Evaluation of the stiffness of normal cervix and its change with different factors using transvaginal two-dimensional shear wave elastography under strict quality control.

BACKGROUND: The usefulness of transvaginal two-dimensional shear wave elastography (2D SWE) for cervical lesions is still uncertain. This study was to explore the value of transvaginal 2D SWE in the evaluation of the stiffness of normal cervix and its change with different factors under strict quality control (QC). METHODS: Two hundred patients with normal cervix were included in this study and were examined using quantitative 2D SWE to evaluate cervical stiffness and its change with different factors under strict QC. RESULTS: Intra-observer concordance of transvaginal 2D SWE parameters in midsagittal planes were acceptable with intraclass correlation coefficients higher than 0.5. Transvaginal 2D SWE parameters were significantly higher than the corresponding transabdominal parameters. 2D SWE parameters of internal cervical os were significantly higher than the corresponding parameters of external cervical os in a transvaginal midsagittal plane. 2D SWE parameters of external cervical os increased significantly over 50 years old, while these parameters of internal cervical os didn't change significantly with increasing age. 2D SWE parameters of internal cervical os of horizontal position cervix were significantly higher than those of vertical position cervix. SWE parameters of normal cervix did not change according to different menstrual cycles, parities and human papilloma virus test results. CONCLUSIONS: Transvaginal 2D SWE under strict QC could provide quantitative, repeatable and reliable cervical stiffness information. Internal cervical os was stiffer than external cervical os. Menstrual cycles, parities and human papilloma virus test results wouldn't affect cervical stiffness. However, age and cervical positions should be taken into condition while interpreting 2D SWE results of cervical stiffness.

Beta-catenin knockdown impairs the viability of ovarian cancer cells by modulating YAP-dependent glycolysis.

OBJECTIVES: Ovarian cancer (OC) ranks fifth among the main causes of cancer-related deaths in women worldwide. PCLAF/KIAA0101 and Yes-associated protein (YAP) have been linked to several human malignant cancers, including OC. However, the roles of KIAA0101 and YAP in glycolysis-dependent OC cell proliferation remain unknown. METHODS: qRT-PCR and western blot were performed to analyze the KIAA0101 expression. Short hairpin RNA transfection was performed to silence KIAA0101 expression in cells. Cell viability and apoptosis were assayed by colony formation and flow cytometry, respectively. Glucose uptake, lactate production, and glycolytic enzyme expression were assessed to determine the level of cellular glycolysis. Phosphorylation and the nuclear localization of YAP were assessed to determine YAP activation. RESULTS: OC tissue and cell lines exhibited higher KIAA0101 expression than the non-cancerous tissues and cells. KIAA0101 silencing reduced the proliferation and increased the apoptosis of both A2780 and ES-2 OC cell lines. Furthermore, KIAA0101 depletion suppressed glycolysis and YAP activation, as evidenced by increased YAP phosphorylation and decreased nuclear localization. Reactivation of YAP was performed by administration of mitochonic acid 5 in both OC cell lines with KIAA0101 knockdown. Glucose uptake, lactate production, phosphofructokinase, pyruvate dehydrogenase beta, pyruvate kinase M2, triosephosphate isomerase 1, glucose-6-phosphate dehydrogenase, enolase 1, and lactate dehydrogenase expression levels in cells recovered after the reactivation of YAP. Additionally, YAP reactivation increased cell proliferation and inhibited apoptosis. CONCLUSIONS: This study showed that KIAA0101 could promote glycolysis during nasopharyngeal carcinoma development through YAP signaling activation, suggesting that KIAA0101 could serve as a target for OC treatment.

