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Supplementary Figure 1. In vitro effects of PR silencing on onapristone sensitivity in PR-high-expressing uterine cancer cell line (Ishikawa). Supplementary Figure 2. In vitro effects of onapristone and trametinib in PR-weak-expressing uterine cancer cell line (SKUT2). Supplementary Figure 3. In vivo effects of therapy with onapristone in uterine cancer model. Supplementary Figure 4. In vivo effect of onapristone, trametinib, and the combination of both drugs on total PR expression in the ISHIKAWA model.

Figure S-1. Chemical structures of aspirin and the predominant phospholipid in soybean phosphatidylcholine (PC).Figure S-2. Evaluation of the effects of aspirin-PC and aspirin on tube-formation. Figure S-3. In vitro evidence that the growth inhibitory activity of aspirin-PC and aspirin of ovarian cancer cell lines.

Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.

Mesenchymal stem/stromal cells (MSCs) exist in many tissues and have pleiotropic potential to self-renew and differentiate into multiple cell types. Recent research in tumor biology has focused on their low immunogenicity and tumorhoming properties. MSCs promote cancer initiation, progression, and metastasis through several different mechanisms, including epithelial-mesenchymal transition (EMT), angiogenesis, and through their interaction with immune cells. In this review, we discuss the recent advances in our understanding of the pathogenic role of MSCs in regulating tumor initiation, progression, and metastasis, thus providing a strong rationale for targeting MSCs in cancer therapy.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. MTHFD2 has been reported to be overexpressed in several malignant tumors and is implicated in cancer development. This study aimed to investigate the effect of MTHFD2 on ovarian cancer progression. The expression of MTHFD2 was detected by bioinformatic analysis, immunohistochemistry, RT‐qPCR (real‐time quantitative PCR analysis), and western blot analysis. The effects of MTHFD2 depletion on cell proliferation, migration, and invasion were determined through in vitro experiments. Cell cycle progression and apoptosis were accessed by flow cytometry. The related signaling pathway protein expression was determined by western blot analysis. We found that MTHFD2 is highly expressed in both ovarian cancer tissues and cell lines. MTHFD2 deletion suppressed cell proliferation and metastasis. Knockdown of MTHFD2 induces cell apoptosis and G2/M arrest, whereas the number of cells in S phase increased with MTHFD2 overexpression. Mechanically, our results indicate that an inhibitory effect of MTHFD2 knockdown may be mediated by the downregulation of cyclin B1/Cdc2 complex and the inhibitory effect on its activity. Additionally, MTHFD2 could regulate cell growth and aggressiveness via activation of STAT3 and the STAT3‐induced epithelial–mesenchymal transition signaling pathway. These findings indicate that MTHFD2 is overexpressed in ovarian cancer and regulates cell proliferation and metastasis, presenting an attractive therapeutic target., Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is overexpressed in ovarian cancer tissues and cell lines. MTHFD2 depletion inhibits cell growth and metastasis and induces G2/M arrest and apoptosis in ovarian cancer cell lines. MTHFD2 regulates cyclin B1/Cdc2 complex and activates the STAT3 and STAT3‐induced epithelial–mesenchymal transition signaling pathway. Taken together, our results suggest that targeting MTHFD2 maybe served as a novel approach for ovarian cancer treatment.

Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using RT-qPCR and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2’-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Taken together, hsa_circ_0061179 knockdown inhibited OC growth in vivo. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.

A transfer RNA (tRNA)-derived fragment (tRF) was found to be a new possible biological marker and target in carcinoma therapy. However, the effect exerted by tRFs on cervical carcinoma remains unclear. In the present study, the potential tumor suppressor gene tRF-Glu49 was identified in cervical carcinoma through tRF and tiRNA microarray investigation. A reverse transcription-quantitative PCR assay then demonstrated that tRF-Glu49 was downregulated in the cervical carcinoma tissue. Further clinicopathological analysis proved that tRF-Glu49 was associated with less aggressive clinical features and improved prognosis. Cell Counting Kit-8 tests, Transwell and Matrigel tests, and xCELLigence system tests revealed that tRF-Glu49 inhibited cervical cell proliferation, migration and invasion processes. Mechanistic investigation revealed that tRF-Glu49 directly regulated the oncogene, fibrinogen-like protein-1 (FGL1). In general, according to the result achieved in the present study, tRF-Glu49 can modulate cervical cell proliferation, migration, and invasion processes through the target process for FGL1, and tRF-Glu49 is likely to be a possible prognostic biological marker in patients with cervical carcinoma.

