Selected markers of ovarian cancer and their relation to targeted therapy (Review).

Despite advances in surgical treatment techniques and chemotherapy-including anti-angiogenic and immune poly (ADP-ribose) polymerase inhibitors, the 5-year survival rate in ovarian cancer (OC) remains low. The reasons for this are the diagnosis of cancer in advanced clinical stages, chemoresistance and cancer recurrence. New therapeutic approaches are being developed, including the search for new biomarkers that are also targets for targeted therapy. The present review describes new molecular markers with relevance to targeted therapy, which to date have been studied only in experimental research. These include the angiogenic protein angiopoietin-2, the transmembrane glycoprotein ectonucleotide pyrophosphatase/phosphodiesterase 1, the adhesion protein E-cadherin, the TIMP metallopeptidase inhibitor 1 and Kruppel-like factor 7. Drugs affecting cancer stem cells (CSCs) in OC, such as metformin and salinomycin, as well as inhibitors of CSCs markers aldehyde dehydrogenase 1 (with the drug ATRA) and the transcription factor Nanog homeobox (microRNA) are also discussed. A new approach to prevention and possible therapies under investigation such as development of vaccines containing a subpopulation of CD117(+) and CD44(+) stem cells with a promising option for use in women with OC was described.

Roles of endothelial cell specific molecule­1 in tumor angiogenesis (Review).

Angiogenesis plays a crucial role in tumor growth and metastasis, and is heavily influenced by the tumor microenvironment (TME). Endothelial cell dysfunction is a key factor in tumor angiogenesis and is characterized by the aberrant expression of pro-angiogenic factors. Endothelial cell specific molecule-1 (ESM1), also known as endocan, is a marker of endothelial cell dysfunction. Although ESM1 is primarily expressed in normal endothelial cells, dysregulated ESM1 expression has been observed in human tumors and animal tumor models, and implicated in tumor growth, metastasis and angiogenesis. The precise role of ESM1 in tumor angiogenesis and its potential regulatory mechanisms are not yet conclusively defined. However, the aim of the present review was to explore the involvement of ESM1 in the process of tumor angiogenesis in the TME and the characteristics of neovascularization. In addition, the present review discusses the interaction between ESM1 and angiogenic factors, as well as the mechanisms through which ESM1 contributes to tumor angiogenesis. Furthermore, the reciprocal regulation between ESM1 and the TME is explored. Finally, the potential of targeting ESM1 as a therapeutic strategy for tumor angiogenesis is presented.

Systematic Review of Endocan as a Potential Biomarker of COVID-19.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, several biomarkers have been proposed to assess the diagnosis and prognosis of this disease. The present systematic review evaluated endocan (a marker of endothelial cell damage) as a potential diagnostic and prognostic biomarker for COVID-19. PubMed, Scopus, Web of Science, and Embase were searched for studies comparing circulating endocan levels between COVID-19 cases and controls, and/or different severities/complications of COVID-19. Eight studies (686 individuals) were included, from which four reported significantly higher levels of endocan in COVID-19 cases compared with healthy controls. More severe disease was also associated with higher endocan levels in some of the studies. Studies reported higher endocan levels in patients who died from COVID-19, were admitted to an intensive care unit, and had COVID-19-related complications. Endocan also acted as a diagnostic and prognostic biomarker with different cut-offs. In conclusion, endocan could be a novel diagnostic and prognostic biomarker for COVID-19. Further studies with larger sample sizes are warranted to evaluate this role of endocan.

Intermittent hypoxia increased the expression of ESM1 and ICAM-1 in vascular endothelial cells via the downregulation of microRNA-181a1.

Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation-related transcripts in vascular endothelial cells (human HUEhT-1 and mouse UV2) exposed to IH by real-time RT-PCR and found that intercellular adhesion molecule-1 (ICAM-1) and endothelial cell-specific molecule-1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM-1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM-1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)-181a1 in IH-treated cells. The introduction of miR-181a1 mimic but not miR-181a1 mimic NC abolished the IH-induced upregulation of Ican-1 and ESM1. These results indicated that ICAM-1 and ESM1 were upregulated by IH via the IH-induced downregulation of miR-181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH-induced upregulation of ICAM-1 and ESM1.

