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.
Highlights
Prostate cancer (PCa) is the second most common malignancy in men worldwide and is the second most common cause of cancer-related death in men in the US1,2
We aimed to elucidate the roles of trefoil factor family 3 (TFF3) overexpression in prostate tumorigenesis by knocking down the overexpressed TFF3
We explored the molecular mechanisms behind its tumorigenic roles and determined that TFF3 is involved in prostate carcinogenesis via blocking the mitochondria-mediated apoptosis pathway
Summary
Prostate cancer (PCa) is the second most common malignancy in men worldwide and is the second most common cause of cancer-related death in men in the US1,2. PCa, and these alterations are potential biomarkers for PCa. For example, the TMPRSS2–ERG gene fusion occurs in 40–50% of primary PCa tissues[7], and over 90% of PCa specimens show overexpression of PCA38. The TMPRSS2–ERG gene fusion occurs in 40–50% of primary PCa tissues[7], and over 90% of PCa specimens show overexpression of PCA38 Their clinical utility is still controversial[9]. The allelic loss of 8p12–21 is reported to commonly occur in PCa (>90%) and high-grade prostatic intraepithelial neoplasia (>60%)[10]. The loss of NKX3–1, located at 8p12–21, is reported to be associated with cancer progression and the poor prognosis of PCa11,12. Recent generation sequencing analyses of PCa reveal recurrent somatic mutations, such as SPOP, MED12, and FOXA113–16
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