Cervical cancer (CC) is a common malignant tumor of the female reproductive system. This study investigated the role of aplysia ras homolog I (ARHI) in resistance to CC in vitro and in patients' tissues. Hela cells were continuously treated with different concentrations of paclitaxel (1-10 nM) to construct paclitaxel-resistant cell model (Hela-TR). CC or CC-TR tissues were obtained from CC patients or CC patients who had developed paclitaxel resistance. The level of ARHI and multidrug resistance gene 1 (MDR1) in cells and tissues were detected by qRT-PCR and immunohistochemistry (IHC) staining. Cell viability, apoptosis and the number of colonies were assessed by MTT, flow cytometry and cell clone assay in Hela and Hela-TR cells after the ARHI plasmid or shARHI were transfected into cells. The autophagy and apoptosis signaling related proteins were analyzed by western blotting. The results revealed that the levels of ARHI mRNA and protein were down-regulated in CC tissues, and were further reduced in paclitaxel-resistant tissues and Hela cell model. High expression of ARHI inhibited the expression of MDR1 in Hela and Hela-TR cells. The cell viability and cell clone of Hela and Hela-TR cells were decreased by ARHI overexpression but increased by ARHI suppression. In addition, highly expressed ARHI promoted apoptosis and activated autophagy by increasing LC3-II/LC3-I through inactivating AKT/mTOR signaling pathway. In conclusion, overexpression of ARHI can increase the sensitivity of CC to paclitaxel through promoting apoptosis and autophagy in a AKT/mTOR inactivation dependent pathway.

Human papillomavirus (HPV) is the most common sexually transmitted virus worldwide. More than 99% of cervical cancer cases are associated with certain types of HPVs, termed high-risk types. In addition to the well-known transformative properties, HPVs-infected cells actively instruct the local milieu and create a supportive post-infection microenvironment (PIM), which is becoming recognized as a key factor for the viral persistence, propagation, and malignant progression. The PIM is initiated and established via a complex interplay among virus-infected cells, immune cells, and host stroma, as well as their derived components including chemokines, cytokines, extracellular vesicles, and metabolites. In this review, we summarize the current understanding of these key components, characteristics, and effects of the PIM, and highlights the prospect of targeting the PIM as a potential strategy to improve therapeutic outcomes for cervical cancer.

OBJECTIVE To evaluate the effects of low-molecular-weight heparin (LMWH) combined with low-dose aspirin (LDA) in pregnant women with a history of pregnancy-related hypertensive disorders. METHODS In the current retrospective stratified cohort study, 33 women with previous hypertensive disorders of pregnancy treated with LMWH and LDA were compared with 37 control women who did not undergo LMWH or LDA treatment. Rates of pre-eclampsia recurrence, placental abruption, and other adverse outcomes for the fetuses and pregnant women were compared in the two groups. RESULTS The pre-eclampsia recurrence rates were 12/33 (36.4%) in the LMWH + LDA group and 28/37 (75.7%) in the control group (P

To comprehensively evaluate and compare outcomes of surgical versus nonsurgical palliative interventions for bowel obstruction due to ovarian cancer. Studies were obtained from database search systems of Pubmed, Medline, Wiley, Springerlink, Kluwer, Web of science and Science direct. Data were analyzed by the meta-analysis method and the random-effect or fixed-effect model. The heterogeneity between the studies was evaluated by I2 index and the data were analyzed using STATA version 14.1. 12 studies involving 2778 cases of bowel obstruction in ovarian cancer were included, including 1225 cases of surgery and 1553 cases of palliative nonsurgical treatment. Surgery group had significantly higher remission rate of bowel obstruction (OR = 0.350, 95% CI 0.067–1.819, P = 0.000),but had no manifesting difference in the recurrence rate compared no-surgery group (RR = 0.88, 95% CI 0.76–1.03, P = 0.106). In 30-day mortality rate, surgery group had higher mortality rate (RR = 0.453, 95% CI 0.161–1.272, P = 0.000). But, surgical treatment can markedly prolong survival period (HR = 0.333, 95% CI 0.275–0.390, P = 0.000) compared nonsurgical treatment. Surgery can significantly relieve the symptom of intestinal obstruction, prolonging the survival period, but had no impact on the recurrence. Compared with no-surgery group, surgery group suffered higher 30-day mortality.

