Overexpression of TFF3 is involved in prostate carcinogenesis via blocking mitochondria-mediated apoptosis

Abstract

The overexpression of trefoil factor family 3 (TFF3) is observed in a variety of cancers, including prostate cancer (PCa), and its potential role in carcinogenesis, such as activating the PI3K/AKT pathway, is suggested. However, its role and its related mechanisms in prostate tumorigenesis remain unknown. To elucidate the role of TFF3 overexpression in PCa, we silenced TFF3 in two PCa cell lines that overexpressed TFF3 and explored the molecular mechanism behind its antiapoptotic role. We also examined TFF3 expression in 108 Korean PCa specimens and 106 normal prostate tissues by immunohistochemistry (IHC) analysis. The mean TFF3 IHC score in the tumor tissues was significantly higher than that in the normal tissues (4.702 vs. 0.311, P = 2.52 × 10-24). TFF3-silenced cells showed suppressed tumor cell growth and migration. TFF3 silencing decreased BCL2 and increased BAX expression. The translocation of BAX to the mitochondria was also confirmed. After TFF3 silencing, the expression of the mitochondrial proapoptotic proteins, cytochrome C and Smac/DIABLO, was elevated, and these proteins were released from the mitochondria to the cytosol. Downstream mediators of mitochondrial apoptosis, including cleaved caspase-3, caspase-9, and PARP, were also elevated. Accordingly, the proportion of apoptotic cells was significantly higher among TFF3-silenced cells. There was no difference in extrinsic apoptosis-related molecules after TFF3 silencing. All the results support that TFF3 silencing induces the downstream signaling pathway of mitochondria-mediated apoptosis. This study provides a better understanding of the mechanism of prostate tumorigenesis, suggesting TFF3 as a potential biomarker and therapeutic target of PCa.

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

“…TFF3 silencing induces the mitochondria-mediated apoptosis signaling pathway by enhancing BAX translocating to the mitochondria and by increasing the expression of the mitochondrial pro-apoptotic proteins. Thus, it is useful to develop mitochondrial biomarkers related to carcinogenesis [ 31 ]. In addition, as important intracellular organelles, the mitochondria play a critical role in regulating cancer signaling pathway, by structural derangement and metabolic modulation.…”

TFF3 and TFF1 expression levels are elevated in colorectal cancer and promote the malignant behavior of colon cancer by activating the EMT process

“…It was also shown that TFF3 overexpression markedly decreased the proliferation of the SW837 and LoVo CCC lines (49). TFF3 has also been reported to promote the migration and invasiveness of rat fibroblasts (50), the migration of gastric mucosal epithelial cells (51), and the proliferation, viability and survival of breast cancer (17) and prostate carcinoma cells (52,53).…”

The Long Non-Coding RNA ENST00000489676 Influences Papillary Thyroid Cancer Cell Proliferation and Invasion through Regulating MiR-922

“…To evaluate the role of lncRNAs in PTC would be of great help to understand the occurrence and progression of PTC. ENST00000489676 is one of the transcripts of TFF3, which is a member of the trefoil family and plays an important role in the formation and progressing of some cancer types 21-23.In the present study, we aimed to explore the expression level and the role of ENST00000489676 in the pathogenesis of PTC.…”