Monensin suppresses cell proliferation and invasion in ovarian cancer by enhancing MEK1 SUMOylation.

Ovarian cancer is the most lethal gynecologic malignancy, and is usually diagnosed at an advanced stage. Most patients relapse within 12-24 months and die from progressive chemotherapy-resistant diseases. Significant progress has been made in developing new targeted therapies for human cancer, including ovarian cancer. However, an effective alternative to drug development is to repurpose drugs. The present study investigated the possibility of reusing the antibiotic monensin as an anti-ovarian cancer drug. After applying a series of titrated monensin on a panel of ovarian cancer cell lines, the growth, migration and invasion of cells were explored. Multiple signaling molecules associated with epithelial-to-mesenchymal transition were also regulated by monensin. The mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway was further found to be the key regulator affected by monensin. Additionally, monensin enhanced the MEK1 SUMOylation in vitro and in vivo, and the SUMOylation degree depended on time and dose. Xenograft studies verified that monensin effectively inhibited xenograft tumor growth by increasing the SUMOylation of MEK1. The aforementioned results suggested that monensin is a good candidate for anti-ovarian cancer by enhancing MEK1 SUMOylation and inhibiting the MEK-ERK pathway.

HTLV screening of blood donors using chemiluminescence immunoassay in three major provincial blood centers of China.

BACKGROUND: Human T-cell lymphotropic virus (HTLV) remains a major safety concern for blood supplies. Despite many HTLV positive cases being reported in southeastern China, the detection of HTLV has not been prioritized in routine blood screening. Additionally, data on the prevalence of HTLV infection among blood donors is also limited. The objective of this study was to investigate the prevalence of HTLV among blood donors in three Chinese provinces through their representative blood centers, to evaluate the feasibility of chemiluminescence immunoassay (CLIA) for blood screening. METHODS: From November 2018 to March 2019, blood plasma samples were collected from Hebei, Changsha, and Shenzhen blood centers and were screened for the HTLV-1/2 antibody using a CLIA and enzyme-linked immunosorbent assay (ELISA). This was followed by confirmatory tests using INNO-LIA HTLV I/II. RESULTS: A total of 59,929 blood donations were collected and screened for HTLV-1/2. The reactive rate of CLIA and ELISA among donations in the Shenzhen blood center (0.0943%, 27/28,621) was higher than Hebei (0.0248%, 4/16,144), and Changsha (0.0198%, 3/15,164) (p < 0.05). After confirmation, 3 samples were confirmed as indeterminate for HTLV antibodies, and only one sample from the Shenzhen blood center was confirmed as HTLV-1. The overall prevalence of HTLV-1/2 was 1.67 per 100,000 (1/59,929). The HTLV-infected blood came from a 32-year-old first-time female donor with a high school degree, who belonged to the SHE ethnic minority and was born in the Fujian province. CONCLUSIONS: In summary, the overall prevalence of HTLV-1/2 among blood donors in the three blood centers in China remains relatively low. However, blood donations with positive or indeterminate results for HTLV antibodies reminded us of the importance of HTLV screening among blood donors in China.

The Clinical Characteristics of Endometrial Cancer With Extraperitoneal Metastasis and the Value of Surgery in Treatment.

