Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome†.

It has been well established that there is a connection between polycystic ovary syndrome pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aß amyloidosis. In this study, the effects of GV-971 on polycystic ovary syndrome-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, and control + GV-971. Glucose metabolism in polycystic ovary syndrome-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of polycystic ovary syndrome-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of polycystic ovary syndrome-like mice were improved. GV-971 restored the fertility of polycystic ovary syndrome-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Impaired decidualization of human endometrial stromal cells from women with adenomyosis†.

Differentiation of endometrial stromal cells (ESCs) into secretory decidualized cells (dESCs) is essential for embryo implantation. Adenomyosis is a common benign gynecological disease that causes infertility. However, whether adenomyosis affects decidualization of human ESCs is elusive. Primary eutopic ESCs were obtained from patients with adenomyosis (n = 9) and women with nonendometrial diseases (n = 12). We determined the capacity of decidualization of human ESCs by qRT-PCR, Edu proliferation assay, cytokine array, and ELISA assay. We found that the expression of decidualization markers (IGFBP1 and PRL) in ESCs of adenomyosis was reduced, concomitant with increased cell proliferation. Differential secretion of cytokines in dESCs, including CXCL1/2/3, IL-6, IL-8, MCP-1, VEGF-A, MIP-3α, OPN, SDF-1α, HGF, and MMP-9, was observed between adenomyosis and nonadenomyosis. Moreover, the expression of decidualization regulators (HOXA10 at both mRNA and protein levels, FOXO1, KLF5, CEBPB, and HAND2 at mRNA levels) in the eutopic endometrium of adenomyosis was lower than that of nonadenomyosis. We propose that ESCs from adenomyosis have defected ability to full decidualization, which may lead to a nonreceptive endometrium.

Scribble downregulation in adenomyosis compromises endometrial stromal decidualization by decreasing FOXO1 expression.

STUDY QUESTION: Does Scribble (SCRIB) contribute to aberrant decidualization of endometrial stromal cells (ESC) in adenomyosis? SUMMARY ANSWER: SCRIB knockdown impairs decidualization of ESC by decreasing Fork-head box O1A (FOXO1) expression through the protein kinase B (AKT) and atypical protein kinase C (aPKC) activated pathways. WHAT IS KNOWN ALREADY: Stromal SCRIB is required for primary decidual zone formation and pregnancy success in mice. In our previous studies, decidualization was dampened in ESC isolated from adenomyosis patients, yet the underlying molecular mechanisms remain elusive. STUDY DESIGN, SIZE, DURATION: Eutopic endometrium tissue samples from diffuse adenomyosis and non-adenomyosis patients in proliferative, early-secretory and mid-secretory phase (n = 10 per phase for each group) were explored. In parallel, in vitro decidualization studies were carried out in ESC isolated from non-adenomyosis women (n = 8). PARTICIPANTS/MATERIALS, SETTING, METHODS: The endometrial SCRIB expression was analyzed using immunohistochemistry staining and western blot. Quantitative RT-PCR (qRT-PCR), western blot and immunofluorescence staining were used to explore the expression of SCRIB in ESC during in vitro decidualization. siRNA-mediated SCRIB knockdown followed by decidual markers expression analysis, flow cytometry for cell cycle analysis and phalloidin staining for morphological analysis were performed to examine the function of SCRIB in ESC decidualization. RNA-sequencing was performed to examine the SCRIB-mediated transcriptional changes in decidualized ESC (DSC). Rescue experiments using an AKT inhibitor MK2206 and aPKC inhibitor NSC37044 were used to investigate the signaling pathways through which could mediate SCRIB-regulated FOXO1 protein expression and ESC decidualization. MAIN RESULTS AND THE ROLE OF CHANCE: We found that the expression of SCRIB in the mid-secretory phase eutopic endometrial stroma of adenomyosis patients was significantly lower than that of non-adenomyosis. SCRIB knockdown reduced the expression of decidual markers, abrogated the epithelioid-like morphological changes, inhibited the mesenchymal-to-epithelial transitions process and promoted the cell cycle progression of ESC during in vitro decidualization. SCRIB knockdown-induced decidualization defects were attributed to a decrease in expression of transcription factor FOXO1, known to regulate decidualization. Furthermore, we found that SCRIB knockdown induced the aberrant activation of AKT and aPKC, which led to FOXO1 phosphorylation and degradation. Rescue assay confirmed that restoring the expression of FOXO1 effectively reversed the decidualization defects and cell cycle progression caused by SCRIB knockdown. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In this study, it was demonstrated that SCRIB knockdown mediated the activation of AKT and aPKC, contributing to FOXO1 degradation and aberrant decidualization, however, the molecular link between AKT and aPKC signaling was not determined, and still requires further exploration. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that adenomyosis interferes with embryo implantation due to insufficient endometrial receptivity. Abnormal decidualization of the endometrial stroma may clarify the possible association between adenomyosis and infertility. Our findings may be clinically useful for counseling and treatment of infertile adenomyosis patients. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82001523 and 82171639). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer.