The mechanism of BRCC3/NLRP3 in promoting the transformation of endometriosis to endometriosis-associated ovarian carcinoma / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨NOD样受体蛋白3（NLRP3）炎症小体的活化在子宫内膜异位症（EMT）进展为EMT相关性卵巢癌（EAOC）过程中的作用及其机制。方法：选取2018年4月至2019年6月上海市长宁区幼保健院收治的EAOC、EMT、正常子宫内膜（CON组）组织标本各15例及患者的临床资料，利用免疫组织化学染色法、WB法检测EAOC、EMT和CON组织中NLRP3、caspase-1和IL-1β及含BRCA1/BRCA2的复杂亚基3（BRCC3）的表达水平。构建过表达BRCC3质粒和si-NLRP3质粒并转染EMT细胞CRL-7566，通过WB法检测转染后细胞中BRCC3蛋白的表达水平，利用MTT法、流式细胞术及Transwell实验分别检测转染后细胞增殖、凋亡、迁移与侵袭能力的变化。对过表达BRCC3组细胞进行干扰NLRP3实验，通过WB法检测干扰后BRCC3和NLRP3蛋白的表达水平，检测干扰后细胞增殖、凋亡、迁移与侵袭能力的变化。结果：EAOC和EMT组织中NLRP3、caspase-1、IL-1β和BRCC3的表达水平较CON组均呈明显升高（均P<0.01），且EAOC组织中NLRP3与BRCC3的表达呈正相关（r=0.65，P<0.01）。在CRL-7566细胞中过表达BRCC3显著促进细胞的增殖、迁移和侵袭并抑制细胞凋亡（均P<0.01），敲减NLRP3则抑制CRL-7566细胞的上述表型（均P<0.01），过表达BRCC3增强NLRP3的表达水平（P<0.01），而干扰BRCC3则抑制NLRP3表达（P<0.01）；干扰NLRP3可以部分逆转BRCC3对细胞凋亡的抑制作用（P<0.01）、对细胞迁移（P<0.05）和侵袭（P<0.01）的促进作用。结论：EAOC和EMT组织中NLRP3和BRCC3均呈高表达，过表达BRCC3可促进CRL-7566细胞的增殖、迁移和侵袭并抑制细胞凋亡，与EMT向EAOC转化有关，BRCC3/NLRP3是潜在的EAOC炎癌转化预测标志物及治疗靶点。

Life Modifications and PCOS: Old Story But New Tales.

Polycystic ovary syndrome (PCOS) is defined as a kind of endocrine and metabolic disorder that affects female individuals of reproductive age. Lifestyle modifications, including diet modifications, exercise, and behavioral modification, appear to alleviate the metabolic dysfunction and improve the reproductive disorders of PCOS patients (particularly in obese women). Therefore, lifestyle modifications have been gradually acknowledged as the first-line management for PCOS, especially in obese patients with PCOS. However, the mechanism of lifestyle modifications in PCOS, the appropriate composition of diet modifications, and the applicable type of exercise modifications for specific female populations are rarely reported. We conducted a systematic review and enrolled 10 randomized controlled trials for inclusion in a certain selection. In this review, we summarized the existing research on lifestyle modifications in PCOS. We aimed to illustrate the relationship between lifestyle modifications and PCOS (referring to hyperandrogenism, insulin resistance as well as obesity) and also considered the priorities for future research. These results might be an invaluable tool to serve as a guide in lifestyle modifications as the intervention for PCOS and other related endocrine disorders.

The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress.

Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers solid tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.

Gut and Vaginal Microbiomes in PCOS: Implications for Women's Health.

PCOS is defined as a kind of endocrine and metabolic disorder which affects females at reproductive ages, is becoming much more common, nowadays. Microbiomes are known as microorganisms that inhabit the body to play a vital role in human health. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and microbiomes (gut microbiomes and vaginal microbiomes). However, the mechanism is still unclear. In this review, we reviewed the relationship between PCOS and microbiomes, including gut/vaginal microbiomes compositions in PCOS, mechanism of microbiomes and PCOS, and then collectively focused on the recent findings on the influence of microbiomes on the novel insight regarding the therapeutic strategies for PCOS in the future clinical practice.

Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway.