OBJECTIVE: To describe the clinical and pathological features of endometrial carcinoma with extraperitoneal metastasis and examine whether surgery could improve the prognosis. METHODS: The Surveillance, Epidemiology, and End Results database was used to analyze 730 patients who were diagnosed with extraperitoneal metastasis of endometrial cancer from 2010 to 2015, including metastasis to the lung, bone, or brain. RESULTS: Of the 730 patients, 372 (50.96%) patients had single lung metastases, and 196(26.85%) patients had multiple organ metastases that included pulmonary invasion. Therefore, the lung was the most common target organ for extraperitoneal metastasis of endometrial cancer. In multivariate risk factor analysis, grade 3 tumor (odds ratio = 3.39, P < .001), positive peritoneal cytology (odds ratio = 2.02, P < .001), and cervical stromal invasion (odds ratio = 1.42, P = .030) were independent risk factors for extraperitoneal metastasis. Once metastasis occurred in the brain or multiple organs, the prognosis was often poor. Of the patients, 362 underwent surgery, and surgery was performed only for primary tumors of the reproductive organs in almost all patients (97.23%) with extraperitoneal metastasis. The median cancer-specific survival periods of patients with solitary pulmonary metastasis undergoing surgery and those without surgery were 23 (16.43-29.57) months and 9 (6.21-11.79) months, respectively (P < .001), and survival superiority also existed in patients with bone metastasis (19 vs 8 months, P = .015) and multiple organs metastases (15 vs 4 months, P < .001). However, patients with brain metastasis had the same median survival period in the 2 groups (6 months, P = .146). CONCLUSIONS: The lung was the most common target organ for extraperitoneal metastasis in patients with endometrial cancer. Surgery was associated with improved survival in women with extraperitoneal metastasis, except for patients with brain metastasis.

The characteristics of isolated para-aortic lymph node metastases in endometrial cancer and their prognostic significance.

BACKGROUND: The aim of this study was to clarify the features and prognostic significance of isolated para-aortic lymphatic metastasis of endometrial cancer. METHODS: A retrospective study of patients with stage IIIC endometrial cancer was performed based on the Surveillance, Epidemiology, and End Results (SEER) database. A total of 2767 patients were divided into three groups according to the lymphatic metastasis patterns: isolated pelvic lymphatic metastasis, isolated para-aortic lymphatic metastasis and dual lymphatic metastasis. The clinic-pathological characteristics and prognosis of patients were compared among the three groups. RESULT: The proportion of patients with isolated para-aortic lymphatic metastasis was 13.70%. Patients with isolated pelvic lymphatic metastasis or isolated para-aortic lymphatic metastasis shared similar histological characteristics, except that patients with isolated para-aortic lymphatic metastasis had a lower proportion of tumors over 5 cm in diameter than patients with isolated pelvic lymphatic metastasis (35.1% versus 45.7%, p = 0.001). Compared with patients with dual lymphatic metastasis, isolated para-aortic lymphatic metastasis was more common in patients with endometrioid tumors (78.6% versus 67.3%, p < 0.001), grade 1-2 cancers (53.3% versus 36.3%, p < 0.001) and negative peritoneal cytology (76.2% versus 61.1%, p < 0.001). Dual lymphatic metastasis was an independent predictive factor for the poor outcomes of patients at stage IIIC. However, in stage IIIC endometrioid tumors, patients with isolated pelvic lymphatic metastasis and those with isolated para-aortic lymphatic metastasis shared similar prognosis. Patients at stage IIIC with nonendometrioid tumors and patients at stage IV could not be further divided into subgroups according to lymphatic metastasis patterns in terms of prognosis. CONCLUSION: Endometrioid patients with isolated pelvic lymphatic metastasis and isolated para-aortic lymphatic metastasis share similar clinical pathological characteristics and prognoses.

The clinical characteristics and prognosis of endometrial carcinomas that occur after breast cancer: does hormone receptor status of breast cancer matter?

OBJECTIVE: To evaluate the clinical and pathological features of endometrial cancer (EC) following breast cancer and to assess the effect of the breast cancer hormone receptor status on subsequent EC. MATERIALS: A retrospective study based on SEER data of EC patients with a history of breast cancer. RESULTS: A total of 2142 cases met the inclusion criteria. Compared to that of the general population, the incidence of EC following estrogen receptor-positive (ER+) breast cancer and hormone receptor-negative (HR-) breast cancer increased by approximately 16-fold and 15-fold, respectively. Histologically, the proportions of type II EC following ER+ breast cancer, HR- breast cancer and primary EC were 39.6%, 39.4% and 31.2%, respectively (P < 0.001). The proportions of G3 ECs were 26.9%, 28.2% and 19.8%, respectively (P < 0.001). The proportion of patients who died from miscellaneous malignant tumors among EC patients following breast cancer was significantly higher than the proportion of patients among primary ECs. The overall survival rate was worse for EC patients with a history of breast cancer (P < 0.001). There were no significant differences between patients with EC following ER+ breast cancer and those with EC following HR- breast cancer with regard to stage, lymphatic metastasis, outcome or cause of death. CONCLUSIONS: Compared to the general population, the incidence of EC in patients with breast cancer was increased markedly. Patients with EC following ER+ or HR- breast cancer shared the same clinicopathological features and prognoses. All patients need close monitoring regardless of breast cancer hormone receptor status.