Timeless is a regulator of molecular clockwork in Drosophila and related to cancer development in mammals. This study aimed to investigate the effect of Timeless on cell proliferation and cisplatin sensitivity in cervical cancer. Timeless expression was determined by bioinformatics analysis, immunohistochemistry, and quantitative polymerase chain reaction (qPCR). Chromatin immunoprecipitation assays and reporter gene assays were applied to determine the transcriptional factor contributing to Timeless upregulation. The effects of Timeless depletion on cell proliferation and cisplatin sensitivity were determined through in vitro and in vivo experiments. Cell apoptosis and senescence were assessed by flow cytometry and β-galactosidase staining. DNA damage and DNA repair pathways were determined by comet assay, immunofluorescent staining, and Western blot analysis. Timeless is aberrantly expressed in ∼52.5% of cervical cancer tissues. E2F1 and E2F4 contribute to the transcriptional activation of Timeless. Timeless depletion inhibits cell proliferation and increases cisplatin sensitivity in vitro and in vivo. Knockdown of Timeless induces cell apoptosis and cell senescence. Mechanically, Timeless silencing leads to DNA damage and impairs the activation of the ATR/CHK1 pathway in response to cisplatin in cervical cancer. Timeless is overexpressed in cervical cancer and regulates cell proliferation and cisplatin sensitivity, presenting an attractive target for cisplatin sensitizer in cervical cancer.

The development of smart drug delivery nanocarriers for tumor-targeted delivery and controllable release of therapeutic agents is appealing to achieve effective cancer chemotherapy. We herein use CaCO

Purpose: To evaluate the ability of WT1 alone, and in combination with P53/Ki-67, to predict recurrence in patients with epithelial ovarian cancer (EOC).Methods: In this retrospective study, we performed immunohistochemistry on surgical specimens acquired from 137 patients with EOC. We analyzed the sensitivity of WT1 alone, and in combination with P53 and Ki-67, to predict the recurrence of EOC by applying Chi-squared and layered Chi-squared tests. The Kaplan–Meier method was used to predict progression-free survival(PFS).Results: The proportion of WT1-positive patients in the recurrent group (80.4%) was significantly higher than that in the non-recurrent group (60.4%; P=0.019). In stratified cohort analysis, the recurrence rate of WT1-positive patients was significantly higher than that of WT1-negative patients in the P53-positive group (P=0.034); similar results were obtained for the group with Ki-67 index >30% (P=0.026). Kaplan–Meier curves showed that WT1-negative patients presented with a significantly longer PFS than WT1-positive patients in the P53(P=0.006) and Ki-67(P=0.016) positive groups.Conclusion: A high level of WT1 is a potent predictor of recurrence for EOC. Our analyses showed that the predictive ability of WT1 was more sensitive when combined with P53/Ki-67. Monitoring the levels of WT1 could have significant therapeutic implications for patients with EOC.

Objective: The mechanism of long non-coding RNA ADAM metallopeptidase with thrombospondin type 1 motif, 9 antisense RNA 2 (ADAMTS9-AS2) has been insufficiently explored in ovarian cancer (OC). Here, the action of ADAMTS9-AS2 in OC with the involvement of DNA methyhransferase l (DNMT1) and septin 6 (SEPT6) was explored. Methods: Epithelial OC tissue and ovarian epithelial tissue specimens were collected to test ADAMTS9-AS2, DNMT1 and SEPT6 expression. An appropriate cell line was screened out and transfected with highly expressed ADAMTS9-AS2 or SEPT6 or lowly expressed DNMT1 to detect their roles in biological functions of OC cells. Tumorigenesis of OC cells in nude mice was projected to validate cell experiment results. The interactions between ADAMTS9-AS2 with DNMT1/SEPT6 were tested. Results: Elevated DNMT1 and reduced ADAMTS9-AS2 and SEPT6 were detected in OC. ADAMTS9-AS2 bound to both DNMT1 and SEPT6. Restoring ADAMTS9-AS2 or SEPT6 or depleting DNMT1 diminished OC cell viability, invasion and migration, arrested cell cycle and accelerated apoptosis in vitro, and repressed tumor growth in vivo. Conclusion: Collectively, ADAMTS9-AS2 fights against OC through recruiting DNMT1 and up-regulating SEPT6.

