ß-resorcylic acid released by Limosilactobacillus reuteri protects against cisplatin-induced ovarian toxicity and infertility.

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

Circ_0008315 promotes tumorigenesis and cisplatin resistance and acts as a nanotherapeutic target in gastric cancer.

INTRODUCTION: Cisplatin-based chemotherapy is one of the fundamental therapeutic modalities for gastric cancer (GC). Chemoresistance to cisplatin is a great clinical challenge, and its underlying mechanisms remain poorly understood. Circular RNAs (circRNAs) are involved in the pathophysiology of multiple human malignancies. METHODS: High-throughput sequencing was performed to determine the differentially expressed profile of circRNA in GC tissues and cisplatin-resistant GC cells. Quantitative real-time polymerase chain reaction and Fluorescence in situ hybridization was utilized to confirm the dysregulation of circ_0008315 in GC tissues. To evaluate the prognostic significance of circ_0008315 in GC, we used Kaplan-Meier plot. The self-renewal ability of drug-resistant GC cell was verified through tumor sphere formation assay. GC organoids were constructed to simulate the tumor microenvironment and verified the function of circ_0008315 in cisplatin resistance of gastric cancer. In vivo evaluation was conducted using patient-derived xenograft models. Dual-luciferase reporter gene, RNA immunoprecipitation and miRNA pull-down assays were employed to investigate the molecular mechanisms of circ_0008315 in GC. RESULTS: We revealed that a novel circRNA hsa_circ_0008315 was upregulated in GC and cisplatin-resistant GC cells. Elevated circ_0008315 was also observed in cisplatin-resistant GC organoid model. High circ_0008315 expression predicted unfavorable survival outcome in GC patients. Downregulation of circ_0008315 expression inhibited proliferation, mobility, and epithelial-mesenchymal transition of GC cells in vitro and in vivo. Reducing circ_0008315 expression in cisplatin-resistant GC organoid model reversed cisplatin resistance. Mechanistically, circ_0008315 modulated the stem cell properties of GC through the miR-3666/CPEB4 signaling pathway, thereby promoting cisplatin resistance and GC malignant progression. Furthermore, we developed PLGA-PEG nanoparticles targeting circ_0008315, and the nanoparticles could effectively inhibit GC proliferation and cisplatin resistance. CONCLUSION: Circ_0008315 exacerbates GC progression and cisplatin resistance, and can be used as a prognostic predictor. Circ_0008315 may function as a promising nanotherapeutic target for GC treatment.

CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer.

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the development and progression of gastric cancer (GC). However, it remains unclear whether dysregulated circRNA affects immune escape and the efficacy of immunotherapy in GC. Our aim is to investigate the molecular mechanism of circRNA affecting GC immunotherapy and identify effective molecular therapeutic targets. METHODS: The differential expression profile of circRNAs was established through circRNA sequencing, comparing three paired GC tissues with their adjacent non-cancerous gastric tissues. The expression level of circRHBDD1 in GC tissues was then assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological characteristics of circRHBDD1 were verified through a series of experiments, including agarose gel electrophoresis assays, RNase R treatment, and actinomycin D experiments. The prognostic value of circRHBDD1 in GC was evaluated by conducting both univariate and multivariate survival analyses. Furthermore, loss- and gain-of-function approaches were utilized to investigate the impact of circRHBDD1 on GC immune escape. RNA-sequencing, immunoprecipitation, flow cytometry, and methylated RNA immunoprecipitation (meRIP) analysis were performed to elucidate the underlying molecular mechanisms. RESULTS: We discovered that circRHBDD1 exhibited remarkably high expression levels in GC tissues and cell lines. Notably, the high expression of circRHBDD1 was significantly correlated with poor overall survival and disease-free survival among GC patients. Both in vitro and in vivo experiments revealed that circRHBDD1 upregulated the expression of PD-L1 and impeded the infiltration of CD8+ T cells. Further, we found that circRHBDD1 binds to IGF2BP2, disrupting the interaction between E3 ligase TRIM25 and IGF2BP2, and ultimately inhibiting IGF2BP2 ubiquitination and degradation. Intriguingly, IGF2BP2 enhances PD-L1 mRNA stability through m6A modification. Additionally, we developed Poly (lactide-co-glycolic acid) (PLGA)-Polyethylene glycol (PEG)-based nanoparticles loaded with circRHBDD1 siRNA. In vivo experiments validated that the combination of PLGA-PEG(si-circRHBDD1) and anti-PD-1 offers a safe and efficacious nano-drug regimen for cancer immunotherapy. CONCLUSION: Our results demonstrated that circRHBDD1 promoted GC immune escape by upregulating the expression of PD-L1 and reprogramming T cell-mediated immune response. Inhibition of circRHBDD1 expression could potentially enhance the response of GC patients to immunotherapy, thus improving treatment outcomes. Additionally, the development of a nanodrug delivery system provides a feasible approach for future clinical applications.