Endocan as a marker of endothelial dysfunction in hypertension: a systematic review and meta-analysis.

Hypertension is one of the foremost risk factors for cardiovascular disease and a significant cause of death worldwide. Importantly, endothelial dysfunction (ED) is one of the primary manifestations that may precede the development of hypertension. Endocan is a novel endothelial dysfunction and inflammation biomarker secreted from endothelial cells. Whether endocan may serve as a biomarker of hypertension is currently debated. This systematic review and meta-analysis aimed at linking endocan to ED in hypertensive patients. International databases, including PubMed, Scopus, Embase, and Web of Science, were systematically searched for studies investigating Endocan serum or plasma levels in hypertensive patients and healthy controls. Random effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI). A total of 20 studies assessing the association between endocan levels and hypertension were included in which 3130 individuals with a mean age of 50.48 ± 8.45 years were assessed. Hypertensive patients presented with higher circulating endocan levels (SMD 0.91, 95% CI 0.44-1.38, p-value < 0.01) compared with healthy controls. Interestingly, our data demonstrated that removing three studies assessing endocan levels in hypertensive patients with different comorbidities or special populations resulted in the same statistically higher endocan levels (SMD 1.16, 95% CI 0.66-1.65, p-value < 0.01). Overall, this systematic review and meta-analysis indicated that in hypertensive patients circulating endocan levels are significantly elevated. Thus, suggesting endocan as an easy-to-use biomarker to detect ED in hypertension. Despite this, more research is warranted to address this potential ability specifically.

Impact of N-terminal pro-B-type natriuretic peptide and related inflammatory biomarkers on periodontal treatment outcomes in patients with periodontitis: An explorative human randomized-controlled clinical trial.

BACKGROUND: N-terminal portion of the B-type natriuretic propeptide (NT-proBNP) has potentially been shown to play an important role in the development of periodontitis and cardiovascular disease (CVD). This study evaluated the efficacy of periodontal treatment on NT-proBNP and related CVD biomarkers and explored whether subjects harboring high NT-proBNP at baseline showed increased clinical benefits with the non-surgical periodontal treatment performed with full-mouth scaling and root planing (FM-SRP) at 6-month follow-up. METHODS: Forty-eight patients with stage III periodontitis were randomized to receive minimal standard oral care (SOC) (n = 24) or FM-SRP (n = 24) protocol. Clinical periodontal parameters (probing depth, clinical attachment loss, bleeding on probing), serum NT-proBNP, α1-antitrypsin, C-reactive protein (hs-CRP), endothelial cell-specific molecule-1 (ECM-1), and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed at baseline and at 1-, 3-, and 6- month follow-up. RESULTS: At 6 months, FM-SRP was more effective than SOC in reducing periodontal parameters and mean proportions of NT-proBNP (p = 0.004), hs-CRP (p = 0.003), α1-antitrypsin (p = 0.012), ECM-1 (p = 0.014), and NGAL (p = 0.045). At 6-month follow-up, the reduced NT-proBNP, α1-antitrypsin, hs-CRP, ECM-1, and NGAL levels were significantly correlated with the extent of periodontitis (p < 0.05). Furthermore, the analysis of variance analysis evidenced that, at 6-month follow-up, FM-SRP significantly impacted the reduction of NT-proBNP, hs-CRP, ECM-1, and NGAL. Moreover, high levels of NT-proBNP, hs-CRP, ECM-1, and NGAL at baseline significantly influenced the efficacy of periodontal treatment positively. CONCLUSION: In this study, FM-SRP was more effective than SOC in reducing clinical variables and NT-proBNP levels, although subjects who harbored high NT-proBNP concentrations at baseline showed greater clinical benefits of periodontal treatment at 6-month follow-up.