Differential metabolomics networks analysis of menopausal status.

Menopause is an endocrine-related transition that induces a number of physiological and potentially pathological changes in middle-aged and elderly women. The intention of this research was to investigate the influence of menopause on the intricate relationships between major biochemical metabolites. The study involved metabolic profiling of 186 metabolic markers measured in blood plasma collected from 120 healthy female participants. We developed a method of network analysis using differential correlation that enabled us to detect and characterize differences in metabolites and changes in inter-relationships in pre- and post-menopausal women. A topological analysis was performed on the differential network that uncovered metabolite differences in pre-and post-menopausal women. In this analysis, our method identified two key metabolites, sphingomyelins and phosphatidylcholines, which may be useful in directing further studies into menopause-specific differences in the metabolome, and how these differences may underlie the body's response to stress and disease following the transition from pre- to post-menopausal status for women.

Upstream transcription factor 1 prompts malignancies of cervical cancer primarily by transcriptionally activating p65 expression.

Cervical cancer is the third-most common cause of female cancer-related mortality worldwide. In cervical cancer, aberrant activation of nuclear factor (NF)-κB signaling is widely reported. However, the transcriptional regulation of NF-κB signaling remains unclear. The present study aimed to explore the underlying mechanism in which NF-κB signaling was activated in cervical cancer cells. Initially, the expression of p65 was demonstrated to be markedly enhanced in grade II, III or IV cervical cancer tissues compared with that of normal cervical tissues, indicating that p65 expression was correlated with tumor grade. In HeLa and CaSki cells, overexpression of p65 markedly enhanced cervical cancer cell invasion and migration. Further experiments demonstrated that p65 overexpression significantly increased the phosphorylation levels of protein kinase B (AKT) and p38. Dual luciferase reporter and chromatin immunoprecipitation assays demonstrated that USF1 was able to bind the promoter region of p65, thereby enhancing the transcriptional activation of p65. Notably, when p65 was silenced, the phosphorylation levels of AKT and p38 were suppressed even in cells transfected with adenovirus vectors expressing upstream transcription factor 1 (USF1). These data indicated that USF1 prompted cervical cancer progression primarily by transcriptionally activating p65. In conclusion, the present study demonstrated that USF1 was able to activate the transcription of p65, thereby enhancing the malignancy of cervical cancer cells.

MicroRNA-217 functions as a tumor suppressor in cervical cancer cells through targeting Rho-associated protein kinase 1.

The abnormal expression of microRNAs (miRNAs/miRs) has been widely reported in various tumor types. miR-217 was demonstrated to be aberrantly expressed in a number of tumors, including pancreatic adenocarcinoma and osteosarcoma; however, its specific expression pattern has never been investigated in cervical cancer cells. Compared with normal control, the level of Rho-associated protein kinase 1 (ROCK1) expression was markedly increased in cervical cancer tissues and cells compared with that in non-cancerous tissues and cells. The expression of miR-217 was significantly reduced in cervical cancer tissues and cell lines. Overexpression of miR-217 could suppress colony formation and the cell invasion capacity of SiHa and HeLa cells. Flow cytometry indicated that miR-217 significantly increased cell apoptosis in SiHa and HeLa cells. Dual-luciferase reporter assays demonstrated that ROCK1 was a target gene of miR-217. In addition, overexpression of ROCK1 also led to an increased invasion capacity in SiHa cells, even when miR-217 was inhibited, indicating that the anti-invasive effects of miR-217 were mediated through ROCK1. In summary, the results of the present study indicated that miR-217 functions as a tumor suppressor in cervical cancer cells, primarily by targeting ROCK1.

miR-148a-3p suppresses epithelial ovarian cancer progression primarily by targeting c-Met.

