Review Article

Trefoil Factor Family in Pre-neoplastic Lesions and Gastric Cancer

Zahra Behrooznia, Pouya Ghaderi, Narges Jafarzadeh, Azra Izanloo, Sepideh Mansoori Majoofardi, Rana Rahimi Kakhki, Maryam Nabipour, Hamid Reza Sima, Ali Reza Sima, Mohammad Reza Farzanehfar, Malihe Saber Afsharian, Ladan Ghoshayeshi, Ali Reza Bary, Masoud Sharifian Razavi, Sara Lary, Kamran Ghaffarzadehgan

Zahra Behrooznia
Gastric Cancer Research Group, Mashhad, Iran. Medical Student, Student Research Committee, Faculty of Medicine, Mashhad Islamic Azad University, Mashhad, Iran.

Pouya Ghaderi
Gastric Cancer Research Group, Mashhad, Iran. Medical Student, Student Research Committee, Faculty of Medicine, Mashhad Islamic Azad University, Mashhad, Iran.

Narges Jafarzadeh
Razavi cancer research center,RazaviHospital,Imam Reza International University,Mashhad,Iran.

Azra Izanloo
Razavi cancer research center,RazaviHospital,Imam Reza International University,Mashhad,Iran.

Sepideh Mansoori Majoofardi
Gastric Cancer Research Group, Mashhad, Iran. Medical Student, Student Research Committee, Faculty of Medicine, Mashhad Islamic Azad University, Mashhad, Iran.

Rana Rahimi Kakhki
Gastric Cancer Research Group, Mashhad, Iran. Medical Student, Student Research Committee, Faculty of Medicine, Mashhad Islamic Azad University, Mashhad, Iran.

Maryam Nabipour
Medical Student, Student Research Committee, Faculty of Medicine, Mashhad Islamic Azad University, Mashhad, Iran.

Hamid Reza Sima
Division of Gastroenterology,Department of Medicine, Mount Sinai Beth Israel, St. Luke's and West Hospital Centers,Icahn School of Medicine at Mount Sinai.

Ali Reza Sima
Digestive Diseases Research Institute, Assistant professor of medicine, Tehran University of Medical Sciences, Tehran, Iran

Mohammad Reza Farzanehfar
AssociateProfessor of Gastroenterology,Department of Internal Medicine,Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Malihe Saber Afsharian
AssociateProfessor of pathology,IslamicAzad University,Faculty of Medicine,Mashhadbranch,Mashhad, Iran.

Ladan Ghoshayeshi
AssociateProfessor of Gastroenterology,Department ofInternal Medicine,Imam Reza Hospital,Mashhad University of Medical Sciences, Mashhad, Iran.

Ali Reza Bary
Associate Professor of Hematology and Oncology, Department of Hematology and Oncology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Masoud Sharifian Razavi
AssociateProfessor ofGastroenterology and Hepatology,Department of Internal Medicine,Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Sara Lary
Gastric Cancer Research Group, Mashhad, Iran.

Kamran Ghaffarzadehgan
Razavi cancer research center,RazaviHospital,Imam RezaInternational University,Mashhad,Iran.. Email: Kghafar46@gmail.com
Online First: December 31, 2018 | Cite this Article
Behrooznia, Z., Ghaderi, P., Jafarzadeh, N., Izanloo, A., Mansoori Majoofardi, S., Rahimi Kakhki, R., Nabipour, M., Sima, H., Sima, A., Farzanehfar, M., Saber Afsharian, M., Ghoshayeshi, L., Bary, A., Sharifian Razavi, M., Lary, S., Ghaffarzadehgan, K. 2018. Trefoil Factor Family in Pre-neoplastic Lesions and Gastric Cancer. The Cancer Press 4(1,2,3,4): 25-35. DOI:10.15562/tcp.70


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.

References

Huang Z, Zhang X, Lu H, Wu L, Wang D, Zhang Q, et al. Serum trefoil factor 3 is a promising non-invasive biomarker for gastric cancer screening: a monocentric cohort study in China. BMC gastroenterology. 2014;14:74.