Endocan: A novel biomarker of endothelial dysfunction in depression?

Endocan is a proteoglycan secreted from endothelium upon endothelial damage. Since depression is associated with higher inflammation and oxidative stress to the vascular endothelium, endothelial dysfunction is prevalent and it is one of the responsible mechanisms for increased cardiovascular morbidity and mortality in depressive disorders. This study aimed to investigate endocan levels in patients with depression (either bipolar or unipolar) and healthy controls to evaluate the projected endothelial injury. We included nonsmoker patients without comorbid inflammatory conditions: 31 with Bipolar Disorder Depression (BDD), 30 with Major Depressive Disorder (MDD) and 25 healthy controls (HC). The severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS). Ultimately, serum endocan levels were significantly higher in patients with BDD than in patients with MDD (p < .000) and HCs (p < .000). Also, patients with MDD had significantly higher endocan levels than HCs (p < .000). The AUC value for the endocan to differentiate patients with depression from controls was 0.990 (95% CI: 0.971-1.000; p < .001) with sensitivity and specificity of 98.4 and 100%, respectively, and an optimal cut-off value of 316.92 ng/L. Serum endocan levels showed a mild positive correlation with HDRS scores (r = 0.372, p = .039) in the BDD group but not in the MDD group (r = -0.242, p = .20). Patients with BDD had higher endocan levels than MDD; this finding, while preliminary, could be an implication of higher endothelial dysfunction in BDD.

Prognostic role of the endothelial cell-specific molecule-1 histopathologic expression in renal cell cancer.

INTRODUCTION: To measure the level of endothelial cell-specific molecule-1 (ESM-1) expression among the Renal Cell Cancer (RCC) variants using by immunohistochemical method and determine the relationship between ESM-1 expression and RCC prognosis. MATERIALS AND METHODS: ESM-1 immunoreactivity scores (IR) were measured in appropriate renal tumoral tissue blocks of 153 consecutive RCC patients in this retrospective analysis of prospectively collected data. Mean ESM-1 IR scores were calculated in patients who were pathologically diagnosed with clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). Progression-free survival and overall survival were evaluated using the log-rank test according to ESM-1 IR scores. Survival rates were calculated using Kaplan-Meier survival analysis. RESULTS: In the ccRCC group, the mean ESM-1 IR scores of those with local invasion were significantly higher than those without local invasion (P = 0.014). The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). Considering all patients regardless of RCC subtype pathologies, the mean ESM-1 IR score in clinical stage 1 tumor was 3.82 ± 1.98, 4.87 ± 1.74 in clinical stage 2, 5.88 ± 2 in clinical stage 3, and 6.60 ± 2.23 in clinical stage 4. The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). The mean follow-up period for all patients in this study was 71 months (range 1-120 months). It has been shown that the higher the ESM-1 IR score, the lower the 10-year overall survival and disease-free survival rates (P = 0.026, P = 0.005). CONCLUSION: Immunohistochemical expression of ESM-1 may be a promising prognostic biomarker in RCC. Currently, some prognostic scoring systems are available for patients with localized and metastasized RCC. Incorporating ESM-1 expression in RCC into these existing prognostic scoring systems could improve these models and enhance the quality of individual oncologic management in RCC patients.

Values of serum human epididymis protein 4, endothelial cell specific molecule-1 and epidermal growth factor receptor in the diagnosis of lung cancer / 肿瘤研究与临床