BACKGROUND: Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. Here, we investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC). METHODS: We characterised TANs using flow cytometric analysis and immunofluorescence analysis. The prognostic merit of TANs in EOC was evaluated using cox regression analysis. Furthermore, we explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment. RESULTS: High level of TANs is associated with a dismal prognosis and immune tolerance in EOC. TANs impaired cytotoxic effects of CD8+ T cells partly through Jagged2 (JAG2). Notch pathway blocked using γ-secretase inhibitor LY3039478 and anti-JAG2 antibody led to retarded tumour growth and augmented cytotoxic effects of CD8+ T cells. IL-8 contributes to the recruitment of TANs and the induction of JAG2 expression in TANs. Blockade of CXCR2 signalling reduces tumour growth rate, accompanied by a decreasing amount of TANs and increasing activity of CD8+ T cells. JAG2+TANs is an independent predictor of clinical outcomes. CONCLUSION: JAG2+TANs are closely linked to IL-8-driven immune evasion microenvironment and may serve as a promising therapeutic target for the reinvigoration of anti-tumour immunity.

Elevated GALNT10 expression identifies immunosuppressive microenvironment and dismal prognosis of patients with high grade serous ovarian cancer.

High grade ovarian serous cancer (HGSC) is a malignant disease with high mortality. Glycosylation plays important roles in tumor invasion and immune evasion, but its effect on the immune microenvironment of HGSC remains unclear. This study examined the association of glycosyltransferase expression with HGSC prognosis and explored the underlying mechanism using clinical specimens and integrated bioinformatic analyses. We identified a cluster of 15 glycogenes associated with reduced overall survival, and GALNT10 was found to be an independent predictor of HGSC prognosis. The high GALNT10 expression was associated with increased regulatory CD4+ T cells infiltration and decreased granzyme B expression in CD8+ T cells. The expression of GALNT10 and its product, Tn antigen, in HGSC specimens was associated with the increased infiltration of M2 macrophages and neutrophils, and the decreased infiltration of CD3+ T cells, NK cells, and B cells. Taken collectively, high GALNT10 expression confers with immunosuppressive microenvironment to promote tumor progression and predicts poor clinical outcomes in HGSC patients.

Estrogen degrades Scribble in endometrial epithelial cells through E3 ubiquitin ligase HECW1 in the development of diffuse adenomyosis†.

Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In previous studies, the protein expression level of the polarity protein Scribble in the eutopic endometrium of patients with adenomyosis was found to be significantly decreased; however, little is known about its regulatory mechanism. In consideration of the important role of supraphysiologic estrogen production in the endometrium in the development of adenomyosis, we analyzed the effect and mechanism of estrogen on the expression of Scribble in vivo and in vitro. Firstly, we found Scribble was downregulated in eutopic endometrium and negatively related with aromatase P450 in tamoxifen-induced adenomyosis. Then, we established a 3D culture of primary endometrial epithelial cells and found that estrogen could disrupt apical-basal polarity of endometrial glandular epithelial cells. Based on the following experiments and GEO dataset screening, we found that estrogen regulates the expression level of Scribble by HECW1 through ubiquitination of Scribble protein. At last, we verified the expression of Scribble, HECW1, and aromatase P450 in eutopic endometrium of human and mouse specimens and found that the expression of HECW1 and aromatase P450 was significantly increased, while the expression of Scribble was significantly downregulated. Furthermore, a positive correlation was found between HECW1 and aromatase P450, while a negative correlation was found between HECW1 and Scribble in human clinical tissue specimens. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis.