MicroRNAs (miRNAs) are a group of small non-coding RNAs that modulate post-transcriptional gene expression. It has been demonstrated that various miRNAs may be expressed at different levels in different types of tumors. The present study assessed the role of microRNA-148a-3p (miR-148a-3p) in epithelial ovarian cancer (EOC). The results demonstrated that miR-148a-3p was decreased in EOC tissues and that a lower miRa-148-3p concentration was associated with a higher overall survival rate. Transfection of miR-148a-3p suppressed the invasive and proliferative capacity of SKOV3 cells. The induced overexpression of miR-148a-3p significantly inhibited the relative luciferase activity of the pmirGLO-c-Met-3'untranslated region compared with an empty vector. In addition, c-Met silencing led to a decrease in the invasive and proliferative capacity of EOC cells. The inhibition of miR-148a-3p did not increase the invasiveness of SKOV3 cells, even when c-Met was silenced. To the best of our knowledge, the present study is the first to demonstrate that miR-148a-3p expression is decreased in EOC cancer tissues and cell lines. The present study therefore demonstrated that miR-148a-3p may serve as a tumor suppressor in EOC by targeting c-Met.

Therapeutic Endoscopy in Combination with Quadruple Therapy in Treating Bleeding Caused by Gastric Ulcer.

OBJECTIVE: To analyze the efficacy of therapeutic endoscopy in combination with quadruple therapy in treating bleeding caused by gastric ulcer and investigate the factors inducing rebleeding. METHODS: Two hundred and twelve patients with bleeding caused by gastric ulcer who were admitted to Binzhou People's Hospital, Shandong, China between April 2015 and April 2016 were selected as research subjects. The patients were randomly divided into a control group and an experimental group. Patients in the control group were treated by quadruple therapy, while patients in the observation group received therapeutic endoscopy treatment in addition to the same treatment as the control group. The treatment efficacy, adverse reaction, H pylori (Hp) clearance rate and rebleeding were compared between the two groups. RESULTS: The effective rate of the observation group was 98.1%, which was significantly higher than that of the control group (80.2%), and the difference had statistical significance (P<0.05). The incidence of adverse reactions in the observation group was lower than that in the control group. The Hp clearance rate of the observation group was higher than that of the control group, and the difference had statistical significance (P<0.05). The multi-factor analysis on rebleeding suggested that whether therapeutic endoscopy was performed or not, hemoglobin level and presence of peptic ulcer stage A1 were independent risk factors. CONCLUSION: Endoscopic treatment in combination with quadruple therapy is better in the treatment of bleeding caused by gastric ulcer as compared to medical treatment alone. Patients with high-risk factors such as low content of hemoglobin and ulcer at stage A1 should be monitored more carefully to prevent the occurrence of rebleeding.

Nigericin Inhibits Epithelial Ovarian Cancer Metastasis by Suppressing the Cell Cycle and Epithelial-Mesenchymal Transition.

Epithelial ovarian cancer (EOC) has the highest mortality among various types of gynecological malignancies. Most patients die of metastasis and recurrence due to cisplatin resistance. Thus, it is urgent to develop novel therapies to cure this disease. CCK-8 assay showed that nigericin exhibited strong cytotoxicity on A2780 and SKOV3 cell lines. Flow cytometry indicated that nigericin could induce cell cycle arrest at G0/G1 phase and promote cell apoptosis. Boyden chamber assay revealed that nigericin could inhibit migration and invasion in a dose-dependent manner by suppressing epithelial-mesenchymal transition (EMT) in EOC cells. These effects were mediated, at least partly, by the Wnt/ß-catenin signaling pathway. Our results demonstrated that nigericin could inhibit EMT during cell invasion and metastasis through the canonical Wnt/ß-catenin signaling pathway. Nigericin may prove to be a novel therapeutic strategy that is effective in patients with metastatic EOC.