The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer.

BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

H2S donor S-propargyl-cysteine for skin wound healing improvement via smart transdermal delivery.

Hydrogen sulfide for wound healing has drawn a lot of attention recently. In this research, the S-propargyl-cysteine (SPRC), an endogenous H2S donor, was loaded on carbomer hydrogel, and a copper sheet rat burn model was developed. Pathological changes in rat skin tissue were examined using hematoxylin-eosin (HE) and Masson staining. The immunohistochemistry (IHC) staining was performed to detect the expression of Collagen I (Col I) and Collagen III (Col III). The mRNA levels of interleukin (IL)-6, Col Iα2, Col IIIα1, tissue inhibitors of metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-ß1 were examined by quantitative real-time chain polymerase reaction. The findings demonstrated that the collagen layer was thicker in the SPRC group during the proliferative phase, SPRC hydrogel promoted VEGF expression. In the late stage of wound healing, the expression of IL-6, TIMP-1, MMP-9, and TGF-ß1 was inhibited, and the Col I content was closer to that of normal tissue. These results surface that SPRC hydrogel can promote wound healing and play a positive role in reducing scar formation. Our results imply that SPRC can facilitate wound healing and play a positive role in reducing scar formation.

The 'Other' subfamily of HECT E3 ubiquitin ligases evaluate the tumour immune microenvironment and prognosis in patients with hepatocellular carcinoma.

Primary liver cancer is the sixth most common cancer and the third leading cause of cancer-related death worldwide. The role of the 'Other' subfamily of HECT E3 ligases (E3s) in hepatocellular carcinoma (HCC) remains unknown. The expression of the 'Other' HECT E3s was performed using The Cancer Genome Atlas (TCGA) data, and the authors found that the 'Other' HECT E3s were differentially expressed in HCC. Prognostic values were assessed using the Kaplan-Meier method and indicated that the high expressions of HECTD2, HECTD3, and HACE1 were associated with a worse clinical prognosis of HCC patients. The expression of HECTD2 was significantly correlated with the infiltration of CD4+ T cells and neutrophils. The levels of HECTD3 and HACE1 were notably related to the dendritic cells and memory B cells infiltrated in HCC. In addition, the three previously mentioned genes have shown to be associated with immune checkpoint genes, such as FOXP3, CCR8, STAT5B, TGFB1 and TIM-3. Moreover, HECTD2 could promote the proliferative activity, cell migration and invasive ability of HCC cells. Collectively, the authors' study demonstrated that HECTD2 was a novel immune-related prognostic biomarker for HCC, providing new insight into the treatment and prognosis of HCC.

TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer.

BACKGROUND: Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. METHODS: We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. RESULTS: TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. CONCLUSION: TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1ß receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (H2S) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular H2S ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway.

Risk Assessment of Pulmonary Metastasis for Cervical Cancer Patients by Ensemble Learning Models: A Large Population Based Real-World Study.

OBJECTIVE: Pulmonary metastasis (PM) is an independent risk factor affecting the prognosis of cervical patients, but it still lacks a prediction. This study aimed to develop machine learning-based predictive models for PM. METHODS: A total of 22,766 patients diagnosed with or without PM from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled in this study. The cohort was randomly split into a train set (70%) and a validation set (30%). In addition, 884 Chinese patients from two tertiary medical centers were included as an external validation set. Duplicated and useless candidate variables were excluded, and sixteen variables were included for the machine learning algorithm. We developed five predictive models, including the generalized linear model (GLM), random forest model (RFM), naive Bayesian model (NBM), artificial neural networks model (ANNM), and decision tree model (DTM). The predictive performance of these models was evaluated by the receiver operating characteristic (ROC) curve and calibration curve. The Cox proportional hazard model (CPHM) and competing risk model (CRM) were also included for survival outcome prediction. RESULTS: Of the patients included in the analysis, 2456 (4.38%) patients were diagnosed with PM. Age, organ-site metastasis (liver, bone, brain), distant lymph metastasis, tumor size, and pathology were the important predictors of PM. The RFM with 9 variables introduced was identified as the best predictive model for PM (AUC = 0.972, 95% CI: 0.958-0.986). The C-index for the CPHM and CRM was 0.626 (95% CI: 0.604-0.648) and 0.611 (95% CI: 0.586-0.636), respectively. CONCLUSION: The prediction algorithm derived by machine-learning-based methods shows a robust ability to predict PM. This result suggests that machine learning techniques have the potential to improve the development and validation of predictive modeling in cervical patients with PM.

The clinical features and prognostic outcomes of primary mediastinal yolk sac tumors: A retrospective analysis of 15 rare cases from multiple centers.