Decreased expression of cell polarity protein Scribble correlated with altered subcellular localization of the Crumbs homologue 3 protein in human adenomyotic endometrial cells.

AIM: Previous studies have revealed that loss of cell apical-basal polarity contributed to the early stages of tumorigenesis. Adenomyosis involves a down-growth and aberrant implantation of the endometrial basalis into the myometrium. This study discovered aberrant expression of polarity protein Scribble (Scrib) and Crumbs homologue 3 protein (CRB3) in epithelial cells of diffuse adenomyosis. METHODS: This was a case-controlled study, including 39 patients with histologic evidence of adenomyosis, and 48 patients with carcinoma in situ of the uterine cervix without adenomyosis or endometriosis as control. Adenomyotic foci, eutopic endometrium of adenomyotic patients as well as normal endometrium were collected. Reverse Transcription Polymerase Chain Reaction (RT-PCR), Immunoreactivity, confocal microscopy and immune electron microscopy were conducted to evaluate Scribble expression and localization of Scribble and CRB3. RESULTS: Scrib was screen out as an abnormally expressed polarity protein in adenomyotic eutopic endometrium (ADM-EU) at messenger RNA (mRNA) level. The ADM-EU and adenomyotic ectopic endometrium showed a significantly decreased expression of Scrib compared with normal endometrium (all P-values <0.05). Scrib decreased significantly in ADM-EU than normal endometrium only in patients at proliferative phase and with severe dysmenorrhea (P-values <0.01, P-values <0.001 respectively). In ADM-EU, Scrib expression significantly lowered in patients with severe dysmenorrhea than mild dysmenorrhea (P-values <0.05). Aberrant redistribution of CRB3 from apical to basal lateral membrane portion was also detected in experiments by confocal microscopy immune electron microscopy (all P-values <0.01). CONCLUSION: Basolateral polarity protein Scrib was found decreased significantly in endometrial cells of adenomyosis at mRNA and protein level, compared with normal endometrium. Menstrual phase and severity of dysmenorrhea has an impact on Scrib expression. Scrib decrease was accompanied by aberrant redistribution of CRB3 from apical to basal lateral membrane portion.

Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma.

Deregulated expression of N-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-type O-glycosylation, could produce abnormal truncated O-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry and in situ hybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cells in vitro as well as tumor growth in vivo The wild-type GALNT4 could modify O-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.

Cellular Senescence in the Treatment of Ovarian Cancer.

OBJECTIVE: This review aimed to update the research and development of cellular senescence in the treatment of ovarian cancer. We discussed the current mechanisms of senescence and the major biomarkers of senescence, especially the methods of cellular senescence in the treatment of ovarian cancer. MATERIALS AND METHODS: We collected all relevant studies in PubMed from 1995 to 2017. The search terms included senescence and cancer, senescence and ovarian cancer, senescence-associated secretory phenotype, ovarian cancer and chemotherapy, radiotherapy, or biotherapy. PubMed search with the key words senescence and ovarian cancer lists approximately 85 publications. After excluding the duplicated articles, we selected 68 articles most relevant to senescence and ovarian cancer in this review. RESULTS: Cellular senescence plays a key role in various biological processes of ovarian cancer, which is closely related with the occurrence, development, and treatment of ovarian cancer. Cellular senescence on the one hand can reduce the dose of chemotherapy in ovarian cancer; on the other hand, it also can solve the problem of tumor resistance to apoptosis. Therefore, cellular senescence has been shown to be the third intracellular mechanism of ovarian cancer prevention followed by cellular DNA repair and apoptosis. CONCLUSIONS: In the near future, cellular senescence therapy could be a powerful tool for ovarian cancer treatment.

Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma.

