Abstract
BackgroundMicroRNAs have recently emerged as promising circulating biomarkers in diverse cancer types, including ovarian cancer. We utilized conditional, doxycycline‐induced fallopian tube (FT)‐derived cancer models to identify changes in miRNA expression in tumors and plasma, and further validated the murine findings in high‐grade ovarian cancer patient samples.MethodsWe analyzed 566 biologically informative miRNAs in doxycycline‐induced FT and metastatic tumors as well as plasma samples derived from murine models bearing inactivation of Brca, Tp53, and Pten genes. We identified miRNAs that showed a consistent pattern of dysregulated expression and validated our results in human patient serum samples.ResultsWe identified six miRNAs that were significantly dysregulated in doxycycline‐induced FTs (P < .05) and 130 miRNAs differentially regulated in metastases compared to normal fallopian tissues (P < .05). Furthermore, we validated miR‐21a‐5p, miR‐146a‐5p, and miR‐126a‐3p as dysregulated in both murine doxycycline‐induced FT and metastatic tumors, as well as in murine plasma and patient serum samples.ConclusionsIn summary, we identified changes in miRNA expression that potentially accompany tumor development in murine models driven by commonly found genetic alterations in cancer patients. Further studies are required to test both the function of these miRNAs in driving the disease and their utility as potential biomarkers for diagnosis and/or disease progression.
Highlights
Ovarian cancer is the fifth leading cause of cancer death among women and remains the leading cause of mortality among all gynecological cancers in the developed world
These new findings have led investigators to search for molecular changes within dysregulated fallopian tubal epithelium (FTE) that may accompany tumor development in patients and animal models, including FTE‐derived genetically engineered mouse models (GEMMs) targeting three key high‐grade serous cancers (HGSC) genetic alterations as shown by The Cancer Genome Atlas (TCGA) and previous studies[5]: Brca1/2(+/- or ‐/‐); Tp53(R172H/‐); and Pten(‐/‐) via a conditional Pax8‐Cre doxycycline‐inducible system.[6]
We performed a miRNA profiling analysis in order to identify changes occurring in doxycycline‐induced fallopian tube (FT) and metastatic tumors associated with inactivation of BRCA, TP53, and PTEN genes, which may accompany tumorigenesis and may be of use as potential circulating biomarkers
Summary
Ovarian cancer is the fifth leading cause of cancer death among women and remains the leading cause of mortality among all gynecological cancers in the developed world. Recent studies have proposed that a significant proportion of high‐grade serous cancers (HGSC), the most common and deadliest ovarian cancer subtype, may arise from the distal fallopian tubal epithelium (FTE)[2,3,4] rather than the ovarian surface epithelium (OSE) These new findings have led investigators to search for molecular changes within dysregulated FTE that may accompany tumor development in patients and animal models, including FTE‐derived genetically engineered mouse models (GEMMs) targeting three key HGSC genetic alterations as shown by The Cancer Genome Atlas (TCGA) and previous studies[5]: Brca1/2(+/- or ‐/‐); Tp53(R172H/‐); and Pten(‐/‐) via a conditional Pax8‐Cre doxycycline‐inducible system.[6]. A recent investigation has employed a complex neural network analysis to identify miRNA signatures from samples obtained prior to surgery and chemotherapy.[12] The same report showed that the miRNA model performed better than the CA‐125 biomarker in being able to better diagnose ovarian cancer All these studies have utilized serum from patients with ovarian cancer, most of whom have been diagnosed at advanced stages. We sought to delineate miRNA changes following doxycycline induction and compared these changes to miRNA patterns seen in patient samples with and without disease
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