ABSTRACT: Primary mediastinal yolk sac tumors (PMYSTs) are a rare occurrence. As such, the clinicopathological features, treatment, and prognosis, of this disease still remain unclear. In this study, we aimed to provide further information relating to this rare malignancy in order to facilitate the creation of more specific clinical guidelines for the diagnosis and treatment of patients with PMYSTs.In this retrospective study, we recruited 15 patients who had been diagnosed with PMYST from four medical institutions to create a population-based cohort. We then used Kaplan-Meier analysis and the log-rank test to investigate and compare overall survival (OS) and progression-free survival (PFS).A total of 15 cases were identified. The mean age was 27.3 years (range: 19-34 years). The estimated 1- and 2-year PFS rates were 66.7% and 60.0%, respectively. The 1- and 2-year OS rates were both 73.3%. Computer tomography scans revealed tumors were located in the anterior middle mediastinum (5 cases), the anterior superior mediastinum (1 case), the left anterior mediastinum (3 cases), and the right anterior mediastinum (6 cases). Of the 15 patients receiving extended resections, the majority (40.0%) underwent tumor resection, partial pericardiotomy, pulmonary wedge resection, and mediastinal lymphadenectomy. R0 resections were achieved in eleven patients. Four patients underwent R2 resection and experienced postoperative complications, including pneumonia (2 cases), atelectasis (1 case), and bronchopleural fistula (1 case). Four patients developed postoperative lung metastasis. Three patients died due to progressive diseases. Disease recurred in all patients at a median of 8.0 months (range: 6.0-11.0 months).PMYST is a rare but highly malignant tumor with a poor prognosis. Tumor resection, with optimal extended surgical management, may provide patients with the best chance of a cure although postoperative complications relating to the pulmonary systems should be treated with caution.

New insights of epigenetics in vascular and cellular senescence.

Vascular senescence plays a vital role in cardiovascular diseases and it is closely related to cellular senescence. At the molecular level, aging begins with a single cell, and it is characterized by telomere shortening, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, and so on. Epigenetics is an independent discipline that modifies DNA activity without altering the DNA sequence. The application of epigenetics helps to alleviate the occurrence of human diseases, inhibit senescence, and even inhibit tumor occurrence. Epigenetics mainly includes the modification of DNA, histone, and noncoding RNA. Herein, the application of epigenetics in vascular senescence and aging has been reviewed to provide the prospects and innovative inspirations for future research.

Improvements in left ventricular regional and global systolic function following treatment with S100A4-shRNA after myocardial infarction in mice.

BACKGROUND: S100A4 plays a vital role in cardiac fibrosis after myocardial infarction (MI), but its effects on myocardial mechanics and remodeling are unknown. We hypothesized that regional and global left ventricular (LV) systolic function as determined by speckle tracking echocardiography (STE) would be improved with inhibition of S100A4 using short hairpin (sh) RNA. This study aimed to investigate whether STE can delineate the efficacy and safety of S100A4-shRNA in MI. METHODS: A total of 48 mice were randomly assigned to sham+S100A4-shRNA, sham+scrambled (Scr) sequence-shRNA, MI+S100A4-shRNA, and MI+Scr-shRNA groups (n=12 per group) and underwent intramyocardial injection of target agents after MI was produced by left anterior descending ligation. Two-dimensional STE and M-mode echocardiography were performed at baseline and at day 7, 14, and 28 post-MI by GE Vivid 7 ultrasound (il3L linear probe, 10.0-14.0 MHz) and Echopac PC software. Radial strain was analyzed from 6 segments of the mid short axis images with 20-30 frames per cardiac cycle. Post-mortem western blotting, immunohistochemistry, and Masson's trichrome stain were performed to quantify infarct size and detect suppression of S100A4. RESULTS: STE detected a statistically significant improvement in peak radial strain (pRS) and time to peak radial strain (pRSt) by day 14 post-MI in the MI+S100A4-shRNA group (P<0.05), especially in the LV anteroseptal wall (pRS: 23.83%±1.12% vs. 20.25%±1.02%, pRSt: 76.75±3.18 vs. 92.00±3.69 ms, P<0.05). After 1 month of S100A4-shRNA administration, cardiac function improved in the MI+S100A4-shRNA group according to both STE and M-mode tracing in mice. Additionally, both biochemical and histopathological examinations found reduced cardiac fibrosis in the MI+S100A4-shRNA group. CONCLUSIONS: S100A4-shRNA can be utilized as a therapeutic target to improve regional deformation and attenuate cardiac fibrosis following MI. Two-dimensional STE is useful in the early and comprehensive assessment of LV systolic function in mice.

Circumferential strain rate to detect lipopolysaccharide-induced cardiac dysfunction: a speckle tracking echocardiography study.