Emerging evidence suggests that physiological distress is highly correlated with cancer incidence and mortality. However, the mechanisms underlying psychological challenges-mediated tumor immune evasion are not systematically explored. Here, it is demonstrated that acute restraint (AR) increases the level of the plasma neuropeptide hormones, kisspeptin, and the expression levels of its receptor, Gpr54, in the hypothalamus, splenic and tumor-infiltrating T cells, suggesting a correlation between the neuroendocrine system and tumor microenvironment. Accordingly, administration of kisspeptin-10 significantly impairs T cell function, whereas knockout of Gpr54 in T cells inhibits lung tumor progression by suppressing T cell dysfunction and exhaustion with or without AR. In addition, Gpr54 defective OT-1 T cells show superior antitumor activity against OVA peptide-positive tumors. Mechanistically, ERK5-mediated NR4A1 activation is found to be essential for kisspeptin/GPR54-facilitated T cell dysfunction. Meanwhile, pharmacological inhibition of ERK5 signaling by XMD8-92 significantly reduces the tumor growth by enhancing CD8+ T cell antitumor function. Furthermore, depletion of GPR54 or ERK5 by CRISPR/Cas9 in CAR T cells intensifies the antitumor responses to both PSMA+ and CD19+ tumor cells, while eliminating T cell exhaustion. Taken together, these results indicate that kisspeptin/GPR54 signaling plays a nonredundant role in the stress-induced tumor immune evasion.

LncRNA HOTAIR Promotes Chemoresistance by Facilitating Epithelial to Mesenchymal Transition through miR-29b/PTEN/PI3K Signaling in Cervical Cancer.

Long non-coding RNA HOTAIR has been revealed to participate in the tumorigenesis of various cancers. However, the mechanism of HOTAIR involvement in cervical cancer has not been identified. Hence, this study aimed to explore the oncogenic and chemoresistant roles of HOTAIR in cervical cancer, and its underlying mechanism. RT-PCR, Western blot, and Luciferase assay were employed to determine the relationship of HOTAIR with miR-29b and PTEN and to study the role of HOTAIR in cervical cancer. CCK8 assay, cell migration, and invasion assay were used to reveal the role of HOTAIR in cervical cancer cell proliferation and metastasis. The inhibitory dose of chemotherapeutics was determined by CCK8 assay using probit analysis. HOTAIR was found to bind with miR-29b, and a negative correlation existed between HOTAIR and miR-29b expression in cervical cancer cells. In addition, HOTAIR promoted the migration and proliferation of cervical cancer cell lines HeLa and Siha, showing effects opposite to miR-29b. Further, HOTAIR facilitated the resistance of both HeLa and Siha cells against cisplatin, paclitaxel and docetaxel, whereas miR-29 suppressed the resistance of both cervical cancer cells against the 3chemotherapeutics. In addition, HOTAIR enhanced epithelial-to-mesenchymal transition (EMT), while miR-29b exerted an inhibitory effect on EMT. In cervical cancer cells, miR-29b did not affect promoter methylation of PTEN but regulated PTEN expression by targeting SP1. Transfection of miR-29b mimics led to a significant downregulation of PI3K. HOTAIR promotes chemoresistance by facilitating EMT through the miR-29b/PTEN/PI3K axis in cervical cancer.

Circular RNA FOXO3 regulates endometrial carcinoma progression through the microRNA-29a-3p/HDAC4 axis.

Previous studies determined that circular RNA FOXO3 (circ_FOXO3) plays a critical role in tumorigenesis. The definite molecular mechanism of cir_FOXO3 in endometrial carcinoma (EC), nevertheless, had not been fully explored. Circ_FOXO3 expression was determined using quantitative real-time polymerase chain reaction in human EC tissues and cell lines, whereas small interfering RNAs were used to specifically silence circ_FOXO3 expression in cultured EC cells. The cell counting kit-8 assay was employed to determine the effect of ectopic circ_FOXO3 expression on cell viability. Cell proliferation and apoptosis were evaluated by flow cytometry. Further, migration and invasion of EC cells were characterized using the Transwell assay. The interaction between microRNA (miR)-29a-3p and circ_FOXO3/histone deacetylase 4 (HDAC4) was validated using dual luciferase reporter assay. Additionally, qRT-PCR and WB were employed to determine HDAC4 levels. We found that circ_FOXO3 was highly expressed in EC cells and tissues. Moreover, suppressing circ_FOXO3 expression abrogated EC by regulating cell proliferation, apoptosis, migration, and invasion. Furthermore, circ_FOXO3 could act as a sponge for miR-29a-3p, and inhibition of miR-29a-3p expression reversed the effects of circ_FOXO3 suppression on EC progression. Overexpression of miR-29a-3p inhibited EC cell growth, migration, and invasion through the regulation of HDAC4, as it is a target of miR-29a-3p. In conclusion, circ_FOXO3 promotes EC progression by sponging miR-29a-3p and upregulating HDAC4, making it a promising therapeutic target in EC.