Objective:To investigate the diagnostic values of human epididymis protein 4 (HE4), endothelial cell specific molecule-1 (ESM-1) and epidermal growth factor receptor (EGFR) for lung cancer.Methods:The clinical data of 90 patients with lung cancer and 50 patients with benign lung diseases diagnosed by the pathological examination in Tangshan People's Hospital from December 2019 to January 2021 were retrospectively analyzed, and 40 healthy physical examiners in the same period were selected as the controls. The serum HE4 levels were detected by electrochemiluminescence method. The serum ESM-1 and EGFR levels were tested by enzyme-linked immunosorbent assay. The differences in serum HE4, ESM-1 and EGFR levels between the three groups were compared; logistic regression analysis was used to screen out the effective indicators for the diagnosis of lung cancer and to construct a prediction model for the diagnosis of lung cancer. Using pathological diagnosis result as the gold standard, the receiver operating characteristic (ROC) curve was drawn, and the diagnostic efficacy of indicators for lung cancer was evaluated.Results:The levels of serum HE4 in lung cancer group, benign lung diseases group and healthy control group were 119.55 pmol/L (82.06 pmol/L, 189.00 pmol/L), 58.84 pmol/L (45.62 pmol/L, 69.41 pmol/L) and 42.67 pmol/L (37.09 pmol/L, 51.84 pmol/L), the levels of ESM-1 were 33.00 ng/ml (25.85 ng/ml, 47.40 ng/ml), 20.14 ng/ml (11.93 ng/ml, 28.90 ng/ml) and 15.39 ng/ml (11.84 ng/ml, 20.19 ng/ml), and the levels of EGFR were 46.60 pg/ml (37.45 pg/ml, 58.98 pg/ml), 32.77 pg/ml (26.27 pg/ml, 40.86 pg/ml) and 30.43 pg/ml (27.54 pg/ml, 35.75 pg/ml), and the differences in each indicator among the three groups were statistically significant (all P < 0.001). The levels of serum HE4, ESM-1 and EGFR in lung cancer group were higher than those in benign lung diseases group and healthy control group. In patients with lung cancer, logistic regression analysis was performed with HE4 (X 1), ESM-1 (X 2) and EGFR (X 3) as the independent variables and pathological diagnosis as the dependent variable, and a lung cancer prediction regression model was established: P = 0.171X 1+0.351X 2+0.184X 3-24.660. The accuracy of this model in predicting lung cancer could reach 98.5%, and serum HE4, ESM-1 and EGFR were risk factors for the occurrence of lung cancer (all P < 0.05). The area under ROC curve from high to low was HE4 (0.960), ESM-1 (0.942) and EGFR (0.859). The diagnostic sensitivity of serum HE4 63.67 pmol/L for lung cancer was 86.7%, and the specificity was 97.5%. Both serum HE4 ( r = 0.304, P = 0.004) and ESM-1 ( r = 0.416, P < 0.001) were correlated with EGFR. Conclusions:Serum HE4, ESM-1 and EGFR can be used as effective indicators for the diagnosis of lung cancer, and the prediction model established based on the three serum tumor markers is of good value for the diagnosis and prediction of lung cancer.

Severe Intrahepatic Cholestasis Pregnancy Is Associated With Maternal Endothelial Dysfunction: A Case-Control Study.

OBJECTIVE: The aim of the present study was to evaluate maternal serum endocan levels, which are markers of vascular pathologies and strongly associated with vascular inflammation and endothelial dysfunction, in pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP). METHODS: The study comprised 30 pregnant women with mild ICP, 30 pregnant women with severe ICP, and 30 healthy pregnant women as a control group. The inclusion criteria were women with ICP, which was diagnosed based upon the presence of pruritus associated with elevated total bile acid (TBA) levels (> 10 µm/L), elevated aminotransferases, or both, and the absence of diseases that may produce similar laboratory findings and symptoms. Severe ICP was defined as TBA > 40 µmol/L. After diagnosis for ICP, blood samples were obtained before medication during hospitalization to analyze maternal serum endocan levels. RESULTS: Gestational age at delivery, delivery induction rates, birth weight, and newborn intensive care unit (NICU) admission rates were significantly higher in the severe ICP group than in the control group and mild ICP group. Gestational age for all groups when blood was sampled was similar. Maternal serum TBAs and aminotransferase levels were significantly higher in the severe ICP group than in the control group and mild ICP group. The mean serum endocan levels were 10.9 ± 2.6 ng/mL in the control group, 12.5 ± 2.8 ng/mL in the mild ICP group, and 24.3 ± 4.8 ng/mL in the severe ICP group (p < 0.001). CONCLUSION: Our results indicated that maternal serum endocan levels were increased in the presence of severe ICP and it can be speculated that increased bile acid levels were associated with maternal endothelial dysfunction.