Objective: We aimed to investigate whether ovarian cancer and cancer-related fatigue are associated with a sudden loss of ovarian dysfunction.Methods: In total, we retrospectively analyzed 211 survivors of ovarian carcinoma from the First Affiliated Hospital of Soochow University between January 2015 and January 2020. Fatigue was measured with the Cancer Fatigue Scale (CFS). Single and multiple linear regression were used to determine statistical differences.Results: Fatigue was reported in 206 of all completed questionnaires. Patients who had a menstrual period prior to treatment had a higher fatigue score. The CRF score was highest during the first two years after treatment and gradually decreased over time. Patients with sleep disorders became fatigued more easily. We identified a negative correlation between hemoglobin and CRF. There were no significant correlations between CRF, the number of chemotherapy cycles, the type of chemotherapy regimen, or the pathological subtype of ovarian cancer.Conclusion: CRF is common in ovarian cancer patients and improve CRF are important for improving the quality of life. The fatigue experienced by patients with ovarian cancer may be related to the deprivation of sex hormones. It may be prudent to add such hormones to the treatment regimen in order to improve CRF.

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR‑302c‑3p and miR‑520a‑3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour‑adjacent tissues were detected. Reverse transcription‑quantitative PCR (RT‑qPCR) was performed to determine the expression of miR‑302c‑3p, miR‑520a‑3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT‑qPCR and western blotting were performed to measure the expression of C‑X‑C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl‑2‑deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR‑302c‑3p and miR‑520a‑3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR‑302c‑3p and/or miR‑520a‑3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro, while the knockdown of miR‑302c‑3p and/or miR‑520a‑3p had the opposite effect. Furthermore, miR‑302c‑3p and miR‑520a‑3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR‑302c‑3p and/or miR‑520a‑3p overexpression exerted proliferation‑suppressive and apoptosis‑stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR‑302c‑3p‑ and miR‑520a‑3p‑induced anti‑proliferative and pro‑apoptotic effects. miR‑302c‑3p and miR‑520a‑3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in human diseases. We aimed to clarify the role of lncRNA X-inactive specific transcript (XIST)/miR-149-3p/forkhead box P3 (FOXP3) axis in ovarian cancer (OC) cell growth. XIST, miR-149-3p and FOXP3 expression in OC tissues and cell lines was assessed, and the predictive role of XIST in prognosis of OC patients was analyzed. The OC cell lines were screened and accordingly treated with silenced/overexpressed XIST plasmid or miR-149-3p mimic/inhibitor, and then the proliferation, invasion, migration, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Effect of altered XIST and miR-149-3p on tumor growth in vivo was observed. Online website prediction and dual luciferase reporter gene were implemented to detect the targeting relationship of lncRNA XIST, miR-149-3p, and FOXP3. XIST and FOXP3 were upregulated, whereas miR-149-3p was downregulated in OC tissues and cells. High XIST expression indicated a poor prognosis of OC. Inhibition of XIST or elevation of miR-149-3p repressed proliferation, invasion, migration, and colony formation ability, and promoted apoptosis and cell cycle arrest of HO-8910 cells. In SKOV3 cells upon treatment of overexpressed XIST or reduction of miR-149-3p, there exhibited an opposite tendency. Based on online website prediction, dual luciferase reporter gene, and RNA pull-down assays, we found that there was a negative relationship between XIST and miR-149-3p, and miR-149-3p downregulated FOXP3 expression. This study highlights that knockdown of XIST elevates miR-149-3p expression to suppress malignant behaviors of OC cells, thereby inhibiting OC development.

