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Abstract Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I–III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-017-0615-x.

Abstract Background Even though aberrant expression of microRNA (miR)-30d has been reported in prostate cancer (PCa), its associations with cancer progression remain contradictory. The aim of this study was to investigate clinical significance, biological functions and underlying mechanisms of miR-30d deregulation in PCa. Methods Involvement of miR-30d deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor angiogenesis were determined. Results miR-30d over-expression was observed in both PCa cells and clinical specimens. High-miR-30d was distinctly associated with high pre-operative PSA and Gleason score, advanced clinical and pathological stages, positive metastasis and biochemical recurrence (BCR), and reduced overall survival of PCa patients. Through gain- and loss-of-function experiments, we found that miR-30d promoted PCa cell proliferation, migration, invasion, and capillary tube formation of endothelial cells, as well as in vivo tumor growth and angiogenesis in a mouse model. Simulation of myosin phosphatase targeting subunit 1 (MYPT1), acting as a direct target of miR-30d, antagonized the effects induced by miR-30d up-regulation in PCa cells. Notably, miR-30d/MYPT1 combination was identified as an independent factor to predict BCR of PCa patients. Furthermore, miR-30d exerted its pro-angiogenesis function, at least in part, by inhibiting MYPT1, which in turn, increased phosphorylation levels of c-JUN and activated VEGFA-induced signaling cascade in endothelial cells. Conclusions miR-30d and/or its target gene MYPT1 may serve as novel prognostic markers of PCa. miR-30d promotes tumor angiogenesis of PCa through MYPT1/c-JUN/VEGFA pathway.

After publication of the article [1], the author reported that this article contained some errors.

Early diagnosis of prostate cancer (PCa), which is a clinically heterogeneous-multifocal disease, is essential to improve the prognosis of patients. However, published PCa diagnostic markers share little overlap and are poorly validated using independent data. Therefore, we here developed an integrative proteomics and interaction network-based classifier by combining the differential protein expression with topological features of human protein interaction networks to enhance the ability of PCa diagnosis.By two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MS using PCa and adjacent benign tissues of prostate, a total of 60 proteins with the differential expression in PCa tissues were identified as the candidate markers. Then, their networks were analyzed by GeneGO Meta-Core software and three hub proteins (PTEN, SFPQ and HDAC1) were chosen. After that, a PCa diagnostic classifier was constructed by support vector machine (SVM) modeling based on the microarray gene expression data of the genes which encode the hub proteins mentioned above. Validations of diagnostic performance showed that this classifier had high predictive accuracy (85.96∼90.18%) and area under ROC curve (approximating 1.0). Furthermore, the clinical significance of PTEN, SFPQ and HDAC1 proteins in PCa was validated by both ELISA and immunohistochemistry analyses. More interestingly, PTEN protein was identified as an independent prognostic marker for biochemical recurrence-free survival in PCa patients according to the multivariate analysis by Cox Regression.Our data indicated that the integrative proteomics and interaction network-based classifier which combines the differential protein expression and topological features of human protein interaction network may be a powerful tool for the diagnosis of PCa. We also identified PTEN protein as a novel prognostic marker for biochemical recurrence-free survival in PCa patients.

Background: Prostate cancer (PCa) is the most common malignancy seen in men and the second leading cause of cancerrelated death in males. The incidence and mortality associated with PCa has been rapidly increasing in China recently. Methods: Multiple diagnostic models of human PCa were developed based on Taylor database by combining the artificial neural networks (ANNs) to enhance the ability of PCa diagnosis. Genetic algorithm (GA) is used to select feature genes as numerical encoded parameters that reflect cancer, metastatic, or normal samples. Back propagation (BP) neural network and learning vector quantization (LVQ) neural network were used to build different Cancer/Normal, Primary/Metastatic, and Gleason Grade diagnostic models. Results: The performance of these modeling approaches was evaluated by predictive accuracy (ACC) and area under the receiver operating characteristic curve (AUC). By observing the statistically significant parameters of the three training sets, our Cancer/ Normal, Primary/Metastatic, and Gleason Grade models' with ACC and AUC can be drawn (97.33%, 0.9832), (99.17%, 0.9952), and (90.48%, 0.8742), respectively. Conclusion: These results indicated that our diagnostic models of human PCa based on Taylor database combining the feature gene expression profiling data and artificial intelligence algorithms might act as a powerful tool for diagnosing PCa. Gleason Grade diagnostic models were used as novel prognostic diagnosis models for biochemical recurrence-free survival and overall survival, which might be helpful in the prognostic diagnosis of PCa in patients. [ABSTRACT FROM AUTHOR]