Our previous studies identified the oncogenic role of p21-activated kinase 1 (PAK1) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Contrarily, PAK6 was found to predict a favorable prognosis in RCC patients. Nevertheless, the ambiguous tumor suppressive function of PAK6 in hepatocarcinogenesis remains obscure. Herein, decreased PAK6 expression was found to be associated with tumor node metastasis stage progression and unfavorable overall survival in HCC patients. Additionally, overexpression and silence of PAK6 experiments showed that PAK6 inhibited xenografted tumor growth in vivo, and restricted cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis and anoikis in vitro. Moreover, overexpression of kinase dead and nuclear localization signal deletion mutants of PAK6 experiments indicated the tumor suppressive function of PAK6 was partially dependent on its kinase activity and nuclear translocation. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components, including EZH2, SUZ12, and EED, elucidated epigenetic control of H3K27me3-arbitrated PAK6 down-regulation in hepatoma cells. More importantly, negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis.

Decreased expression of hepatocyte nuclear factor 4α (Hnf4α)/microRNA-122 (miR-122) axis in hepatitis B virus-associated hepatocellular carcinoma enhances potential oncogenic GALNT10 protein activity.

MicroRNA-122 (miR-122), a mammalian liver-specific miRNA, has been reported to play crucial roles in the control of diverse aspects of hepatic function and dysfunction, including viral infection and hepatocarcinogenesis. In this study, we explored the clinical significance, transcriptional regulation, and direct target of miR-122 in hepatitis B virus (HBV)-associated hepatocellular carcinoma. Reduced expression of miR-122 in patients with HBV-associated hepatocellular carcinoma was correlated with venous invasion and poor prognosis. Furthermore, UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-10 (GALNT10) was identified as a bona fide target of miR-122 in hepatoma cells. Ectopic expression and knockdown studies showed that GALNT10 indeed promotes proliferation and apoptosis resistance of hepatoma cells in a glycosyltransferase-dependent manner. Critically, adverse correlation between miR-122 and GALNT10, a poor prognosticator of clinical outcome, was demonstrated in hepatoma patients. Hepatocyte nuclear factor 4α (Hnf4α), a liver-enriched transcription factor that activates miR-122 gene transcription, was suppressed in HBV-infected hepatoma cells. Chromatin immunoprecipitation assay showed significantly reduced association of Hnf4α with the miR-122 promoter in HBV-infected hepatoma cells. Moreover, GALNT10 was found to intensify O-glycosylation following signal activation of the epidermal growth factor receptor. In addition, in a therapeutic perspective, we proved that GALNT10 silencing increases sensitivity to sorafenib and doxorubicin challenge. In summary, our results reveal a novel Hnf4α/miR-122/GALNT10 regulatory pathway that facilitates EGF miR-122 activation and hepatoma growth in HBV-associated hepatocarcinogenesis.

High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma.

Interleukin-11 (IL-11), a member of the IL-6 family of cytokines, exerts pleiotropic oncogenic activities by stimulating angiogenesis and metastasis in many cancer types. The present study aims to evaluate the impact of IL-11 expression on recurrence and mortality of patients with clear-cell renal cell carcinoma (ccRCC). We retrospectively enrolled 193 ccRCC patients undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS) and overall survival (OS) were recorded. IL-11 intensity was assessed by immunohistochemistry in tumor specimens. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. The concordance index (C-index) was calculated to assess predictive accuracy. High IL-11 expression is associated with increased risk of recurrence and poor survival for ccRCC patients (P < 0.001 and P < 0.001, respectively), especially those with early-stage disease (TNM stage I + II). Multivariate analyses confirmed that IL-11 expression was an independent prognostic factor for RFS and OS (P = 0.006 and P = 0.008, respectively). The predictive accuracy of well-established prognostic models was improved when IL-11 expression was integrated. In conclusion, high IL-11 expression is an independent predictor of poor prognosis in ccRCC patients. It may help identify patients who could benefit from additional treatments and closer follow up.

Elevated Expression of N-Acetylgalactosaminyltransferase 10 Predicts Poor Survival and Early Recurrence of Patients with Clear-Cell Renal Cell Carcinoma.