Amori N, Aghajani M, Asgarian FS, Jazayeri M. Epidemiology and trend of common cancers in Iran (2004-2008). European journal of cancer care. 2016.

Movahedi M, Afsharfard A, Moradi A, Nasermoaddeli A, Khoshnevis J, Fattahi F, et al. Survival rate of gastric cancer in Iran. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2009;14(6):367-73.

Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, Sima HR, Esmaili-Shandiz E, Hosseinnezhad H, et al. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance. 2008;14(41):6376.

Gonzalez CA, Pardo ML, Liso JM, Alonso P, Bonet C, Garcia RM, et al. Gastric cancer occurrence in preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. International journal of cancer. 2010;127(11):2654-60.

Dinis-Ribeiro M, Areia M, de Vries AC, Marcos-Pinto R, Monteiro-Soares M, O'Connor A, et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy. 2012;44(1):74-94.

Xiao P, Ling H, Lan G, Liu J, Hu H, Yang R. Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer. Clinica chimica acta; international journal of clinical chemistry. 2015;450:127-34.

Kaise M, Miwa J, Tashiro J, Ohmoto Y, Morimoto S, Kato M, et al. The combination of serum trefoil factor 3 and pepsinogen testing is a valid non-endoscopic biomarker for predicting the presence of gastric cancer: a new marker for gastric cancer risk. J Gastroenterol. 2011;46(6):736-45.

Boroumand-Noughabi S, Sima HR, Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, Hosseinnezhad H, et al. Soluble Fas might serve as a diagnostic tool for gastric adenocarcinoma. 2010;10(1):275.

Jin Z, Jiang W, Wang L. Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). Oncology letters. 2015;9(4):1502-8.

Jin EH, Lee SI, Kim J, Seo EY, Lee SY, Hur GM, et al. Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population. Journal of Korean medical science. 2015;30(8):1035-41.

Dhar DK, Wang TC, Tabara H, Tonomoto Y, Maruyama R, Tachibana M, et al. Expression of trefoil factor family members correlates with patient prognosis and neoangiogenesis. Clin Cancer Res. 2005;11(18):6472-8.

Taupin D, Podolsky DK. Trefoil factors: initiators of mucosal healing. Nature reviews Molecular cell biology. 2003;4(9):721.

Hoffmann W. Trefoil factors. Cellular and molecular life sciences. 2005;62(24):2932-8.

Katoh M. Trefoil factors and human gastric cancer (review). International journal of molecular medicine. 2003;12(1):3-9.

Wright N. Interaction of trefoil family factors with mucins: clues to their mechanism of action? Gut. 2001;48(3):293-4.

Tomasetto C, Masson R, Linares JL, Wendling C, Lefebvre O, Chenard MP, et al. pS2/TFF1 interacts directly with the VWFC cysteine-rich domains of mucins. Gastroenterology. 2000;118(1):70-80.

Machado JC, Nogueira AM, Carneiro F, Reis CA, Sobrinho‐Simões M. Gastric carcinoma exhibits distinct types of cell differentiation: an immunohistochemical study of trefoil peptides (TFF1 and TFF2) and mucins (MUC1, MUC2, MUC5AC, and MUC6). The Journal of pathology. 2000;190(4):437-43.

Baus-Loncar M, Giraud AS. Multiple regulatory pathways for trefoil factor (TFF) genes. Cellular and molecular life sciences: CMLS. 2005;62(24):2921-31.

Soutto M, Chen Z, Saleh MA, Katsha A, Zhu S, Zaika A, et al. TFF1 activates p53 through down-regulation of miR-504 in gastric cancer. Oncotarget. 2014;5(14):5663-73.

Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, et al. Loss of TFF1 promotes Helicobacter pylori-induced beta-catenin activation and gastric tumorigenesis. Oncotarget. 2015;6(20):17911-22.

Thim L. Trefoil peptides: from structure to function. Cellular and Molecular Life Sciences. 1997;53(11):888-903.

Dubeykovskaya Z, Dubeykovskiy A, Solal-Cohen J, Wang TC. Secreted trefoil factor 2 activates the CXCR4 receptor in epithelial and lymphocytic cancer cell lines. Journal of Biological Chemistry. 2009;284(6):3650-62.