Endothelial-Specific Molecule 1 Inhibition Lessens Productive Angiogenesis and Tumor Metastasis to Overcome Bevacizumab Resistance.

The development of drug resistance in malignant tumors leads to disease progression, creating a bottleneck in treatment. Bevacizumab is widely used clinically, and acts by inhibiting angiogenesis to "starve" tumors. Continuous treatment can readily induce rebound proliferation of tumor blood vessels, leading to drug resistance. Previously, we found that the fragment crystallizable (Fc) region of bevacizumab cooperates with the Toll-like receptor-4 (TLR4) ligand to induce M2b polarization in macrophages and secrete tumor necrosis factor-α (TNFα), which promotes immunosuppression, tumor metastasis, and angiogenesis. However, the downstream mechanism underlying TNFα-mediated bevacizumab resistance requires further investigation. Our RNA-Seq analysis results revealed that the expression of endothelial cell specific molecule-1 (ESM1) increased significantly in drug-resistant tumors and promoted metastasis and angiogenesis in vitro and in vivo. Furthermore, TNFα induced the upregulation of ESM1, which promotes metastasis and angiogenesis and regulates matrix metalloprotease-9 (MMP9), vascular endothelial growth factor (VEGF), and delta-like ligand-4 molecules (DLL4). Accordingly, the curative effect of bevacizumab improved by neutralizing ESM1 with high-affinity anti-ESM1 monoclonal antibody 1-2B7 in bevacizumab-resistant mice. This study provides important insights regarding the molecular mechanism by which TNFα-induced ESM1 expression promotes angiogenesis, which is significant for elucidating the mechanism of bevacizumab drug resistance and possibly identifying appropriate biosimilar molecules.

The effects of Anisodamine-Tirofiban Combined Therapy in acute myocardial infarction treated with Percutaneous Coronary Intervention (PCI).

Objectives: To study the effects of anisodamine-tirofiban combined therapy on cardiac function and serological expression of serum NGF and ESM-1 in patients with acute myocardial infarction treated with percutaneous coronary intervention (PCI). Methods: Eighty patients with myocardial infarction treated in Cangzhou Medical College, Hebei, China from February 2015 to April 2017 were selected and divided into the control group and the research group according to the principle of random draw, 40 patients per group. The patients in the control group received symptomatic routine treatment, while the patients in the research group received anisodamine-tirofiban combined therapy on the top of symptomatic routine treatment. Differences between the two groups in TIMI flow grades, cardiac function, levels of NGF and ESM-1 and adverse response were observed. Results: The recovery of cardiac function in the research group was statistically significant with P value (p<0.05) and better than the control group in TIMI flow grades, myocardial perfusion capacity and cardiac function. The serological indicators in the research group had a higher level of NGF and a lower level of ESM-1 than the control group, and the differences were statistically significant (p<0.05). In terms of safety, neither group showed significant hepatorenal disorders. Conclusion: The combined treatment of anisodamine-tirofiban in patients with acute myocardial infarction after percutaneous coronary intervention (PCI) can recover NGF and ESM-1 related proteins, improve postoperative myocardial perfusion, and accelerate the recovery of cardiac function. It is worth promoting in clinic.

Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer.