PURPOSE: The aim of this study was to evaluate the potential prognostic significance of N-acetylgalactosaminyltransferase 10 (GALNT10) in patients with clear-cell renal cell carcinoma (ccRCC) after surgical resection. METHODS: We retrospectively enrolled 271 patients (202 in the training cohort and 69 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, overall survival (OS), and recurrence-free survival (RFS) were recorded. GALNT10 intensities were assessed by immunohistochemistry in the specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on OS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. RESULTS: In both cohorts, elevated GALNT10 expression in tumor tissues positively correlated with advanced TNM stage. High GALNT10 expression indicated poor survival and early recurrence of patients with ccRCC, particularly with early-stage disease. After backward elimination, GALNT10 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of TNM, University of California Los Angeles Integrated Staging System, and stage, size, grade, and necrosis prognostic models was improved when GALNT10 expression was added. CONCLUSIONS: GALNT10 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection.

The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients.

Galectin-9 predicts postoperative recurrence and survival of patients with clear-cell renal cell carcinoma.

Galectin-9 (Gal-9), a member of animal lectin family with evolutionary conserved carbohydrate recognition domains, has been reported to exert a large variety of functional roles in tumorigenesis due to its ß-galactoside-binding affinity. The aim of this study is to evaluate the expression and prognostic significance of Gal-9 in patients with clear-cell renal cell carcinoma (ccRCC). The expression of Gal-9 was assessed by immunohistochemistry in 196 patients with ccRCC who underwent nephrectomy. In the cohort, 48 patients died and 61 patients suffered recurrence. Kaplan-Meier method with log-rank test was applied to compare survival curves. The authors employed univariate and multivariate Cox regression models to evaluate the prognostic value of Gal-9 expression in overall survival (OS) and recurrence-free survival (RFS). In patients with ccRCC, Gal-9 expression, which was positively associated with tumor size (P = 0.014), Fuhrman grade (P = 0.010), and necrosis (P = 0.025), was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 2.394; P = 0.005) and RFS (HR 2.096; P = 0.006). High expression of Gal-9 was associated with poor survival (P = 0.001) and early recurrence (P = 0.006). Furthermore, Gal-9 expression could significantly stratify the patients in early (grades I + II) tumor, node, and metastasis (TNM) stage (OS: P = 0.005; RFS: P = 0.041) and low (grades 1 + 2) Fuhrman grade (OS: P = 0.004; RFS: P = 0.006). The prognostic accuracy of TNM, SSIGN, and UISS prognostic models was improved when Gal-9 expression was added. Gal-9 expression is a potential independent prognostic factor for OS and RFS in patients with ccRCC.

Increased expression of colony stimulating factor-1 is a predictor of poor prognosis in patients with clear-cell renal cell carcinoma.

BACKGROUND: This study aims to evaluate the impact of colony stimulating factor-1 (CSF-1) expression on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. METHODS: We retrospectively enrolled 267 patients (195 in the training cohort and 72 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, cancer-specific survival (CSS) and recurrence-free survival (RFS) were recorded. CSF-1 levels were assessed by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on CSS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. RESULTS: In both cohorts, CSF-1 expression positively correlated with advanced Fuhrman grade and necrosis. High CSF-1 expression indicated poor survival and early recurrence of ccRCC patients after surgery, especially those with advanced TNM stage disease. Multivariate Cox regression analysis showed CSF-1 expression was an independent unfavorable prognostic factor for recurrence and survival. The predictive accuracy of the University of California Los Angeles Integrated Staging System (UISS) was significantly improved when CSF-1 expression was incorporated. CONCLUSIONS: High CSF-1 expression is a potential adverse prognostic biomarker for recurrence and survival of ccRCC patients after nephrectomy.

ß1,6-N-acetylglucosaminyltransferase V predicts recurrence and survival of patients with clear-cell renal cell carcinoma after surgical resection.

PURPOSE: ß1,6-N-acetylglucosaminyltransferase V (MGAT5), which is required for the biosynthesis of ß1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins, accounts for oncogenic growth signal transduction during the development and progression of various malignancies. Our present study aimed to evaluate the impact of MGAT5 expression on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. METHODS: We retrospectively enrolled 265 patients (196 in the training cohort and 69 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, overall survival (OS) and recurrence-free survival (RFS) were recorded. MGAT5 intensities were assessed by immunohistochemistry in specimens of patients. Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on OS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. RESULTS: In both cohorts, MGAT5 expression positively correlated with metastatic and advanced TNM stage. High MGAT5 expression indicated poor survival (P < 0.001 in training set and P < 0.001 in validation set) and early recurrence (P < 0.001 in training set and P = 0.004 in validation set) of patients with ccRCC. After multivariate Cox regression analysis, MGAT5 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of TNM, UISS and SSIGN prognostic models was improved when MGAT5 expression was added. CONCLUSIONS: MGAT5 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Prognostic significance of ß1,6-N-acetylglucosaminyltransferase V expression in patients with hepatocellular carcinoma.

