The Expression and Role of Trefoil Factors in Human Tumors
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1617 Review Article The expression and role of trefoil factors in human tumors Yifan Zhang1, Yang Liu1,2, Lei Wang3, Haiyan Song1,2 1Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; 2China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China; 3Department of Liver Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China Contributions: (I) Conception and design: H Song; (II) Administrative support: H Song; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Y Zhang, Y Liu; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Haiyan Song. Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Email: [email protected]. Abstract: Trefoil factor (TFF) family is a type of small secreted peptide characterized by a stable trefoil structure, and it includes three members: TFF1, TFF2 and TFF3. TFFs were initially found mainly distributed in the gastrointestinal mucosa and were subsequently found in the uterus, breast, hypothalamus, pituitary, respiratory tract, conjunctiva and other tissues, with the biological function of mucosal protection, epithelial restitution, inflammatory regulation, etc. Recent studies have found that TFFs’ expression was up- regulated in multiple malignant tumors, including gastric cancer, colon cancer, hepatocellular carcinoma (HCC), breast cancer, prostate cancer, etc. In addition, TFFs’ levels in these tumor tissues or in the serum of patients were closely correlated with malignancy and prognosis. TFFs promote tumorigenesis and metastasis by enhancing cell proliferation, invasion, metastasis, and angiogenesis and by inhibiting cell apoptosis. On the contrary, several recent studies have shown a down-regulation of TFFs in some cancers, and a tumor suppressing role of TFFs through the inhibition of tumor cell proliferation and the promotion of apoptosis. Do TFFs play a tumor-promoting or tumor-inhibiting role? Can they be used as a reliable biomarker for tumor diagnosis and prognosis, or as a treatment target? What is the underlying regulatory mechanism? Currently, these questions still need to be elucidated. This review summarizes current studies about the expression and role of TFFs in human tumors. Keywords: Trefoil factor (TFF); tumor; role; regulatory mechanism; biomarker Submitted Sep 07, 2018. Accepted for publication Jul 11, 2019. doi: 10.21037/tcr.2019.07.48 View this article at: http://dx.doi.org/10.21037/tcr.2019.07.48 Introduction One such motif is found in TFF1 and TFF3, whereas TFF2 possesses two trefoil domains. The trefoil domain is The trefoil factor (TFF) family consists of three members: very stable; such that TFFs are strongly resistant to acid, TFF1, TFF2, and TFF3. They are also called breast cancer-associated peptide (pS2), spasmolytic peptide (SP), protease hydrolysis and heat. Therefore, TFFs can maintain and intestinal trefoil factors (ITF). The gene encoding the their biological activity in the complex physiological human TFF family is located on chromosome 21q22.3 (1). environment of the gastrointestinal tract, with the function This family is made of small cysteine-rich polypeptide of mucosal protection and epithelial restitution (2). whose secondary structure consists of 38–39 amino acids In normal tissues, TFFs are mainly expressed in mucosal formed by 6 highly conserved cysteine residues to form epithelium, co-secreted with mucins in the gastrointestinal three intramolecular disulfide bonds folded into a “trefoil” tract and respiratory tract to form protective barriers, as structure. The “trefoil domain” is also called the P domain. well as expressed in the central nervous system, eyes, and © Translational Cancer Research. All rights reserved. Transl Cancer Res 2019;8(4):1609-1617 | http://dx.doi.org/10.21037/tcr.2019.07.48 1610 Zhang et al. Role of TFFs in tumor other tissues (3). Among the TFF family, TFF1 is mainly gastric cancer was significantly higher than that in the expressed in the mucosal epithelial cells of the gastric body healthy counterparts (20). The increased expression of and gastric antrum, followed by low-level expression in the TFF3 protein in breast cancer was positively correlated empty ileum, colon, salivary glands, pancreas and other with tumor size, lymph node metastasis, poor survival and mucous epithelial tissues (4). TFF2 is mainly expressed in prognosis (26). In addition, a two-step immunohistochemical the mucous cells of the gastric body and gastric antrum method was used to detect the expression of TFF3 in and the lower duodenum (5). TFF3 is mainly expressed 90 pairs of hepatocellular carcinomas (HCC) tumor tissues in the small intestine and colon goblet cells, as well as in and non-cancerous adjacent tissues. The results showed the uterus, breast, hypothalamus, pituitary, salivary gland, that the positive expression rate of TFF3 was 62.1% in respiratory tract, ocular conjunctiva, nasal mucosa, gastric tumor tissues and 33.8% in adjacent tissues. The difference juice and duodenum ampulla (6). between the two groups was statistically significant(17) . TFFs function to protect mucosa, promote epithelial Contrary to the aforementioned studies, the expression of repair, inhibit inflammation, regulate cell proliferation, TFF1 and TFF2 in normal gastric mucosa, paracancerous apoptosis and migration. Rapid increase in expression tissues and gastric cancer tissues decreased gradually, of TFF1 and TFF2 at the margins of digestive tract suggesting that TFF1 and TFF2 proteins may be specific ulcers promotes migration of epithelial cells (7). TFF2 inhibitors of gastric cancer and important protective promotes the repair of gastric mucosal injury by increasing factors for the digestive tract mucosa (21). There are the migration of human colonic epithelial cells and by two explanations for the deletion of TFF1 expression in inhibiting the occurrence of acute gastric injury (8). gastric cancer. The first is a somatic mutation, since the TFF3 plays a pivotal role in maintaining the integrity of TFF1 gene locus 21q22 is frequently mutated and allelic the gastrointestinal mucosa and promoting repair (9). In deletion is common (36). The second explanation is the addition, TFF3 expression increases in corneal diseases and hypermethylation of the promoter region of the TFF1 promotes corneal repair (10). gene in gastric cancer and intestinal metaplasia, resulting Over the past few decades, a large number of studies in transcriptional silencing of the TFF1 gene (37). Buache have found abnormal expression of TFFs in many types et al. (38) found that the incidence rate, number and size of tumors, where they were involved in tumorigenesis of breast tumors induced by dimethylbenzanthracene and tumor development, which are closely related to (DMBA) in TFF1-KO mice were higher than those in wild- the malignancy and prognosis of tumors. However, type mice. TFF1 can act as a tumor suppressor and inhibit contradictory results were also found in some tumors. the development of tumors in breast epithelial cells. This is consistent with the clinical findings of primary breast cancer, in which patients with TFF1 positive expression The expression of TFFs in tumors received better prognosis. In addition, in type I endometrial As shown in Table 1, studies have found increased expression carcinoma, TFF3 up-regulation was found to be positively of TFF members in multiple tumors. In addition to the correlated to the outcome of patients (9). high expression of TFF1 in gastric cancer, TFF1 and TFF3 in 97 patients with colon cancer were significantly The role and mechanism of TFFs higher than those in 79 healthy people (32). Using an immunohistochemical method, researchers found that In vitro and in vivo experiments showed that TFFs can the expression of TFF3 in thyroid papillary carcinoma affect tumor development mainly by affecting tumor cell was higher than in adjacent precarcinomatous tissue in apoptosis, cell proliferation, metastasis and angiogenesis, 31 cases of thyroid papillary carcinoma (13). A clinical which are summarized in Figure 1. study showed that the positive expression rate of TFF3 increased from normal gastric tissues to paracancerous Apoptosis tissues and gastric cancer tissues, which were 5.0%, 40.0% and 58.6% respectively. The expression of TFF3 TFF1 can not only protect epithelial cells from apoptosis in gastric cancer tissues was related to the stage of local induced by chemical toxic reagents, but can also prevent lymph node metastasis and prognosis (19). Another study gastric cancer cells from apoptosis induced by etoposide (63). found that the serum TFF3 concentration in patients with TFF2 can inhibit the apoptosis of breast cancer cells such © Translational Cancer Research. All rights reserved. Transl Cancer Res 2019;8(4):1609-1617 | http://dx.doi.org/10.21037/tcr.2019.07.48 Translational Cancer Research, Vol 8, No 4 August 2019 1611 Table 1 Expression change of TFFs in different type of tumors Expression change of TFFs Tumor type Tumor vs. normal tissues or Serum of patients Ref. Ref. positive ratio in tumor tissues vs. healthy people Retinal neuroblastoma TFF1 ↑ (11) – – Oral carcinoma TFF2 ↓, TFF3 ↓ (12) – – Thyroid papillary carcinoma 83.87% TFF3 ↑ (13) – – Lung cancer – – TFF3 ↑ (14) Cholangiocarcinoma