A Modified Technique of Bipolar Loop Resectoscopic Slicing for Treating Submucous Fibroids With Enucleation Makes the Operation Safer.

Background: In this study, a modified technique of resectoscopic slicing with a common bipolar loop was introduced, which facilitated the complete removal of the submucous fibroid inside the uterine cavity without any novel equipment. Results: Compared with the classical technique, our modified procedure possessed a shorter operation time (22.9 ± 7.3 vs. 38.9 ± 13.0 min, p < 0.05) and a smaller distending media volume (1,495.6 ± 540.1 vs. 2,393.1 ± 719.4 ml, p < 0.01). Conclusion: As a result, the current study suggested that the enucleation of submucous fibroid under hysteroscopy could be achieved by using only the bipolar loop, which reduced the consumption for novel equipment and enhanced the safety of the technique.

HOTAIR Contributes to Stemness Acquisition of Cervical Cancer through Regulating miR-203 Interaction with ZEB1 on Epithelial-Mesenchymal Transition.

Cervical cancer stem cells contribute respond to considerable recurrence and metastasis of patients with cervical cancer. The stemness properties were partly regulated by the interaction of lncRNAs and miRNAs. HOTAIR functions as an oncogenic lncRNA. Previous research studies revealed its role in regulating stemness properties in various cancers. However, the role of HOTAIR in cervical cancer stem cells is still unknown. Here, cisplatin-resistant and serum-free cultured cells exhibited stem cells properties. Cervical cancer stem cells exhibited greater invasion and migration compared with their parental cells, which was similar to cells overexpressing HOTAIR. HOTAIR was significantly overexpressed in cervical cancer stem cells, and knockdown of HOTAIR generated statistical downregulation of stemness markers. Additionally, HOTAIR expression was negatively correlated with the level of miR-203, which was found to be an inhibitory miRNA in regulating the expressions of stemness markers. Also, miR-203 expression was negatively correlated with ZEB1. These findings suggested that HOTAIR should be a positive contributor in stemness acquisition of cervical cancer cells, and this effect should correlate with the interaction with miR-203, which can be suppressed by ZEB1.

Histone deacetylase 1 facilitates aerobic glycolysis and growth of endometrial cancer.

The deregulation of histone deacetylase 1 (HDAC1) is reportedly involved in the progression of several cancer types. However, its function in endometrial cancer remains unknown. The aim of the present study was to clarify the role of HDAC1 in aerobic glycolysis and the progression of endometrial cancer. Lentiviral vector transfection was used to up- and downregulate HDAC1 expression in HEC-1-A endometrial cancer cells. The effects of HDAC1 on cellular proliferation, apoptosis, migration, invasiveness and tumorigenesis were determined by CCK-8, flow cytometry, wound-healing, transwell chamber and in vivo tumor formation experiments, respectively. HDAC1 level was significantly increased in endometrial cancer tissues and cells, and its high expression was associated with advanced clinicopathological progression. HEC-1-A cell proliferation, invasiveness, migration and tumorigenesis were enhanced, and apoptosis was inhibited when HDAC1 was overexpressed. Moreover, upregulation of HDAC1 significantly promoted the epithelial-mesenchymal transition of HEC-1-A cells, and increased glucose consumption, lactate secretion and ATP levels. Collectively, the present study revealed that HDAC1 promoted the aerobic glycolysis and progression of endometrial cancer, which may provide a potential target for endometrial cancer treatment.

Titanium Implants and Local Drug Delivery Systems Become Mutual Promoters in Orthopedic Clinics.