Shi S-Q, Cai J-T, Yang J-M. Expression of trefoil factors 1 and 2 in precancerous condition and gastric cancer. World journal of gastroenterology. 2006;12(19):3119.

Durer U, Hartig R, Bang S, Thim L, Hoffmann W. TFF3 and EGF induce different migration patterns of intestinal epithelial cells in vitro and trigger increased internalization of E-cadherin. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2007;20(5):329-46.

Meng JR, Tang HZ, Zhou KZ, Shen WH, Guo HY. TFF3 and survivin expressions associate with a lower survival rate in gastric cancer. Clinical and experimental medicine. 2013;13(4):297-303.

Dossinger V, Kayademir T, Blin N, Gott P. Down-regulation of TFF expression in gastrointestinal cell lines by cytokines and nuclear factors. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2002;12(4):197-206.

Emami S, Rodrigues S, Rodrigue CM, Le Floch N, Rivat C, Attoub S, et al. Trefoil factor family (TFF) peptides and cancer progression. Peptides. 2004;25(5):885-98.

Shi SQ, Cai JT, Yang JM. Expression of trefoil factors 1 and 2 in precancerous condition and gastric cancer. World journal of gastroenterology. 2006;12(19):3119-22.

Ren JL, Luo JY, Lu YP, Wang L, Shi HX. Relationship between trefoil factor 1 expression and gastric mucosa injuries and gastric cancer. World journal of gastroenterology. 2005;11(17):2674-7.

Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, et al. Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis. Cancer. 2015;121(24):4348-58.

Peterson AJ, Menheniott TR, O'Connor L, Walduck AK, Fox JG, Kawakami K, et al. Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology. 2010;139(6):2005-17.

Michelis R, Sela S, Sbeit W, Cohen HI, Reshef R. Decreased TFF2 expression in the gastric antrum in patients infected with CagA-positive Helicobacter pylori. Isr Med Assoc J. 2009;11(1):11-5.

Xia HH, Yang Y, Lam SK, Wong WM, Leung SY, Yuen ST, et al. Aberrant epithelial expression of trefoil family factor 2 and mucin 6 in Helicobacter pylori infected gastric antrum, incisura, and body and its association with antralisation. J Clin Pathol. 2004;57(8):861-6.

Im S, Yoo C, Jung JH, Choi HJ, Yoo J, Kang CS. Reduced expression of TFF1 and increased expression of TFF3 in gastric cancer: correlation with clinicopathological parameters and prognosis. International journal of medical sciences. 2013;10(2):133-40.

Shi S, Cai J. The expression of trefoil factor 1 and trefoil factor 2 in gastric cancer and precancer. Zhonghua nei ke za zhi. 2004;43(3):195-7.

Perry JK, Kannan N, Grandison PM, Mitchell MD, Lobie PE. Are trefoil factors oncogenic? Trends in Endocrinology & Metabolism. 2008;19(2):74-81.

Song JY, Kim BW, Lee AW, Lee KY, Chung IS, Lee BI, et al. Expression of MUC5AC and Trefoil Peptide 1 (TFF1) in the Subtypes of Intestinal Metaplasia. Clinical endoscopy. 2012;45(2):151-4.

Chen Z, Soutto M, Rahman B, Fazili MW, Peng D, Blanca Piazuelo M, et al. Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia. 2017;56(7):535-47.

Yang J, Li CX, Dai YY, Peng F, Weng XM, Ji MX. [Expression and significance of trefoil factor 1 protein and serum pepsinogen in benign and malignant gastric ulcers]. Zhonghua yi xue za zhi. 2012;92(22):1540-3.

Wu CS, Wei KL, Chou JL, Lu CK, Hsieh CC, Lin JM, et al. Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer. International journal of molecular sciences. 2016;17(9).

Ge Y, Zhang J, Cao J, Wu Q, Sun L, Guo L, et al. TFF1 inhibits proliferation and induces apoptosis of gastric cancer cells in vitro. Bosnian journal of basic medical sciences. 2012;12(2):74-81.