We aimed to study the function and mechanism of endothelial cell-specific molecule 1 (ESM1) in endometrial cancer (EC). The binding relationship between SPI1 and ESM1 was predicted by bioinformatics analysis and verified by the dual-luciferase reporter assay. The expressions and effects of SPI1 and ESM1 were determined using quantitative real-time PCR, immunohistochemistry, Western blot, and functional experiments. ESM1 was highly expressed in EC and was associated with the poor prognosis of patients. ESM1 silencing suppressed the viability, proliferation, invasion, and angiogenesis of EC cells, down-regulated expressions of PCNA, N-cadherin, Vimentin, VEGFR-1, VEGFR2, and EGFR, but upregulated E-cadherin level, while ESM1 overexpression did oppositely. Moreover, SPI1 bound to ESM1. Overexpressed SPI1 promoted the expression of ESM1 and induced malignant phenotype (viability, proliferation, and invasion), which were countervailed by ESM1 silencing. Collectively, ESM1 induced by SPI1 promotes the malignant phenotype of EC.

Significance of Endocan Expression in Various Types of Epithelial Ovarian Tumors.

Background & Objective: Ovarian cancer is associated with the highest mortality rate among gynecologic malignancies. Despite new therapeutic strategies, ovarian cancer still has a high risk of metastasis and mortality. Endocan is a newly identified endothelial cell activation marker, which is responsible for angiogenesis, tumor invasion, and aggressive behavior of tumors. The aim of this study was to assess Endocan expression in different types of ovarian tumors and to identify its relationship with clinicopathologic characteristics of ovarian tumors. Methods: This cross-sectional study was conducted on 183 tissue samples, including benign, borderline, and malignant ovarian tumors collected from the University Kebangsaan Malaysia Medical Center archive of Pathology during 2005-2015. Mouse monoclonal anti-human Endocan/ESM-1 Clone MEP08 was used at a dilution of 1:400 for immunohistochemical (IHC) staining. All the information was collected by a checklist, and the association between clinicopathological features and high or low levels of Endocan -MVD was evaluated using Pearson chi-square, Fischer's exact, or Monte Carlo tests. Results: The prevalence of Endocan positivity was significantly higher in malignant compared to borderline and benign ovarian tumors (P<0.001). There was also a significant association between type of tumor and Endocan status in malignant ovarian tumors (P=0.02), indicating that Endocan positivity was more likely in serous malignant ovarian tumors compared to other ovarian tumor types. However, the tumor stage was not significantly associated with Endocan status (P=0.31). Conclusion: This study showed that Endocan positivity may show the highest prevalence among malignant tumors suggesting that high Endocan expression would be negatively associated with ovarian tumor behavior.

Targeting Endothelial Cell-Specific Molecule 1 Protein in Cancer: A Promising Therapeutic Approach.

Despite the dramatic advances in cancer research in the past few years, effective therapeutic strategies are urgently needed. Endothelial cell-specific molecule 1 (ESM-1), a soluble dermatan sulfate proteoglycan, also known as endocan, serves as a diagnostic and prognostic indicator due to its aberrant expression under pathological conditions, including cancer, sepsis, kidney diseases, and cardiovascular disease. Significantly, ESM-1 can promote cancer progression and metastasis through the regulation of tumor cell proliferation, migration, invasion, and drug resistant. In addition, ESM-1 is involved in the tumor microenvironment, containing inflammation, angiogenesis, and lymph angiogenesis. This article reviews the molecular and biological characteristics of ESM-1 in cancer, the underlying mechanisms, the currently clinical and pre-clinical applications, and potential therapeutic strategies. Herein, we propose that ESM-1 is a new therapeutic target for cancer therapy.

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer that tests negative for PR, ER and excess HER2 protein. TNBC has a greater progression potential with poorer prognosis, compared with other types of breast cancer. Endothelial cell-specific molecule 1 (ESM1), also known as endocan, is overexpressed in various cancers including breast cancer and may play an important role in cancer progression. METHODS: The online resource of The Cancer Genome Atlas (TCGA) was used for analyzing the expression alteration of ESM1 in breast cancer patient tissues. We examined the changes of various malignant behaviors of TNBC cell and in vivo tumor growth after inhibiting or overexpressing ESM1 in two human TNBC cell lines, MDA-MB-468 and MDA-MB-231. When ESM1 was knocked down or overexpressed in TNBC cell, AKT and p65 phosphorylation and Cyclin D1 expression were analyzed by western blotting. The ESM1-overexpressing TNBC cell was treated with MK-2206 and BAY-117082 at various concentrations. RESULTS: Our analyses show that ESM1 is overexpressed in TNBC cell lines as well as patient tissues, which is correlated to poor prognosis. Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro proliferation, migration and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo TNBC tumor growth. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating an Akt-dependent NF-κB/Cyclin D1 pathway. CONCLUSIONS: Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro migration, proliferation and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo tumor growth of TNBC in the xenograft mouse model. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating the Akt-dependent NF-κB/CyclinD1 pathway. Our findings expand the knowledge about the molecular mechanisms underlying TNBC progression and provide rationale for using ESM1 as a therapeutic target or prognostic marker for TNBC.