Background: Even though aberrant expression of microRNA (miR)-30d has been reported in prostate cancer (PCa), its associations with cancer progression remain contradictory. The aim of this study was to investigate clinical significance, biological functions and underlying mechanisms of miR-30d deregulation in PCa. Methods: Involvement of miR-30d deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor angiogenesis were determined. Results: miR-30d over-expression was observed in both PCa cells and clinical specimens. High-miR-30d was distinctly associated with high pre-operative PSA and Gleason score, advanced clinical and pathological stages, positive metastasis and biochemical recurrence (BCR), and reduced overall survival of PCa patients. Through gainand loss-of-function experiments, we found that miR-30d promoted PCa cell proliferation, migration, invasion, and capillary tube formation of endothelial cells, as well as in vivo tumor growth and angiogenesis in a mouse model. Simulation of myosin phosphatase targeting subunit 1 (MYPT1), acting as a direct target of miR-30d, antagonized the effects induced by miR-30d up-regulation in PCa cells. Notably, miR-30d/MYPT1 combination was identified as an independent factor to predict BCR of PCa patients. Furthermore, miR-30d exerted its pro-angiogenesis function, at least in part, by inhibiting MYPT1, which in turn, increased phosphorylation levels of c-JUN and activated VEGFAinduced signaling cascade in endothelial cells. Conclusions: miR-30d and/or its target gene MYPT1 may serve as novel prognostic markers of PCa. miR-30d promotes tumor angiogenesis of PCa through MYPT1/c-JUN/VEGFA pathway. [ABSTRACT FROM AUTHOR]

Background: Novel molecular markers are important diagnostic tools for the assessment of cancer progression and evaluation of effectiveness of the treatment. SOX9, a key regulator of developmental processes, is overexpressed in various neoplasms, such as prostate, breast, and colorectal cancers. However, the utilization of SOX9 as a biomarker for other urological cancers has not yet been investigated. Methods: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the SOX9 protein expression was quantitated as immunoreactive scores in patients with renal cell carcinoma (RCC), bladder cancer (BCa), and penile cancer (PC). Results: In comparison with normal tissues, SOX9 protein expression was significantly upregulated in RCC (p < 0.001) and BCa (p < 0.001), and significantly correlated with the advanced pathological grade (RCC: p = 0.023) and clinical stage (RCC: p = 0.022 and BCa: p = 0.046) of patients. Based on the mRNA level in the TCGA dataset, SOX9 was upregulated in RCC with gender (p = 0.027), advanced pathological grade (p = 0.003) and advanced clinical stage (p = 0.001). Kaplan-Meier survival curves revealed that RCC patients with high SOX9 levels had shorter survival (p < 0.001). Further, high SOX9 expression was an independent prognostic factor for RCC patients (hazard ratio 0.056, 95% confidence interval 0.607-1.184; p < 0.001). Conclusion: These findings suggest that SOX9 may play an important role in tumor progression of RCC and BCa and it may be used as a biomarker of this malignancy. [ABSTRACT FROM AUTHOR]

B-cell lymphoma 9 (BCL9), a component of aberrantly activated Wnt signaling, is an important contributing factor to tumor progression. Our previous data indicated that downregulation of the tumor suppressor microRNA-30c (miR-30c) was a frequent pathogenetic event in prostate cancer (PCa). However, a functional link between miR-30c and BCL9/Wnt signaling, and their clinical and pathological significance in PCa, have not been well established. The present study demonstrated that miR-30c serves as a key negative regulator targeting BCL9 transcription in PCa cells. Ectopic expression of miR-30c was associated with reduced expression of Wnt pathway downstream targets, including c-Myc, cluster of differentiation 44 and sex determining region Y-box 9 in DU145 human PCa cells. Examination of clinical prostate specimens revealed higher levels of BCL9 expression in PCa compared with that in benign prostate tissues. After substantiating this finding by patient sample analysis, BCL9 expression or activity was observed to be closely correlated with PCa biochemical recurrence (BCR) and disease progression, whereas it was inversely associated with miR-30c. Furthermore, overexpression of BCL9 in PCa acted cooperatively with miR-30c low expression to predict earlier BCR in PCa. These findings indicate that inhibition of BCL9/Wnt signaling by miR-30c is important in the progression of PCa. Furthermore, the combined analysis of miR-30c and BCL9 may be valuable tool for prediction of BCR in PCa patients following radical prostatectomy. [ABSTRACT FROM AUTHOR]

