NF-κB-miR-155 axis activation mediates ovulation-induced oncogenic effects in fallopian tube epithelium

Abstract

<jats:title>Abstract</jats:title> <jats:p>The fallopian tube secretory epithelial cells (FTSECs) are the cell-of-origin of most high grade serous ovarian carcinomas (HGSOC). FTSECs are repeatedly exposed to inflammation induced by follicular fluid (FF) that is released with every ovulation cycle throughout a woman’s reproductive years. Uninterrupted ovulation cycles are an established risk factor for HGSOC. Stimuli present in the FF induce an inflammatory environment which may cause DNA damage eventually leading to serous tumorigenesis. With the aim of elucidating possible mechanistic pathways, we established an ‘ex vivo persistent ovulation model’ mimicking the repeated exposure of human benign fallopian tube epithelium (FTE) to FF. We performed mass spectrometry analysis of the secretome of the ex vivo cultures as well as confirmatory targeted expressional and functional analyses. We demonstrated activation of the NF-κB pathway and up-regulation of miR-155 following short-term exposure of FTE to human FF. Increased expression of miR-155 was also detected in primary HGSOC tumors compared to benign primary human FTE and corresponded with changes in the expression of miR-155 target genes. The phenotype of miR-155 overexpression in FTSEC cell line is of increased migratory and altered adhesion capacities. Overall, activation of the NF-κB-miR-155 axis in FTE may represent a possible link between ovulation-induced inflammation, DNA damage, and transcriptional changes that may eventually lead to serous carcinogenesis.</jats:p>

NF‐κB‐upregulated miR‐155‐5p promotes hepatocyte mitochondrial dysfunction to accelerate the development of nonalcoholic fatty liver disease through downregulation of STC1

“…The NF‐κB/miR‐155‐5p axis causes inflammation, DNA damage, transcriptional changes, and thus promotes cancer. [ 9 ] Therefore, we speculated whether there was NF‐κB/miR‐155‐5p axis affecting NAFLD?…”

“…[ 8 ] Moreover, it has been found that the expression of NF‐κB and microRNA‐155‐5p (miR‐155‐5p) is upregulated in the follicular fluid of ovarian cancer, and the NF‐κB/miR‐155‐5p axis causes inflammation, DNA damage, transcriptional changes, and promotes the occurrence of cancer. [ 9 ] miR‐155‐5p is a well‐known carcinogenic microRNA (miRNA), which is often overexpressed in human malignant tumors. [ 10 ] The expression of miR‐155‐5p is confirmed to be elevated in the aged NAFLD liver tissues.…”

Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

“…The etiology of HGSCs appears to be multifactorial ( Figure 2 ). Inflammation, which is induced by follicular fluid released at ovulation and by blood from the endometrial cavity, may play a major role in high-grade serous carcinogenesis [ 7 , 16 , 59 , 60 , 61 , 62 , 63 ]. At sites of inflammation, epithelial cells are exposed to high levels of inflammatory mediators such as reactive oxygen species (ROS), cytokines, and growth factors, which contribute to cell proliferation, genetic and epigenetic changes, and cancer development [ 64 ].…”

“…Ovulation is an acute inflammatory process [ 59 ], and follicular fluid released from ovulation bathes the fimbrial epithelium and OSE [ 60 ]. ROS contained in follicular fluid induce inflammation and DNA double-strand breaks, leading to apoptosis, but if apoptotic failure occurs, neoplastic transformation in fimbrial and ovarian epithelial cells may occur [ 60 , 61 , 62 , 65 ]. Exposure of the FTE to follicular fluid can lead to activation of the NF-κB-miR-155 axis, which may represent a possible link between inflammation and DNA damage [ 62 ].…”

“…ROS contained in follicular fluid induce inflammation and DNA double-strand breaks, leading to apoptosis, but if apoptotic failure occurs, neoplastic transformation in fimbrial and ovarian epithelial cells may occur [ 60 , 61 , 62 , 65 ]. Exposure of the FTE to follicular fluid can lead to activation of the NF-κB-miR-155 axis, which may represent a possible link between inflammation and DNA damage [ 62 ]. Insulin growth factor axis proteins in the follicular fluid confer stemness activation and clonal expansion [ 63 ].…”