Silenced lncRNA SNHG14 restrains the biological behaviors of bladder cancer cells via regulating microRNA-211-3p/ESM1 axis.

BACKGROUND: Bladder cancer (BCa) is a malignant tumor that occurs on the mucosa of the bladder, in which dysregulated long non-coding RNAs (lncRNAs) are involved. This study investigated the effect of lncRNA small nucleolar RNA host gene 1 (SNHG14) on the biological characteristics of BCa cells from microRNA (miR)-211-3p/ESM1 signaling axis. METHODS: BCa tissues and the matched normal tissues were collected to test SNHG14, miR-211-3p and ESM1 levels. SNHG14, miR-211-3p and ESM1 levels in BCa cell lines (T24, 5637, UMUC-3 and EJ) and normal bladder epithelial cells SV-HVC-1 were detected for screening the cell lines for follow-up experiments. T24 and UMUC-3 cells were transfected with different plasmids of SNHG14, miR-211-3p or ESM1 to observe the biological characteristics of BCa cells by MTT, colony formation, Transwell assays and flow cytometry. Tumor xenograft was implemented to inspect tumor growth in vivo. The targeting relationships of SNHG14, miR-211-3p and ESM1 were verified by bioinformatics software, RNA pull down assay and luciferase reporter assay. RESULTS: Enhanced SNHG14, ESM1 and suppressed miR-211-3p were found in BCa tissues and cells. SNHG14 up-regulated ESM1 via competitive binding with miR-211-3p. Decreased SNHG14 or up-regulated miR-211-3p depressed cell cycle entry, colony formation, invasion, migration and proliferation abilities, and facilitated apoptosis of BCa cells. Decreased SNHG14 or up-regulated miR-211-3p reduced the tumor volume and weight of nude mice with BCa, as well as promoted apoptosis and restrained proliferation of tumor cells. miR-211-3p inhibition or ESM1 overexpression reversed the effects of down-regulation of SNHG14 on BCa, and miR-211-3p up-regulation or ESM1 downregulation reversed the effect of SNHG14 overexpression on BCa. SNHG14 targeted miR-211-3p to regulate ESM1 expression. CONCLUSION: Our study highlights that silenced SNHG14 or elevated miR-211-3p represses the tumorigenic ability of BCa cells, which may be linked to ESM1 knockdown.

Endocan as a potential biomarker of disease severity and exacerbations in COPD.