Milne AN, Carvalho R, Morsink FM, Musler AR, De Leng WW, Ristimäki A, et al. Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers. Modern Pathology. 2006;19(4):564.

Bossenmeyer-Pourié C, Kannan R, Ribieras S, Wendling C, Stoll I, Thim L, et al. The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. The Journal of cell biology. 2002;157(5):761-70.

May FE, Griffin SM, Westley BR. The trefoil factor interacting protein TFIZ1 binds the trefoil protein TFF1 preferentially in normal gastric mucosal cells but the co-expression of these proteins is deregulated in gastric cancer. The international journal of biochemistry & cell biology. 2009;41(3):632-40.

Kim BW, Kim KM, Lee BI, Maeng LS, Choi H, Cho SH, et al. Expression of trefoil peptides in the subtypes of intestinal metaplasia. Peptides. 2004;25(5):779-83.

Shi SQ, Cai JT. [The expression of trefoil factor 1 and trefoil factor 2 in gastric cancer and precancer]. Zhonghua Nei Ke Za Zhi. 2004;43(3):195-7.

Kirikoshi H, Katoh M. Expression of TFF1, TFF2 and TFF3 in gastric cancer. International journal of oncology. 2002;21(3):655-9.

Dhar DK, Wang TC, Maruyama R, Udagawa J, Kubota H, Fuji T, et al. Expression of cytoplasmic TFF2 is a marker of tumor metastasis and negative prognostic factor in gastric cancer. Laboratory investigation. 2003;83(9):1343-52.

Azarschab P, Al-Azzeh E, Kornberger W, Gott P. Aspirin promotes TFF2 gene activation in human gastric cancer cell lines. FEBS Lett. 2001;488(3):206-10.

Leung WK, Yu J, Chan FK, To KF, Chan MW, Ebert MP, et al. Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. J Pathol. 2002;197(5):582-8.

Cai Y, Yi M, Chen D, Liu J, Guleng B, Ren J, et al. Trefoil factor family 2 expression inhibits gastric cancer cell growth and invasion in vitro via interactions with the transcription factor Sp3. International journal of molecular medicine. 2016;38(5):1474-80.

Otto WR, Patel K, McKinnell I, Evans MD, Lee CY, Frith D, et al. Identification of blottin: a novel gastric trefoil factor family-2 binding protein. Proteomics. 2006;6(15):4235-45.

Aikou S, Ohmoto Y, Gunji T, Matsuhashi N, Ohtsu H, Miura H, et al. Tests for serum levels of trefoil factor family proteins can improve gastric cancer screening. Gastroenterology. 2011;141(3):837-45.e1-7.

Abbaszadegan MR, Moaven O, Sima HR, Ghafarzadegan K, A'rabi A, Forghani MN, et al. p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer. 2008;14(13):2055.

Park WS, Oh RR, Park JY, Lee JH, Shin MS, Kim HS, et al. Somatic mutations of the trefoil factor family 1 gene in gastric cancer. Gastroenterology. 2000;119(3):691-8.

Yio X, Diamond M, Zhang JY, Weinstein H, Wang LH, Werther L, et al. Trefoil factor family-1 mutations enhance gastric cancer cell invasion through distinct signaling pathways. Gastroenterology. 2006;130(6):1696-706.

Carvalho R, Kayademir T, Soares P, Canedo P, Sousa S, Oliveira C, et al. Loss of heterozygosity and promoter methylation, but not mutation, may underlie loss of TFF1 in gastric carcinoma. Laboratory investigation. 2002;82(10):1319.

Nishizuka S, Tamura G, Terashima M, Satodate R. Loss of heterozygosity during the development and progression of differentiated adenocarcinoma of the stomach. The Journal of pathology. 1998;185(1):38-43.

Sakata K, Tamura G, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, et al. Commonly deleted regions on the long arm of chromosome 21 in differentiated adenocarcinoma of the stomach. Genes, Chromosomes and Cancer. 1997;18(4):318-21.

Xiao P, Ling H, Lan G, Liu J, Hu H, Yang R. Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer. Clinica Chimica Acta. 2015;450:127-34.


No Supplementary Material available for this article.
Article Views      : 58
PDF Downloads : 11