BACKGROUND: Lipopolysaccharide (LPS)-induced myocardial dysfunction is a widely used indicator to study septic cardiomyopathy (SC). This study investigated the efficiency of strain rate imaging (SRI) in detecting LPS-induced myocardial dysfunction. METHODS: A total of 30 mice were randomly assigned to saline group (n=10), 10 mg/kg LPS group (n=10) and 20 mg/kg LPS group (n=10). Then at baseline, 6 and 20 h after LPS injection, 2-D and M-mode echocardiography were conducted with GE Vivid 7 ultrasound (il3L linear probe, 10.0-14.0 MHz) and Echopac PC software. Ejection fraction (EF) and fractional shortening (FS) were measured with M-mode tracings. Serum biochemical examination was then performed to evaluate sepsis-induced myocardial injury. RESULTS: In LPS 20 mg/kg group, at 6 h after LPS injection, SRI found significantly decreased early diastolic strain rate (SRe, 1.76±1.05 vs. 3.18±0.83 unit/s, P<0.05), but M-mode echo found no change in EF and FS. In 10 mg/kg LPS group, compared with those at 6 h after LPS injection, SRI found a decline in SRe (1.57±0.75 vs. 3.18±0.83 unit/s, P<0.05), and M-mode tracings found an elevation in EF (71.31%±11.68% vs. 55.36%±7.42%, P<0.05) and FS (35.67%±8.79% vs. 25.43%±4.32%, P<0.05) at 20 h. Furthermore, LPS elevated the levels of serum creatine kinase-MB (CK-MB) and cardiac troponin-T (cTnT) at 20 h. CONCLUSIONS: SRI is useful to early assess LPS-induced cardiac deformation in mice. circumferential strain rate (SRcirc) is a sensitive indicator for LPS-induced myocardial injury in severe sepsis.

Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/ß -Catenin Pathway in Mice.

BACKGROUND/AIMS: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. METHODS: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson's trichrome staining to explore the function of S100A4. RESULTS: We found significant increases of S100A4 level and cardiac fibrosis markers, and ß-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and ß-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited ß-catenin signal pathway. CONCLUSION: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/ß -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin.

Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, shows higher metastases and relapse rates than other subtypes. The metastasis of TNBC is the main reason for the death of TNBC patients. Increasing evidence has shown that inhibiting the metastasis of TNBC is a good method for TNBC treatment. Here, VSP-17 was designed and synthesized as an agonist of PPARγ, evidenced by upregulating the expression of CD36 and increasing the activity of PPARγ reporter gene. VSP-17 obviously inhibited the migration and invasion process of MDA-MB-231 cells but showed little effect on the viability of MDA-MB-231 cells. Notably, VSP-17 could selectively promote the expression of E-cadherin without affecting the expression of BRMS1, CXCL12, MMP9, Orai1, Stim1, TGF-ß, and VEGF. In addition, VSP-17 significantly suppressed the metastasis of liver and promoted the expression of E-cadherin in MDA-MB-231 xenograft model. In conclusion, VSP-17 inhibited the metastasis process of TNBC via upregulating the expression of E-cadherin.

17ß­Estradiol treatment drives Sp1 to upregulate MALAT­1 expression and epigenetically affects physiological processes in U2OS cells.

Osteosarcoma is the most common primary bone tumor characterized by high risk of metastasis, thus presents with an overall survival rate of 60%, despite the use of chemotherapy and surgery. Metastasis­associated lung adenocarcinoma transcript 1 (MALAT­1) has been reported to upregulated and epigenetically regulate the metastasis in osteosarcoma; however, the regulatory mechanisms of MALAT­1 expression remain unclear. In the current study, significant upregulation of MALAT­1 was observed subsequent to exposure to low concentrations of 17ß­estradiol (E2) in U2OS cells. Using chromatin immunoprecipitation assays, E2­activated estrogen receptor α (ERα) was identified to promote the binding of specificity protein 1 (Sp1) to the MALAT­1 promoter. Electrophoretic mobility shift assay and immunoprecipitation results demonstrate that ERα binds indirectly to the MALAT­1 promoter by binding directly to Sp1 protein. Notably, without E2 stimulation, overexpressed ERα results in no significant promotion of the Sp1/MALAT­1 promoter, indicating that the translocation of ERα to nuclei stimulated by E2 is necessary. The immunofluorescence assay confirmed that E2 stimulation promotes the translocation of Sp1 to the nuclei in an ERα­dependent manner. Subsequently, the effects of E2 on osteosarcoma physiological processes were further analyzed. Consistently, E2 treatment was observed to promote proliferation, colony formation, migration and invasion in U2OS cells. Taken together, the results indicate a role for E2 in regulating the physiological processes of osteosarcoma cells by regulating MALAT­1 expression levels.