Guanosine monophosphate synthase (GMPS) participates in chromatin and gene regulation in multiple types of organisms, and is highly expressed in a variety of human malignancies. The purpose of the present study was to explore the expression of GMPS and its role in cervical cancer (CC), and to provide ideas for improving the clinical efficacy of CC treatment. In the present study, immunohistochemistry, reverse transcription-quantitative PCR analysis, Cell Counting Kit-8 assay, 5-ethynyl-2′-deoxyuridine assay, flow cytometry, western blotting and immunofluorescence assays were conducted to detect the expression of GMPS in normal cervical tissues, CC tissues, para-cancerous tissues and CC cell lines. Moreover, the present study detected the effect of GMPS knockdown on CC cell proliferation, clonal formation ability, aging and apoptosis, as well as on the expression levels of apoptosis-related proteins in tumor cells. The present results demonstrated that the expression level of GMPS in CC was significantly higher compared with that of adjacent tissues; the expression rate of GMPS in CC was 57.36%. GMPS expression was found to successively and gradually increase from that in normal cervical tissues, to that in cervical intraepithelial neoplasia and CC tissues. The abnormal expression of GMPS was positively associated with the degree of CC differentiation and the depth of early invasion. Small interfering (si) RNA knockdown of GMPS inhibited proliferation and colony formation, and promoted aging and apoptosis of CC cells. Furthermore, subcutaneous injection of GMPS-knockdown tumor cells in nude mice resulted in a decrease in the proliferative ability of the tumor. The animal experimental results showed that the tumor growth rate of the short hairpin (sh) RNA-GMPS group was significantly slower than that of the HeLa sh-negative control group. It was identified that GMPS may inhibit CC cell senescence and apoptosis via the Stat3/P53 molecular pathway. Collectively, the present results suggested that GMPS may be a marker of unfavorable prognosis of CC, and it may also be a potential therapeutic target for CC.

Endometriosis is a common gynecological disease associated with infertility, and it represents an economic burden worldwide. However, the molecular mechanisms underlying endometriosis development have not yet been fully elucidated. Here, we aimed to identify reliable key genes and the related regulatory network that may be involved in endometriosis. Differentially expressed genes (DEGs) were identified through integrated analysis of four expression datasets of endometriosis from Gene Expression Omnibus. Gene functional analysis and protein-protein interaction network construction were performed to reveal the potential function of DEGs. Subsequently, candidate hub genes were defined and validated in GSE105764 dataset, and the associated regulatory networks were constructed. Additionally, GSE120103 dataset was applied to identify the differential expression between the infertile and fertile groups of patients with stage IV endometriosis. Finally, real-time quantitative polymerase chain reaction analysis was performed to identify the differential expression of hub genes in the collected clinical specimens. Robust rank aggregation integrated analysis determined 158 DEGs. Epithelial cell differentiation was the most significantly enriched biological process, and leukocyte transendothelial migration was the most significantly enriched pathway. Eight hub genes including CLDN3, CLDN5, CLDN7, CLDN11, HOXC8, HOXC6, HOXB6, and HOXB7 were identified, and most of these were validated as abnormally expressed genes in both the infertile group and patients with endometriosis. Transcriptional factors and microRNAs related to these genes were identified. Altogether, our integrated analysis identified critical gene signatures, involved pathways, and regulatory networks, which could provide clinically significant insights into the molecular mechanisms underlying endometriosis and its related infertility.

