Elevated LINC00909 Promotes Tumor Progression of Ovarian Cancer via Regulating the miR-23b-3p/MRC2 Axis

Ovarian cancer (OC), the third common gynecologic malignancy, contributes to the most cancer-caused mortality in women. However, 70% of patients with OC are diagnosed at an advanced stage, of which the 5-year survival is less than 30%. Long noncoding RNAs (long ncRNAs or lncRNA), a type of RNA with exceeding 200 nucleotides in length but no protein-coding capability, have been demonstrated to involve the pathogenesis of various cancers and show considerable potential in the diagnosis of OC. In this study, we found that the LINC00909 expression in tumor and serum specimens of OC patients was elevated, determined by real-time quantitative, and droplet digital PCR. In receiver operating characteristic (ROC) analysis, our results revealed that serum LINC00909 distinguished cancers from normal ovarian tissue with 87.8% of sensitivity and 69.6% of specificity (AUC, 81.2%) and distinguished serous ovarian cancer from normal ovarian tissue with 90.0% of sensitivity and 75.9% of specificity (AUC, 84.5%). Furthermore, we observed that the tumor and serum LINC00909 level was positively associated with the International Federation of Gynecology and Obstetrics (FIGO) stage and the Eastern Cooperative Oncology Group (ECOG) score (reflecting patients’ performance status). Also, patients with low serum LINC00909 level showed a longer overall (hazard ratio, HR = 1.874 , p = 0.0004 ) and progression-free ( HR = 1.656 , p = 0.0017 ) survival. Functional assays indicated that the elevation of LINC00909 expression contributes to cell proliferation, migration, and invasion capability of ovarian cancer cells. Besides, we demonstrated that LINC00909 functions as a competing endogenous RNA (ceRNA) of MRC2 mRNA by sponging miR-23-3p, and thereby promotes epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells. Therefore, we highlight that the LINC00909/miR-23b-3p/MRC2 axis is implicated in the pathogenesis of ovarian cancer, and serum LINC00909 may be a promising biomarker for the diagnosis of OC.

Evaluation of protective effects of mirtazapine and mesna on cisplatin-induced ovarian damage in rats

To evaluate whether mirtazapine and mesna have protective effects on cisplatin-induced ovarian injury. A total of 32 female Wistar Albino rats were divided into 4 groups (8 rats per group) and included in the study. No medication was administered to the first group; only intervention was that their ovaries were removed and anti-mullerian hormone (AMH) values were measured. The second group received intramuscular cisplatin at a single dose of 7.5 mg/kg. The third group received a single dose of 200 mg/kg mesna intraperitoneally, and 30 minutes later, a single dose of 7.5 mg/kg intramuscular cisplatin was administered. The fourth group received oral 30 mg/kg mirtazapine, and 60 minutes later, a single dose of 7.5 mg/kg intramuscular cisplatin was administered. Oral 30 mg/kg mirtazapine was continued for ten days. Ovaries and AMH values of all groups were evaluated at the end of tenth day. In the cisplatin group when compared to normal ovarian tissue total histopathological damage score increased (p=0.037), preantral follicle count decreased (p=0.003) and AMH levels decreased (p<0.001). In the cisplatin + mesna group total ovarian damage score was also increased (p=0.005), preantral and antral follicles decreased (p<0.001 and p=0.001, respectively), and AMH levels decreased (p<0.001). In the cisplatin + mirtazapine group, total ovarian damage score (p<0.001), preantral follicle count (p=0.002) and AMH values were decreased (p<0.001). It was concluded that mesna and mirtazapine were not effective in preventing ovarian damage due to cisplatin.

63,XX, SRY-negative, pseudohermaphroditism in a Somali wild ass (Equus asinus somalicus)

A six-month-old Somali wild ass (Equus asinus somalicus) scheduled for a routine health exam presented with masculinised external genitalia, which included an enlarged phallus-like clitoris that was not connected to the urethra. A gonadectomy was conducted to sterilise the individual. Histological examination of the gonads revealed normal ovarian tissue with a recent corpus luteum, developing follicles and no testicular tissue. Karyotype analysis classified the individual as female, 63,XX, sex-determining region Y-negative, which is normal for a female Somali wild ass. Serum testosterone was analysed via enzyme immunoassay and was found to be below detectable concentrations. Although similar cases have been reported in domestic equids, this is the first case of intersex reported in a non-domestic equid.

Transcription factors HIF-1 α and NF- kB of tumor tissue and ascites cells in advanced ovarian cancer

