High grade serous ovarian carcinoma (HGSC) is a DNA instable tumor
High grade serous ovarian carcinoma (HGSC) is a DNA instable tumor and its precursor is commonly found originating from the fimbriated end of the fallopian tube secretory epithelial (FTSE) cells. premature senescence (SIPS). However ROS-induced miR-182 is regulated by β-catenin not by p53. In normal FTSE cells miR-182 overexpression triggers cellular senescence by p53-mediated upregulation of p21. Conversely in cells with p53 mutations miR-182 overexpression no longer enhances p21 but functions as an “Onco-miR”. p53 dysfunction is a prerequisite for miR-182-mediated tumorigenesis. In addition we found that human follicular fluid could significantly induce intracellular ROS in normal FTSE cells. These findings suggest that ROS and p53 mutations may trigger a series of events beginning with overexpressing miR-182 by ROS and β-catenin impairing the DNA damage response promoting DNA instability bypassing senescence and eventually leading to DNA instable tumors in FTSE cells.  and mutations  wherein mutation alone is not sufficient to trigger a sequence of neoplasia . A recent mouse model by combining inactivation of produced tumors mimicking human HGSC  indicates these tumor suppressor genes are critical in the development of HGSC. Recent studies suggest that some miRNAs are sensitive to oxidative stress (OS) and that ROS Poziotinib exposure can induce the expression of specific microRNAs [6 7 These miRNAs react to stresses through coordination of the target gene regulation. Interestingly most stress-induced miRNAs are mediated by . It can be speculated that the stress-induced miRNA expression and function may play a central role in determining the cell fate and may trigger sequential and as of yet not fully characterized pathways thus increasing the risk for HGSC transformation. Fallopian tube secretory epithelial (FTSE) but not ciliate (FTCE) cells are the cell origin of HGSC . HGSC precursor lesions known as serous tubal intraepithelial carcinoma (STIC) [10 11 exist in the distal (fimbriated) ends Poziotinib of the fallopian tubes but are rarely seen elsewhere. While the mechanisms for why FTSE at fimbriae are the targets of HGSC remain largely unknown as local microenvironmental stress induced by ovulation is a risk factor for ovarian cancer . Monthly ovulation may produce trauma-induced inflammation and unbalanced ROS for local OS . Cellular response to microenvironmental stresses is intricately regulated by a complex network of molecules. While stress-induced premature cellular senescence (SIPS) has been considered as a protective mechanism against tumorigenesis as the accumulation of cells undergoing SIPS may contribute to double strand Rabbit Polyclonal to APPL1. DNA breaks mitochondrial OS injury chronic inflammation abnormal proliferation and cellular transformation . How normal and defected FTSE cells respond to OS should be investigated. To investigate how FTSE cells react to stress in this study we examined ROS-induced miRNA (we defined as ROSmiRs) dysregulation and their molecular regulation mechanism; miRNA functions in response to OS in the presence and absence of and and family members (Figure ?(Figure1A 1 Suppl Table 1 Suppl Figure 1A). Moreover upregulation of three different forms of (pre- pri- and mature) and family members (and is at transcriptional level and dose dependent in primary FTE (Figure ?(Figure1B)1B) and immortalized FTSE cell lines (Suppl Figure 1B). Figure 1 ROS-induced miRNA (ROSmiRs) and mRNA expression in FTE cells Many ROSmiRs (and seemed to be dependent . To investigate whether ROS induced miRNA expression was dependent we first examined ROSmiR expression in FTSE cell lines. FTE237 was immortalized by (Suppl Table 2) and absent of expression while FTE194 had moderate TP53 expression. When both cells were treated by 100 μM H2O2 Poziotinib for 24 hours upregulation was noted (data not shown). To determine the role of in ROSmiR expression the primary cultured FTE cells were prepared in culture in which was blocked by and were inducible when was present but only was significantly induced by H2O2 when was blocked by was highly induced Poziotinib by ROS in cells with and without expression. ROS resulted in significant gene alterations in primary culture.