Titanium implants have always been regarded as one of the gold standard treatments for orthopedic applications, but they still face challenges such as pain, bacterial infections, insufficient osseointegration, immune rejection, and difficulty in personalizing treatment in the clinic. These challenges may lead to the patients having to undergo a painful second operation, along with increased economic burden, but the use of drugs is actively solving these problems. The use of systemic drug delivery systems through oral, intravenous, and intramuscular injection of various drugs with different pharmacological properties has effectively reduced the levels of inflammation, lowered the risk of endophytic bacterial infection, and regulated the progress of bone tumor cells, processing and regulating the balance of bone metabolism around the titanium implants. However, due to the limitations of systemic drug delivery systems-such as pharmacokinetics, and the characteristics of bone tissue in the event of different forms of trauma or disease-sometimes the expected effect cannot be achieved. Meanwhile, titanium implants loaded with drugs for local administration have gradually attracted the attention of many researchers. This article reviews the latest developments in local drug delivery systems in recent years, detailing how various types of drugs cooperate with titanium implants to enhance antibacterial, antitumor, and osseointegration effects. Additionally, we summarize the improved technology of titanium implants for drug loading and the control of drug release, along with molecular mechanisms of bone regeneration and vascularization. Finally, we lay out some future prospects in this field.

Comprehensive Analysis of circRNA-miRNA-mRNA Network in Cervical Squamous Cell Carcinoma by Integrated Analysis.

PURPOSE: Cervical squamous cell carcinoma (CSCC) seriously affects women's health worldwide, and it is of great significance to illuminate the specific role of circRNAs in CSCC. MATERIALS AND METHODS: Three mRNA datasets, two miRNA datasets and one circRNA dataset of CSCC, downloaded from GEO, were utilized in this study. Differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) were identified, and a ceRNA (DEcircRNA-DEmiRNA-DEmRNA) regulatory network was constructed. GO and pathway analyses of DEcircRNAs and DEmRNAs in the ceRNA regulatory network were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) validation of the expression of the selected DEmRNAs, DEmiRNAs and DEcircRNAs was performed. RESULTS: A total of 1356 DEmRNAs, 13 DEmiRNAs and 77 DEcircRNAs were obtained. The ceRNA network contained 3 circRNA-miRNA pairs and 158 miRNA-mRNA pairs, including 3 circRNAs, 3 miRNAs, and 138 mRNAs. Functional annotation of DEmRNAs in the ceRNA regulatory network revealed that these DEmRNAs were significantly enriched in cell cycle, p53 signalling pathway and DNA replication. The qRT-PCR results were generally consistent with those of our integrated analysis. CONCLUSION: In conclusion, we speculate that the regulation of the hsa_circ_0000069/hsa-miR-125b-5p/CDKN2A and hsa_circ_0020594/hsa-let-7c-5p/CCNB2 axes may be involved in CSCC.

Prognostic Value of Programmed Cell Death 1 Ligand-1 in Patients With Bone and Soft Tissue Sarcomas: A Systemic and Comprehensive Meta-Analysis Based on 3,680 Patients.

Background: Programmed cell death 1 ligand-1 (PD-L1) is an immune checkpoint molecule that acts to protect cancer cells from immune surveillance and is considered as a prognostic biomarker in several cancers, but the prognostic value of PD-L1 in bone and soft tissue sarcomas remains inconclusive. In the present meta-analysis, the clinicopathological and prognostic value of PD-L1 in sarcomas was evaluated. Method: We performed a systemic and comprehensive meta-analysis by searching the PubMed, Medline, Cochrane Library, EMBASE, and Web of Science databases up to October 31, 2019. Eligible articles were incorporated, and pooled hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were used to estimate the outcomes. Results: Thirty-six articles containing 39 independent studies with 3,680 bone and soft tissue sarcoma patients were included in our meta-analysis. The pooled results showed that PD-L1 overexpression could predict poor overall survival (HR 1.45, 95% CI 1.11-1.90, P < 0.01), metastasis-free survival (HR 1.58, 95% CI 1.14-2.19, P < 0.01), and event-free survival (HR 2.82, 95% CI 1.69-4.71, P < 0.01) in sarcomas. Furthermore, PD-L1 overexpression was correlated with a higher rate of tumor metastasis (OR 2.95, 95% CI 1.32-6.60, P < 0.01), a more advanced tumor grade (OR 3.63, 95% CI 2.55-5.16, P < 0.01), and more T lymphocyte infiltration (OR 5.55, 95% CI 2.86-10.76, P < 0.01). No obvious publication bias was observed, and the sensitivity analysis showed that our results were robust. Conclusion: The results of our meta-analysis indicate that high PD-L1 expression might serve as a valuable and predictive biomarker for adverse clinicopathological features and poor prognosis in patients with sarcoma.