At present, hyperthermia combined with chemotherapy has become a clinical treatment means Despite some research reports investigating the effects of heat elevation on inducing the DNA damage response and interfering with various DNA repair pathways, but the underlying coalition mechanisms of combined with PARP inhibitorss are not yet completely elucidated. In this study, We use a variety of OC cell lines treat by thermo-chemotherapy and then the proliferation, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Here, We found that in heat sensitive cell line A2780cells treat by thermo-chemotherapy combined wint PARPi, could induces Ppromote OC cells apoptosis and inhibit proliferation, aggravate DNA damage and arrests OC in the cell cycle S phase, buthowever, in heat resistance cell line SKOV3 cells there exhibited an Constant tendency. Western blot analysis shows hyperthermia down-regulated the levels of PARP1 and XRCC1.In addition, hyperthermia combined with chemotherapy could increase the expressions of ATM and NBS1 in the double-stranded DNA damage pathway. Meanwhile, The expression of DNA damage-related proteins increased after PARP1 inhibitors eliminated single-strand repair. Based on these results, we conclude hyperthermia confers sensitization of ovarian cancer to oxaliplatin via interference with XRCC1/PARP1-mediated base excision repair be consumed and Promotes DNA double strand breakage, thereby inhibiting OC development. Citation Format: Fangrong Shen. Thermotherapy interferes with XRCC1/PARP1-mediated DNA repair and confers sensitization of ovarian cancer to oxaliplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5671.

Ovarian cancer is one of the most frequent carcinomas in females, and the occurrence rate is still rising despite many advances made. The pathogenesis of ovarian cancer remains greatly unclear. Here, we investigated the mechanisms of ovarian cancer, with the focus on circATRNL1. Human ovarian cancer tissues and cell lines were used to examine levels of circATRNL1, miR‐378, Smad4, AKT, and other proliferation‐related and migration‐related proteins. Cellular assays were used to determine cancer cell proliferation, invasion, migration, apoptosis, and angiogenesis. We validated the interactions of circATRNL1/miR‐378 and miR‐378/Smad4, and a mouse tumor xenograft model was employed to assess the effect of circATRNL1 on tumor growth and metastasis in vivo. We found that circATRNL1 was decreased while miR‐378 was increased in human ovarian cancer tissues and cells. circATRNL1 bound to miR‐378 while miR‐378 directly targeted Smad4. Overexpression of circATRNL1 or knockdown of miR‐378 suppressed angiogenesis and ovarian cancer cell proliferation, invasion, and migration via decreasing proliferation‐ and migration‐related proteins via miR‐378 or Smad4, respectively. Overexpression of circATRNL1 restrained ovarian cancer growth and abdominal metastasis in vivo. Our findings indicate that circATRNL1 acts as a miR‐378 sponge to active Smad4 signaling and suppresses angiogenesis and ovarian cancer metastasis., Here, we report that the expression of circATRNL1 is low in ovarian cancer cells, leading to increased miR‐378 levels and reduced levels of the downstream target Smad4. Concomitantly, activated AKT signaling promoted cancer cell proliferation, angiogenesis, as well as metastasis.

Ovarian cancer (OC) is a malignant tumor with high mortality in women. Although cancer patients initially respond to paclitaxel chemotherapy following surgery, most patients will relapse after 12–24 months and gradually die from chemotherapy resistance. In OC, cancer cells become resistant to paclitaxel chemotherapy under hypoxic environment. The miR-27a has been identified as an oncogenic molecular in ovarian cancer, prostate cancer, liver cancer etc. In addition, the miR-27a is involved in hypoxia-induced chemoresistance in various cancers. However, the role of miR-27a in hypoxia-induced OC resistance remains unclear. The aim of the present study was to investigate the regulatory mechanism of miR-27a in hypoxia-induced OC resistance. The expression of HIF-1α induced Hypoxia overtly up-regulated. At the same time, hypoxia increased viability of Skov3 cells and decreased cell apoptosis when treated with paclitaxel. The expression of the miR-27a was obviously up-regulated under hypoxia and involved in hypoxia-induced paclitaxel resistance. Follow-up experiments portray that miR-27a improved paclitaxel resistance by restraining the expression of APAF1 in OC. Finally, we further elucidated the important regulatory role of the miR-27a-APAF1 axis in OC through in vivo experiments. According to our knowledge, we first reported the regulation of miR-27a in hypoxia-induced chemoresistance in OC, providing a possible target for chemoresistance treatment of OC.

