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Gastric cancer is the fourth most common cancer and the second leading cause of cancer death worldwide. Although the global incidence of gastric cancer has been decreased dramatically in recent decades, north and northwest of Iran have the highest incidence rate of gastric cancer. Whilst the surgical procedures for gastric cancer have been improved, there is no cure for that. The intestinal type of GC results from pre-neoplastic conditions including atrophic gastritis, intestinal metaplasia and dysplasia. Trefoil Factors Family proteins (TFFs) are small and stable molecules secreted by the mammalian gastrointestinal tract. TFFs constitute a family of three peptides (TFF1, TFF2and TFF3) that are widely expressed in a tissue specific manner in the gastrointestinal tract. Variable TFFs expression in gastric cancer and pre-neoplastic lesions has been found. TFF1 has a tumor suppressor activity and inhibits tumorogenesis in gastric cancer. Its expression decreases in gastritis, gastric atrophy, dysplasia, intestinal metaplasia and gastric cancer.TFF2 has a protective effect on gastrointestinal epithelium. As a prognostic factor, TFF2 expression decreases in gastric ulcer, chronic atrophic gastritis and gastric cancer. TFF3 is considered as an oncogenic factor in gastric tissues. Whilst the normal gastric tissues don’t express TFF3, it increases in intestinal metaplasia. Therefore, more studies are necessary to clarify the role of TFFs in GC and pre-neoplastic conditions. This review has focused on elucidating the important role of TFFs in gastric cancer and pre-neoplastic lesions.

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