Untargeted LC-MS/MS analysis reveals metabolomics feature of osteosarcoma stem cell response to methotrexate.

BACKGROUND: Cancer stem cell (CSC) is identified in osteosarcoma (OS) and considered resistant to chemotherapeutic agents. However, the mechanism of osteosarcoma stem cell (OSC) resistant to chemotherapy remains debatable and vague, and the metabolomics feature of OSC is not clarified. MATERIALS AND METHODS: OSC was isolated by using sphere forming assay and identified. Untargeted LC-MS/MS analysis was performed to reveal the metabolomics feature of OSC and underlying mechanisms of OSC resistant to methotrexate (MTX). RESULTS: OSC was efficiently isolated and identified from human OS 143B and MG63 cell lines with enhanced chemo-resistance to MTX. The untargeted LC-MS analysis revealed that OSC showed differential metabolites and perturbed signaling pathways, mainly involved in metabolisms of fatty acid, amino acid, carbohydrate metabolism and nucleic acid. After treated with MTX, metabolomics feature of OSC was mainly involved metabolisms of amino acid, fatty acid, energy and nucleic acid. Moreover, compared with their parental OS cells response to MTX, the differential metabolites and perturbed signaling pathways were mainly involved in metabolism of amino acid, fatty acid and nucleic acid. What's more, Rap1 signaling pathway and Ras signaling pathway were involved in OS cells and their SCs response to MTX. CONCLUSION: Sphere-forming assay was able to efficiently isolate OSC from human OS cell lines and the untargeted LC-MS/MS analysis was suggested a sufficient methodology to investigate metabolomics features of OS cells and OSCs. Moreover, the metabolomics features of OSCs response to MTX might reveal a further understanding of chemotherapeutic resistance in OS.

Blocking STAT3 by pyrvinium pamoate causes metabolic lethality in KRAS-mutant lung cancer.

Signal transducer and activator of transcription 3 (STAT3) exerts a profound role in regulating mitochondrial function and cellular metabolism. Mitochondrial STAT3 supports RAS-dependent malignant transformation and tumor growth. However, whether pharmacological blockade of STAT3 leads to metabolic lethality in KRAS-mutant lung cancer remains unclear. Pyrvinium pamoate, a clinical antihelminthic drug, preferentially inhibited the growth of KRAS-mutant lung cancer cells in vitro and in vivo. Mechanistic study revealed that pyrvinium dose-dependently suppressed STAT3 phosphorylation at tyrosine 705 and serine 727. Overexpression mitochondrial STAT3 prominently weakened the therapeutic efficacy of pyrvinium. As a result of targeting STAT3, pyrvinium selectively triggered reactive oxygen species release, depolarized mitochondrial membrane potential and suppressed aerobic glycolysis in KRAS-mutant lung cancer cells. Importantly, the cytotoxic effects of pyrvinium could be significantly augmented by glucose deprivation both in vitro and in a patient-derived lung cancer xenograft mouse model in vivo. The combined efficacy significantly correlated with intratumoural STAT3 suppression. Our findings reveal that KRAS-mutant lung cancer cells are vulnerable to STAT3 inhibition exerted by pyrvinium, providing a promising direction for developing therapies targeting STAT3 and metabolic synthetic lethality for the treatment of KRAS-mutant lung cancer.

PLK1 Knockdown Inhibits Cell Proliferation and Cell Apoptosis, and PLK1 Is Negatively Regulated by miR-4779 in Osteosarcoma Cells.

