MicroRNA-125 and FBI-1 in choriocarcinoma

Choriocarcinoma is a malignant form of gestational trophoblastic disease arising from the trophoblastic epithelium. It is characterized by the presence of a mixed population of mononuclear cytotrophoblasts and multinucleated syncytotrophoblasts surrounded by hemorrhage and necrosis. Clinically, it is difficult to distinguish postmolar choriocarcinoma from an invasive mole. They also share similar histopathological features and are only distinguishable from invasive moles by the absence of chorionic villi. Since choriocarcinoma is an aggressive tumor with a high tendency to metastasize, it is better to have a definitive diagnosis to detect the disease at an earlier stage in order to tackle the problem before it becomes too advanced. It is thus necessary to investigate new potential markers which could help in making diagnosis at the early stage of the disease. MicroRNAs are recognized as a new class of non-coding RNAs that regulate gene expressions post-transcriptionally through translational repression or degradation of the target messenger RNAs. They are involved in almost every biological process, including cell proliferation, differentiation as well as apoptosis. MiR-125 is one of the most widely investigated microRNAs in recent years, particularly in cancers. It is a highly conserved sequence that expresses ubiquitously in multiple human organs in a tissue-specific manner. The deregulation of miR-125 was commonly found in various types of cancers. Depending on the target messenger RNAs, miR-125 exerts either tumor suppressive or oncogenic effects. There are three homologues of miR-125, including miR-125a, miR-125b-1 and miR125b-2. Since all three homologues have very similar sequence and have the same seed region, they have common mRNA targets and similar functions but may express differentially in different tissues. Factor that binds to inducer of short transcript-1(FBI-1) is a transcription factor that is involved in cell cycle arrest and terminal differentiation in different tissues. The deregulation of FBI-1 was associated with oncogenesis and the overexpression of FBI-1 was frequently demonstrated in multiple human cancers. However, the connection between miR-125 and FBI-1 in choriocarcinoma has not been reported. In this study, an inverse relationship between miR-125, including both miR-125a and miR-125b, and FBI-1 was demonstrated. Higher expression levels of miR-125a and miR-125b were demonstrated in the first-trimester extravillous trophoblasts,TEV-1, than in the JAR and JEG-3 choriocarcinoma cells, whereas the protein and mRNA expression levels of FBI-1 were significantly higher in JAR and JEG-3 cells than in TEV-1 cells. Moreover, the overexpression of miR-125 down-regulated the FBI-1 expression level in both JAR and JEG-3 cells, suggesting that miR-125 may regulate FBI-1 through a direct interaction. By treating JEG-3 cells with a histone deacetylase inhibitor, trichostatin A (TSA), the expression levelsof miR-125a and miR-125b were up-regulated while the FBI-1 was down-regulated, suggesting the possible transcriptional silencing effect on miR-125 through histone deacetylation. Altogether, miR-125 affects FBI-1 expression and may serve as a new marker to differentiate malignant tumors from the benign GTD as well as a therapeutic target.published_or_final_versionPathologyMasterMaster of Medical Science