Interferon-γ-inducible factor 16 (IFI16) triggers stimulator of interferon (IFN) genes (STING)-dependent type I IFN production during host antiviral immunity and facilitates p53-dependent apoptosis during suppressing tumorigenesis. We have previously reported that STING-mediated IFI16 degradation negatively regulates type I IFN production. However, it is unknown whether STING also suppresses IFI16/p53-dependent apoptosis via degradation of IFI16. Here, our results from flow cytometry apoptosis detection and immunoblot assays show that IFI16 and nutlin-3, a p53 pathway activator, synergistically induce apoptosis in U2OS and A549 cells. Protein kinase R-triggered phosphorylation of p53 at serine 392 is critical for the IFI16-p53-dependent apoptosis. However, overexpression of STING suppresses p53 serine 392 phosphorylation, p53 transcriptional activity, expression of p53 target genes, and p53-dependent mitochondrial depolarization and apoptosis. In summary, our current study demonstrates that STING-mediated IFI16 degradation negatively regulates IFI16-mediated p53-dependent apoptosis in osteosarcoma and non-small cell lung cancer cells, which suggests a protumorigenic role for STING in certain cancer types because of its potent ability to degrade upstream IFI16.

To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose–response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50% to 90% (depending on the ovarian cell line). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis, and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust antineoplastic action in the presence of VEGF-blocking drugs. Mol Cancer Ther; 15(12); 2894–904. ©2016 AACR.

LncRNA CASC11 promotes gastric cancer and colon cancer. Our study analyzed the role of CASC11 in ovarian squamous cell carcinoma (OSCC). In the present study we showed that plasma CASC11 was upregulated in OSCC, and the upregulation of CASC11 distinguished OSCC patients from control group. Plasma levels of CASC11 were further increased after chemotherapy. Treatment with oxaliplatin, tetraplatin, cisplatin, and carboplatin mediated the upregulation of CASC11 in cells of OSCC cell line. In addition, overexpression of CASC11 led to increased cancer cell viability under oxaliplatin, tetraplatin, cisplatin, and carboplatin treatment, while CASC11 siRNA silencing played an opposite role. Therefore, overexpression of CASC11 in OSCC mediated the development of cancer cell resistance to chemotherapy.

Objective To investigate the expression of the lncRNA ZFAS1 in cervical cancer and its relationship with patient prognosis and cervical cancer cell chemosensitivity. Methods The expression of ZFAS1 in cervical cancer tissues and cell lines was detected by qRT-PCR. The cervical cancer CaSki and the HeLa cell lines were transfected to be divided into Blank, siR-Control, and siR-ZFAS1 groups. MTT, wound-healing, and transwell assays were used to evaluate cell biological function. Cisplatin with different concentrations was used to treat cells in different transfection groups, and MTT assays were used to detect the cell growth inhibition rate and the half-inhibitory concentration (IC50) of cisplatin was measured. Cell apoptosis was determined by flow cytometry. A xenograft mouse model was used to investigate the effects of siR-ZFAS1 on the chemosensitivity to cisplatin. Results ZFAS1 was significantly upregulated in cervical cancer tissues and cell lines, and increased ZFAS1 levels led to poor prognoses in patients. In addition, cells in the siR-ZFAS1 group showed remarkably reduced ZFAS1 expression as well as cell proliferation, invasion and migration. After being treated with cisplatin at different concentrations, cells in the siR-ZFAS1 group had dramatically increased cell growth inhibition and apoptosis but lower cisplatin IC50s. In addition, siR-ZFAS1 reduced the volumes and weights of tumors in nude mice treated with cisplatin and enhanced the chemosensitivity of cervical cancer cells to cisplatin. Conclusion The lncRNA ZFAS1 was upregulated in cervical cancer tissues, and its high expression indicated a poor prognosis. Silencing ZFAS1 may inhibit cell proliferation, migration and invasion and enhance cisplatin chemosensitivity.

Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT‐qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair‐related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

Amniotic fluid embolism (AFE) is an unpredictable and unpreventable complication of maternity. The presentation may range from relatively subtle clinical events to sudden maternal cardiac arrest. However, the neglected diagnosis of non-classical form of AFE (atypical AFE) is very common. The aim of this study was to examine population-based regional data from Suzhou, China. Based on the analysis of all available case reports, we put forward an outline of atypical AFE and investigate whether any variation identified could be ascribed to methodology. Retrospective study from January 2004 to December 2013, 53 cases was identified from the database of Center for Disease Control (CDC) in the city of Suzhou. We investigated the presentations of atypical AFE and maternal characteristics with potential factors underlying AFE. Multiple-regression analysis was used to calculate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). The incidence of AFE was 6.91 per 100,000 deliveries (53/766,895). Seventeen deaths occurred, a mortality rate of 32 %. Atypical AFE may as the earlier stage or mild form of AFE, there was no death case in the study with timely remedy. The atypical AFE appear is obstetric hemorrhage and/or pulmonary and renal dysfunction postpartum. Hyperfibrinolysis and coagulopathy may the early laboratory findings of atypical AFE. Atypical and classical AFE shared the same risks, such as advanced maternal age, placental abnormalities, operative deliveries, eclampsia, cervical lacerations, and induction of labor. Staying alert to premonitory symptoms of AFE is critical to turn it to a remediable disease. Patient complaints such as breathlessness, chest pain, feeling cold, distress, panic, a feeling of nausea, and vomiting should elicit close attention. The management of a suspected episode of amniotic fluid embolism is generally considered to be supportive. Hysterectomy must be performed if there is further progression of symptoms. Due to advances in acute care, mortality has decreased in recent years, highlighting the importance of early detection and treatment.

Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.

INTRODUCTION:To investigate the effect of low-molecular-weight heparin (LMWH) added low dose aspirin (LDA) in the subsequent pregnancy of the women who have the previous history of hypertensive disorder of pregnancy.METHODS:Prophylactically adding LMWH and LDA in 33 women who has previous hypertensi

UNLABELLED Prostate cancer is one of the most common malignancies in men. The multidrug resistance 1 gene (MDR1) is an important candidate gene for prostate cancer. The aim of this study was to evaluate the association between MDR1 gene polymorphisms and the risk of prostate cancer. MDR1 gene polymorphism and its association with the risk of prostate cancer were investigated in 357 Chinese men. A novel c.1465C>T polymorphism was detected with created restriction site-polymerase chain reaction and DNA sequencing. We found a significantly increased risk of prostate cancer in the homozygote comparison [TT vs CC: odds ratio (OR) = 2.300, 95% confidence interval (95%CI) = 1.261-4.196, chi-square = 7.53, P = 0.007], heterozygote comparison (TC vs CC: OR = 1.667, 95%CI = 1.049-2.648, chi-square = 4.71, P = 0.030), dominant model (TT/TC vs CC: OR = 1.835, 95%CI = 1.197-2.815, chi-square = 7.81, P = 0.005), recessive model (TT vs TC/CC OR = 1.776, 95%CI = 1.023- 3.085, chi-square = 4.23, P = 0.041), and allele contrast (T vs C: OR = 1.625, 95%CI = 1.199-2.202, chi-square = 9.87, P = 0.002). These findings suggested that the c.1465C>T polymorphism of MDR1 may be risk factors for prostate cancer in Chinese men.

A deeper mechanistic understanding of tumour angiogenesis regulation is needed to improve current anti-angiogenic therapies. Here we present evidence from systems-based miRNA analyses of large-scale patient data sets along with in vitro and in vivo experiments that miR-192 is a key regulator of angiogenesis. The potent anti-angiogenic effect of miR-192 stems from its ability to globally downregulate angiogenic pathways in cancer cells through regulation of EGR1 and HOXB9. Low miR-192 expression in human tumours is predictive of poor clinical outcome in several cancer types. Using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoliposomes, we show that miR-192 delivery leads to inhibition of tumour angiogenesis in multiple ovarian and renal tumour models, resulting in tumour regression and growth inhibition. This anti-angiogenic and anti-tumour effect is more robust than that observed with an anti-VEGF antibody. Collectively, these data identify miR-192 as a central node in tumour angiogenesis and support the use of miR-192 in an anti-angiogenesis therapy., The formation of blood vessels in tumours, angiogenesis, is a promising target for therapy. Here, the authors show that microRNA192 has anti-angiogenic functions and negatively regulates EGR1 and HOXB9, and that delivery of this microRNA to tumours in vivo can reduce angiogenesis and tumour growth.