Background and Aim. CC chemokine ligand 18 (CCL18) promotes malignant behaviors of various human cancer types. However, its involvement in human prostate cancer has not been fully elucidated. The aimof this studywas to investigate the role of CCL18 in PCa. Methods. Expression ofCCL18 atmRNAand protein levels was detected using real-time qRT-PCR and immunohistochemistry analysis. We analyzed the associations of CCL18 expression with clinical features of human PCa. The effects of PCa cell migration, invasion, and apoptosis were tested. The efficiency of CCL18 on prostate tumor growth was assessed in a subcutaneous xenograft model. Results. CCL18 expression was upregulated (both P < 0.01) in PCa tissues compared with those in noncancerous prostate tissues. CCL18 upregulation was correlated with high Gleason score (P = 0.034) of patients with PCa. rCCL18 stimulation in PCa cells promoted cell migration and invasion but decreased DU145 cells apoptosis rate. Furthermore, subcutaneous homografts models showed the increased tumor growth and tumor vascularization with the CCL18 stimulation, and the expression of Ki67, PCNA, and CD31 in CCL18 stimulation mice was also significantly increased. Conclusions. Our data offer the convincing evidence that the upregulation of CCL18 may be involved in the malignant progression of PCa. [ABSTRACT FROM AUTHOR]

Background: To clarify the involvement of HIVEP3 and SOX9 coexpression in prostate cancer (PCa). Methods: A small interfering RNA was used to knockdown SOX9 expression in a PCa cell line and to analyze the effects of SOX9 inhibition on the expression of HIVEP3 in vitro. Then, HIVEP3 and SOX9 expression patterns in the human PCa tissues were detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry. Results: We found that the downregulation of SOX9 could inhibit the expression of HIVEP3 in the PCa cells in vitro. In addition, both HIVEP3 and SOX9 messenger RNA expression levels in the PCa tissues were significantly higher than those in the noncancerous prostate tissues (P=0.006 and P,0.001, respectively). Moreover, the immunohistochemical staining scores of HIVEP3 in the PCa tissues with PSA failure were significantly higher than those without (P=0.042); the increased SOX9 protein expression was more frequently found in the PCa tissues with a high Gleason score (P=0.045) and a high clinical stage (P=0.012). The tumors showing the HIVEP3- high/SOX9-high expression more frequently had PSA failure (P=0.024). When the patients with an HIVEP3 overexpression combined with the SOX9 overexpression, this group had a worse biochemical recurrence-free survival (P,0.001). Furthermore, the multivariate analysis showed that the HIVEP3/SOX9 coexpression was an independent predictor of an unfavorable biochemical recurrence-free survival. Conclusion: Our data offer the convincing evidence for the first time that a combined analysis of HIVEP3 and SOX9 may help to predict the tumor progression and prognosis of PCa patients. In particular, the overexpression of HIVEP3 in PCa might partly explain the poor prognosis of patients with an upregulation of SOX9. [ABSTRACT FROM AUTHOR]

Background Our recent study showed the global physiological function of the differentially expressed genes of prostate cancer in Chinese patients was different from that of other non-Chinese populations. microRNA are estimated to regulate the expression of greater than 60% of all protein-coding genes. To further investigate the global association between the transcript abundance of miRNAs and their target mRNAs in Chinese patients, we used microRNA microarray approach combined with bioinformatics and clinical-pathological assay to investigate the miRNA profile and evaluate the potential of miRNAs as diagnostic and prognostic markers in Chinese patients. Results A total of 28 miRNAs (fold change ⩾1.5; P ⩽ 0.05) were differentially expressed between tumor tissue and adjacent benign tissue of 4 prostate cancer patients.10 top Differentially expressed miRNAs were validated by qRT-PCR using all 20 tissue pairs. Compared to the miRNA profile of non-Chinese populations, the current study showed that miR-23b, miR- 220, miR-221, miR-222, and miR-205 maybe common critical therapeutic targets in different populations. The integrated analysis for mRNA microarray and miRNA microarray showed the effects of specifically inhibiting and/or enhancing the function of miRNAs on the gene transcription level. The current studies also identified 15 specific expressed miRNAs in Chinese patients. The clinical feature statistics revealed that miR-374b and miR-19a have significant correlations with clinical-pathological features in Chinese patients. Conclusions Our findings showed Chinese prostate cancer patients have a common and specific miRNA expression profile compared with non-Chinese populations. The miR-374b is down-regulated in prostate cancer tissue, and it can be identified as an independent predictor of biochemical recurrence-free survival. [ABSTRACT FROM AUTHOR]