By contrast, TFF2 exhibits low expression levels in other normal tissues, including the small and large intestine. Furthermore, TFF2 expression has not been detected in DLD-1 cells, a cell line derived from human colon cancer. The trigger of TFF2 expression in normal and tumor cells remains unknown. Highly malignant tumor tissues are characterized by higher temperatures and lower pH (6.2-6.9) than in normal tissues, where the normal pH ranges from 7.2 to 7.4. This microenvironment exacerbates malignancy by promoting the acquisition of cell death resistance, drug resistance and immune escape. Therefore, the present study examined how TFF2 expression is affected in cultured cells that imitate the tumor tissue microenvironment. The incubation temperature was increased from 37 to 40˚C, but no expression of TFF2 was induced. Subsequently, a culture solution with an acidic pH was prepared to simulate the Warburg effect in tumors. TFF2 expression was increased by 42.8- and 5.8-fold in cells cultured in acidic medium at pH 6.5 and 6.8 compared with at pH 7.4, respectively, as determined using the relative quantification method following quantitative polymerase chain reaction. The present study also analyzed fluctuations in the expression levels of genes other than TFF2, under acidic conditions. Acidic conditions upregulated the expression of genes related to cell membranes and glycoproteins, based on the Database for Annotation, Visualization, and Integrated Discovery. In conclusion, TFF2 was highly expressed under acidic conditions, implying that it may have an important function in protecting the plasma membrane from acidic environments in both normal and cancer cells. These findings warrant further investigation of TFF2 as a target of cancer therapy and diagnosis.
