Fig. 2: Carcinogenic mechanism of TFF3.

TFF3 affects apoptosis (A) and cell cycle progression (B) by activating MAPK, NF-κB, PI3K, STAT3, and HIF-1α signaling pathways. TFF3 does not bind to EGFR, but it can induce its phosphorylation. Treatment with the specific EGFR inhibitors tyrphostin A25 and AG1478 can significantly inhibit TFF3-induced cell survival and proliferation. C The promoter region of TFF3 contains the binding sites of HIF-1α and STAT3, which enables TFF3 to achieve self-induction. On the one hand, TFF3 enhanced the induction of VEGF by HIF-1α; on the other hand, it induced IL-8 expression via STAT3 to promote angiogenesis. D TFF3 regulates the expression of proteins related to cell migration by activating the MAPK, NF-κB, PI3K, STAT3, mTOR, and HIF-1α signaling pathways. CXCR, TX2A-R, and PG-R are involved in this biological effect of TFF3. Although TFF3 does not directly bind to TXA2-R and PG-R, it may activate them by increasing the expression of COX or COX derivatives such as prostaglandin E(2) and prostaglandin I(2). The combination of TFF3 and CXCR4/7 can induce cell migration; however, the signaling pathway underlying this effect remains to be verified. Established functions are denoted by solid arrows, whereas unidentified pathways are indicated by question marks. PRINS: psoriasis susceptibility-related RNA gene induced by stress; PMAIP1: phorbol-12-myristate-13-acetate-induced protein 1; TERT, telomerase reverse transcriptase; LINGO2, leucine-rich repeat receptor and nogo interacting protein 2; PI3K, phosphoinositide 3-kinase; NF-κB, nuclear factor κB; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; STAT:, signal transducer and activator of transcription; GSK-3β, glycogen synthase kinase 3 beta; HIF, hypoxia-inducible factor; CDC, cell division cycle; CKDI, cyclin-dependent kinase inhibitor; VEGF, vascular endothelial growth factor; IL, Interleukins; CXCR, C-X-C chemokine receptor; HUVEC, human umbilical vein endothelial cells, mTOR, mammalian target of rapamycin; COX, cyclooxygenase; TXA2-R, thromboxane A2 receptor; PG-R: prostaglandin receptor; MMP, matrix metalloproteinase; ZEB2, zinc finger E-box-binding homeobox 2; CA9, carbonic anhydrase IX; ZO-1, zonula occludens-1; CK-8, cytokeratin-8; PLC, phospholipase C; PKC, protein kinase C.