Polo-like kinase 1 (PLK1) is a ubiquitous serine/threonine protein kinase. It is reported to be involved in the occurrence and progression of various human cancers. In the present study, we explored the role and molecular mechanism of PLK1 in the proliferation of osteosarcoma (OS) cells. We found that PLK1 expression was higher in MG63/Dox cells than in MG63 cells, while inhibiting or interfering with the level of PLK1 suppressed cell proliferation of MG63/Dox cells. TargetScan analysis predicted that miR-4779 would interact with the 3'-UTR of PLK1 mRNAs and also inhibit cell autophagy of MG63/Dox cells. The data demonstrated that miR-4779 negatively regulates the expression of PLK1, and both miR-4779 and PLK1 regulate cell proliferation and cell apoptosis of MG63/Dox cells, processes that are involved in the drug resistance of OS cells.

The clinical prognostic significance of ezrin in patients with bone and soft tissue sarcomas: a meta-analysis.

Ezrin is a member of the ezrin-radixin-moesin (ERM) protein family and has been shown to be associated with poor prognosis in patients with a variety of solid tumors. However, the clinical prognostic significance of ezrin in patients with bone and soft tissue sarcomas remains unclear. Here, we performed a systematic meta-analysis by searching PubMed, the Cochrane Library Database, EMBASE, the Web of Science, and the CBM, WanFang Med Online and CNKI databases. In total, 19 studies with a total of 1316 bone and soft tissue sarcoma patients were included. Pooled analyses showed that ezrin overexpression was correlated with a higher rate of tumor metastasis (OR 6.59, 95% CI: 2.84-15.33, P < 0.01, PFDR  < 0.01) and recurrence (OR 3.18, 95% CI: 1.88-5.37, P < 0.01, PFDR  < 0.01) and a more advanced tumor grade (OR 3.252, 95% CI: 1.371-7.715, P = 0.01, PFDR  = 0.03). Moreover, elevated ezrin expression could predict poor OS (HR 3.02, 95% CI: 2.35-3.89, P < 0.01, PFDR  < 0.01), MFS (HR 5.22, 95% CI: 2.08-13.08, P < 0.01, PFDR  < 0.01), and EFS (HR 1.07, 95% CI: 1.03-1.11, P < 0.01, PFDR  < 0.01). Subgroup analyses revealed the underlying sources of heterogeneity. Publication bias was observed in the analysis of metastasis. Sensitivity analysis revealed that the results were robust. Our findings indicated that ezrin overexpression was significantly correlated with poor survival and more advanced tumor progression in bone and soft tissue sarcomas, which suggests that ezrin might be a valuable prognostic biomarker and a potential therapeutic target.

MiR-369-3p participates in endometrioid adenocarcinoma via the regulation of autophagy.

BACKGROUND: The aim of this study is to examine miRNA profiling and miR-369-3p participates in endometrioid adenocarcinoma (EEC) via the regulation of autophagy. METHODS: EEC and its adjacent normal tissues were obtained from 20 clinical patients after surgery. MiRNA profiling was performed using next generation sequencing (NGS) and was validated with quantitative real time PCR (qRT-PCR). qRT-PCR was also employed to measure miR-369-3p and autophagy-related protein 10 (ATG10) expression levels. Western blotting assay was performed to measure the expressions of ATG10 and LC3B. Luciferase reporter assay was conducted to confirm the direct targeting of ATG10 by miR-369-3p. Cell proliferation and migration assays were utilized to analyze the role of miR-369-3p in HEC-1-A cells. RESULTS: We found that miR-369-3p expression levels were down-regulated in EEC compared to the control tissues. The overexpression of miR-369-3p inhibited cell proliferation and migration in EEC; furthermore, ATG10 expression increased in EEC tissues. ATG10 was found to be a potential target of miR-369-3p via a dual-luciferase reporter assay, and ATG10 was shown to be down-regulated by miR-369-3p in protein levels. CONCLUSIONS: This study revealed that miR-369-3p inhibited cell proliferation and migration by targeting ATG10 via autophagy in EEC.