Введение. Транскрипционный фактор NF-kB относят к эндогенным промоторам, вовлечённым в опухоль-индуцированное воспаление связанное с раком, который может быть активирован в ответ на гипоксию как и HIF-1α. При этом между системами NF-kB и HIF-1α могут существовать взаимосвязии компенсаторные пути. Цель исследования - изучение уровня экспрессии транскрипционных факторов HIF-1α и NF-kB в ткани первичной опухоли и опухолевых клетках асцитической жидкости и их корреляции с чувствительностью к платиносодержащей химиотерапии у больных распространённым раком яичников. Методика. У 20 больных с впервые диагностированным асцитным серозным раком яичников стадии Т3NX-1M0 и Т3NX-1M1 сразу после верификации диагноза получали асцитическую жидкость и выделяли эпителиальные клетки, а также забирали интраоперационно опухолевую и гистологически неизмененную ткань яичника, в которых оценивали уровень HIF-1α и NF-kB методом иммуноферментного анализа (eBioscience, США и Cloud-CloneCorp., США). Ядерные экстракты для определения содержания HIF-1α и NF-kB готовили в соответствии с инструкцией изготовителя. В зависимости от распространенности опухолевого процесса определяли экспрессию транскрипционных факторов, их корреляцию, а также прогностическую значимость в оценке безрецидивной выживаемости при раке яичников. Результаты. Корреляционные исследования показали статистически значимое увеличение (в 12 раз) содержания HIF-1α в опухолевой ткани рака яичников по сравнению с гистологически неизмененной тканью, в асцитической жидкости - в 3,1 раза; уровень NF-kB в опухолевой ткани значимо возрастал в 6,5 раза, в асцитической жидкости - в 2,2 раза. В гистологически неизмененной ткани яичников, у пациенток стадии Т3NX-1M1 по сравнению с материалом от больных стадии Т3NX-1M0 экспрессия обоих факторов была снижена. Корреляционные связи между содержанием HIF-1α и NF-kB как в опухолевой так и в гистологически неизмененной ткани были положительными сильными у пациентов на стадии Т3NX-1M0, и в клетках асцитической жидкости на стадии Т3NX-1M1.Установлено, что высокие уровни экспрессии в ткани опухоли HIF-1α и NF-kB резко сокращают длительность безрецидивного периода. Заключение. Полученные данные позволяют предполагать активацию основных сигнальных путей, обеспечивающих ассоциированные с опухолью воспалительные реакции при раке яичников стадии Т3NX-1M1 . Introduction. NF-kB belongs to endogenous promoters involved in tumor-associated inflammation. Like HIF-1α, NF-kB can also be activated in response to hypoxia. In this case, cross-talks and compensatory pathways can link the NF-kB and HIF-1α systems. The aim of this study was to evaluate the expression of transcription factors HIF-1α and NF-kB in primary tumor tissue and ascites tumor cells and their correlation with sensitivity to platinum-containing chemotherapy (CT) in patients with advanced ovarian cancer (OC). Methods. Samples of ascitic fluid were obtained from 20 patients with first diagnosed and verified stage T3NX-1M0 and T3NX-1M1 ascitic serous OC immediately after diagnosis, and epithelial cells were isolated from the ascitic fluid. Samples of tumor tissue and histologically normal ovarian tissue were also obtained from patients intraoperatively. Contents of HIF-1α and NF-kB were measured using enzyme immunoassay (eBioscience, USA and Cloud-Clone Corp., USA) in all samples. Nuclear extracts for measuring HIF-1α and NF-kB were prepared according to the manufacturer’s instructions. Expression of transcription factors, their correlation, and prognostic significance for relapse-free survival were determined depending on the tumor spread. Results. The content of HIF-1α was 12 times higher in the ovarian tumor tissue (p <0.05) and 3.1 times higher in ascitic fluid (p <0.05) than in histologically normal tissue; the content of NF-kB was increased 6.5 times in the tumor tissue (p ≤ 0.05) and 2.2 times in ascitic fluid (p ≤0.05). The expression of both factors was reduced in histologically normal ovarian tissue from patients with the T3NX-1M1 stage compared to patients with the T3NX-1M0 stage. A strong positive correlation was observed for contents of HIF-1α and NF-kB in both tumor and histologically unchanged tissue from patients with the T3NX-1M0 stage and in ascites cells from patients with the T3NX-1M1 stage. It was established that high levels of HIF-1α and NF-kB expression in tumor tissue dramatically reduced duration of the relapse-free period. Conclusion. The study results suggest activation of major signaling pathways for tumor-associated inflammatory reactions in T3NX-1M0 stage OC.

CPED1 is differentially expressed in ovarian cancer.

Ovarian cancer is most common reason for a gynecological cancer death in the developed world (1). There are zero targeted chemotherapies available for the treatment of ovarian cancer. We studied the transcriptomes of tumors from ovarian cancer by comparing them to the transcriptome of normal ovarian tissue using two separate datasets (2, 3). We found that the cadherin-like and PC esterase domain containing 1, CPED1, was among the genes whose expression changed the most between ovarian tumors and the normal ovary. This is the first report of differential expression of CPED1 in ovarian cancer.

Mining expression and prognosis of FOLR1 in ovarian cancer by using Oncomine and Kaplan-Meier plotter

Objective: To further explore folate receptor 1 (FOLR1) gene expression in ovarian cancer and its association with patients’ prognosis by deep mining the Oncomine and Kaplan-Meier plotter databases. Methods: FOLR1 mRNA expression data of ovarian cancer were retrieved from the Oncomine database and further analyzed by comparing tumor to healthy tissue. The prognostic value of FOLR1 in ovarian cancer was analyzed by Kaplan-Meier Plotter, an online survival analysis database. Results A total of 439 studies were included in the Oncomine database in multiple types of cancers. Of the 439 studies, there were 54 with statistical differences for the expression of FOLR1, 19 with increased expression of FOLR1 and 35 with decreased expression comparing ovarian cancer to normal ovary tissue. After searching the Oncomine database, six datasets were discovered comparing the mRNA expression in ovarian tumor to healthy tissue. FOLR1 mRNA expression in ovarian tumor was significantly higher than that of normal ovarian tissue (all p<0.05). The Kaplan-Meier Plotter database analyzed the correlation between FOLR1 expression and ovarian cancer patient’s prognosis. A significant difference of progression-free survival between FOLR1 high and low expressing groups was found in ovarian cancer patients (HR=1.14, 95%CI: 1.00-1.29, p=0.043). However, the overall survival was not statistically different between high and low FOLR1 expressing patients (HR=0.95, 95%CI: 0.84-1.09, p=0.48). Conclusion FOLR1 mRNA was found to be highly expressed in ovarian tumor compared to normal ovarian tissue. Elevated FOLR1 mRNA expression was associated with the poor progression-free survival.