INTRODUCTION: Endocan is a proteoglycan that is regarded as a novel marker of endothelial dysfunction. Endothelial dysfunction in pulmonary vascular bed is known to play an important role for the pathogenesis of COPD. OBJECTIVE: This study aimed to determine serum endocan levels in patients with stable COPD and acute exacerbation of COPD (AECOPD) and to test the relationship between serum endocan levels and exacerbations. METHODS: This study enrolled a total of 55 COPD patients, 24 of which had AECOPD and 31 had stable COPD. All patients' basic demographic and clinical data were recorded and blood samples were collected. RESULTS: Serum endocan levels were significantly higher in the AECOPD group compared to the stable COPD and control groups (for both p < 0.001) and stable COPD group had higher levels than the control group (p < 0.005). Additionally, serum endocan levels were negatively correlated with FVC, FEV1, partial oxygen pressure and oxygen saturation (r = -0.30, p = 0.03; r = -0.34, p = 0.01; r = -0.34, p = 0.01 and r = -0.36, p = 0.007 respectively), and positively correlated with disease duration and systolic pulmonary artery pressure (r = 0.47, p < 0.001; r = 0.31, p = 0.02 respectively). A cut-off value of 434.29 pg/ml for endocan predicted exacerbation with a sensitivity of 79% and a specificity of 84% (AUC: 0.778, 95% Cl 0.648-0.909; p < 0.001). Logistic regression analysis revealed that increased endocan levels was independent predictor of COPD exacerbation (OR = 9.32, 95%CI, 1.64-52.95; p = 0.01). CONCLUSION: Endocan may be a novel biomarker for detection of endothelial dysfunction and prediction of exacerbations in patients with COPD.

Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer.

BACKGROUND: Recent studies highlight the crucial role of endothelial cell-specific molecule 1 (ESM1) in the development of multiple cancer types. However, its aberrant expression and prognostic value in human pan-cancer have largely not been described. METHODS AND RESULTS: In this study, we used The Cancer Genome Atlas (TCGA) analysis databases to explore the expression level and prognostic significance of ESM1 in 33 types of human cancer. ESM1 was shown to be over-expressed in 12 cancer types, including BLCA, BRCA, COAD, CHOL, ESCA, HNSC, KIRC, KICH, LIHC, STAD, THCA, and UCEC. The expression of ESM1 was significantly correlated with the overall survival (OS) of patients in CESC, ESCA, KIRC, and KIRP. In addition, high ESM1 level indicated poor disease-free survival (DFS) of patients with ACC, ESCA, PRAD, LIHC, KIRP, and UCS. Through comparative analysis, we discovered that ESM1 was dramatically up-regulated in esophageal cancer (ESCA) and associated with worse patient OS and DFS. The elevation of ESM1 in ESCA was confirmed by the datasets from Cancer RNA-Seq Nexus (CRN) and Gene Expression Omnibus (GEO). Based on Gene Set Enrichment Analysis (GSEA), we analyzed the co-expressed genes of ESM1 in ESCA, and found that ESM1 was closely implicated in cell proliferation and migration and the regulation of Janus kinase (JAK) signaling pathway. Functionally, knockdown of ESM1 significantly suppressed cell proliferation and migration, and decreased the protein level of JAK1. CONCLUSIONS: Taken together, our results suggest for the first time that ESM1 functions as an oncogene and may be a clinical biomarker and/or therapeutic target in ESCA.

Endothelial Cell-Specific Molecule 1 Promotes Endothelial to Mesenchymal Transition in Renal Fibrosis.

The endothelial-to-mesenchymal transition (EndoMT) is involved in the complex pathogenesis of renal fibrosis. The soluble proteoglycan endothelial cell-specific molecule 1 (ESM1) is significantly upregulated in many tumor cells and cirrhosis-related disease. The role of ESM1 in renal fibrosis is unknown. This study investigates the role of ESM1 in renal fibrosis, using an in vivo unilateral ureteral obstruction (UUO) mouse model of renal fibrosis and in vitro mouse kidney MES 13 cells overexpressing ESM1. We observed that ESM1 overexpression significantly increased the motility and migration of MES 13 cells, independent of cell viability. In ESM1-overexpressing MES 13 cells, we also observed elevated expression of mesenchymal markers (N-cadherin, vimentin, matrix metallopeptidase 9 (MMP9)) and the fibrosis marker α-smooth muscle actin (α-SMA) and decreased expression of the endothelial marker vascular endothelial cadherin (VE-cadherin) and CD31. In a mouse model of fibrosis induced by unilateral ureter obstruction, we observed time-dependent increases in ESM1, α-SMA, and vimentin expression and renal interstitial collagen fibers in kidney tissue samples. These results suggest that ESM1 may serve as an EndoMT marker of renal fibrosis progression.