OBJECTIVE: Alterations to the N-glycans in glycoproteins have been suggested to play important roles in the proliferation, differentiation, invasion and metastasis of hepatocellular carcinoma (HCC). This study aims to evaluate the potential prognostic value of ß1,6-N-acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma patients after surgical resection. METHODS: We retrospectively enrolled 300 patients (156 in the training cohort and 144 in the validation cohort) with hepatocellular carcinoma undergoing hepatectomy at a single institution. Mgat5 intensities were assessed by immunohistochemistry in the specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on overall survival and recurrence-free survival. The concordance index was calculated to assess predictive accuracy. RESULTS: Intratumoral Mgat5 expression was significantly higher than non-tumoral tissues (P < 0.001). In both cohorts, elevated Mgat5 expression in tumor tissues positively correlated with vascular invasion and advanced tumor-node-metastasis stage. High Mgat5 expression indicated poor survival (P < 0.001 in the training cohort and P < 0.001 in the validation cohort) and recurrence (P < 0.001 in both cohorts, respectively) in patients with hepatocellular carcinoma, particularly with early-stage disease. Mgat5 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of tumor-node-metastasis and Barcelona Clinic Liver Cancer prognostic models was improved when Mgat5 expression was added. CONCLUSION: Mgat5 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with hepatocellular carcinoma after hepatectomy.

Interleukin-11 receptor predicts post-operative clinical outcome in patients with early-stage clear-cell renal cell carcinoma.

OBJECTIVE: To investigate the prognostic value of interleukin-11 receptor α chain in patients with early-stage clear-cell renal cell carcinoma. Interleukin-11 receptor α chain, a member of the gp130-dependent receptors, exerts pleiotropic oncogenic activities by promoting proliferation, angiogenesis and metastasis in many cancers. METHODS: We retrospectively enrolled 293 patients (130 in the training cohort and 163 in the validation cohort) with early-stage (TNM Stage I + II) clear-cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathologic features, recurrence-free survival and overall survival were recorded. Interleukin-11 receptor α chain intensities were assessed by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves between groups. Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival and overall survival. The concordance index was calculated to assess predictive accuracy. RESULTS: In both training and validation cohorts, high interleukin-11 receptor α chain expression was associated with early recurrence (P = 0.004 and P = 0.015, respectively) and poor survival (P < 0.001 and P = 0.019, respectively) of patients with early-stage clear-cell renal cell carcinoma. Multivariate analyses confirmed that interleukin-11 receptor α chain expression was an independent prognostic factor for recurrence-free survival (P = 0.004) and overall survival (P = 0.001). The predictive accuracy of the Leibovich prognostic score was improved when interleukin-11 receptor α chain expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score. CONCLUSION: High Interleukin-11 receptor α chain expression is an independent predictor of poor clinical outcome in patients with early-stage clear-cell renal cell carcinoma, and the prognostic value is more prominent in those with low-risk disease.

Tumor miR-125b predicts recurrence and survival of patients with clear-cell renal cell carcinoma after surgical resection.

The present study aims to evaluate the impact of tumor microRNA-125b (miR-125b) on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. We retrospectively enrolled 276 patients (200 in the training cohort and 76 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, cancer-specific survival (CSS) and recurrence-free survival (RFS) were recorded. Tumor miR-125b levels were assessed by in situ hybridization (ISH) in specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on CSS and RFS. A concordance index (C-index) was calculated to assess predictive accuracy. In both cohorts, tumor miR-125b positively correlated with Fuhrman grade. High tumor miR-125b indicated poor survival and early recurrence for patients with ccRCC, especially with advanced stage disease. After multivariable adjustment, tumor miR-125b was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of traditional TNM and UCLA Integrated Staging System prognostic models was improved when tumor miR-125b was added. The results showed that tumor miR-125b is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.