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Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, on p. 1969, two pairs of panels shown for the DU145 data appeared to contain overlaps, such that they may have been derived from the same original source (specifically, relating to the shCon and the shSMC1A experiments). The authors have referred back to their original data, and realize that inadvertent errors were made during the assembly of these figures. The corrected version of Fig. 5, showing discrete representative images for the shCon and the shSMC1A experiments with the DU145 cell line, is shown on the next page. All the authors agree to this corrigendum. Note that the revisions made to this figure do not adversely affect the results reported in the paper, or the conclusions stated therein. The authors regret that Fig. 5 was not presented in its correct form in their paper, thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum, and offer their apologies to the Editor and to the readers of the Journal. [the original article was published in International Journal of Oncology 49: 1963-1972, 2016; DOI: 10.3892/ijo.2016.3697].

Advanced-stage prostate cancer (PCa) is often diagnosed with bone metastasis, for which there are limited therapies. Transforming growth factor β (TGF-β) is known to induce epithelial–mesenchymal transition (EMT), and abundance of TGF-β in the bone matrix is one of the important growth factors contributing to bone metastasis. TGF-β is reported as a key mediator of bone metastasis, but the underlying mechanism has not been elucidated. It was found in our study that Interferon-inducible Transmembrane Protein 3 (IFITM3) played a key role in the regulation of malignant tumor cell proliferation, invasion, and bone migration by binding to Smad4, thus activating the TGF-β-Smads Signaling Pathway. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of IFITM3 inhibited cell proliferation and colony formation, induced apoptosis and inhibited migration by reversing EMT and downregulating the expression of metastasis-related molecules including FGFs and PTHrP. Microarray analysis showed that IFITM3 knockdown could alter the MAPK pathway associated with TGF-β-Smads signaling. By knocking down and overexpressing IFITM3, we demonstrated that IFITM3 expression level had an effect on MAPK pathway activation, and this change was more pronounced upon exogenous TGF-β stimulation. These results suggest that IFITM3 played an oncogenic role in PCa progression and bone metastasis via a novel TGF-β-Smads-MAPK pathway.

Background In the clinic, how to stratify renal cell carcinoma (RCC) patients with different risks and to accurately predict their prognostic outcome remains a crucial issue. In this study, we assessed the expression and prognostic value of gankyrin in RCC patients. Methods The expression of gankyrin was examined in public databases and validated in specimens from two independent centers. The clinical practice and disease correlation of gankyrin in RCC were evaluated in RCC patients, various cell lines and an orthotopic RCC model. Findings Upregulation of gankyrin expression in RCC was corroborated in two independent cohorts. High gankyrin expression positively associated with disease progression and metastasis of RCC patients. A positive correlation between gankyrin and sunitinib-resistance was also observed in RCC cell lines and in an orthotopic RCC model. Kaplan-Meier analysis revealed that patients with higher gankyrin expression presented worse prognosis of RCC patients in the two cohorts. Gankyrin served as an independent prognostic factor for RCC patients even after multivariable adjustment by clinical variables. Time-dependent AUC and Harrell's c-index analysis presented that the incorporation of the gankyrin classifier into the current clinical prognostic parameters such as TNM stage, Fuhrman nuclear grade or SSIGN score achieved a greater accuracy than without it in predicting prognosis of RCC patients. All results were confirmed in randomized training and validation sets from the two patient cohorts. Interpretation Gankyrin can serve as a reliable biomarker for disease progression and for prognosis of RCC patients. Combining gankyrin with the current clinical parameters may help patient management. Fund National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Medical Discipline Construction Project of Pudong New Area Commission of Health and Family Planning (PWYgf2018-03), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (No. PWR12016-05)

Additional file 1: Figure S1. The markers labeledcell types plot. Figure S2. A Expressed ATG genes per single cell in SSBprand leukocytes. B, C inferCNV results of NPC and IPC derived fetal renalcells. Figure S3. ASIX2 expression in Monocle 3 cluster of NPCs. B IL1R1 expression in Monocle 3cluster of SSBpod and pods. (IL1R1 is the marker of SSBpod). C CENPKexpression in Monocle 3 cluster of IPC and ICs. (CENPK is the marker of IPC). Figure S4. UMAP plot of different samples in all weeks.

Background Renal cell carcinoma (RCC) is one of the most common malignant tumors originating from the renal parenchymal urinary epithelial system. Tripartite motif 47 (TRIM47) is a member of the TRIM family proteins, which has E3 ligase activity and has been demonstrated to be involved in the occurrence and prognosis of many tumors. The main purpose of this study is to explore the role and potential mechanism of TRIM47 in promoting malignant biological behavior of RCC. Materials and methods TRIM47 mRNA and protein levels in human renal cancer and paired normal adjacent tissues were detected by qRT-PCR and Western blot. The effects of TRIM47 knockdown and overexpression in renal cell carcinoma cells on cell proliferation, invasion and xenograft tumor growth in nude mice were analyzed. The molecular mechanism was explored by mass spectrometric exploration,Western blot and immunoprecipitation assays. Results TRIM47 promoted RCC cell proliferation in vitro and in vivo as an oncogene. Mechanistically, TRIM47 exerted an E3 ligase activity by interacting with P53 protein to increase its ubiquitination and degradation, which further promoted the malignant biological behavior of RCC. Conclusions Our study demonstrated that the TRIM47-P53 axis played a functional role in RCC progression and suggested a potential therapeutic target for RCC.

Objective: To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC.Methods: We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by co-immunoprecipitation and Western blot assays. Results: The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (PConclusion: USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through promoting VEGF-A alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.

Background: Cancer stem cells (CSCs) are biologically characterized by self-renewal, multi-directional differentiation and infinite proliferation, inducing anti-tumor drug resistance and metastasis. In the present study, we attempted to depict the baseline landscape of CSC-mediated biological properties, knowing that it is vital for tumor evolution, anti-tumor drug selection and drug resistance against fatal malignancy. Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis in 15208 cells from a pair of primary and metastatic sites of collecting duct renal cell carcinoma (CDRCC). Cell subpopulations were identified and characterized by t-SNE, RNA velocity, monocle and other computational methods. Statistical analysis of all single-cell sequencing data was performed in R and Python. Results: A CSC population of 1068 cells was identified and characterized, showing excellent differentiation and self-renewal properties. These CSCs positioned as a center of the differentiation process and transformed into CDRCC primary and metastatic cells in spatial and temporal order, and played a pivotal role in promoting the bone destruction process with a positive feedback loop in the bone metastasis microenvironment. In addition, CSC-specific marker genes BIRC5, PTTG1, CENPF and CDKN3 were observed to be correlated with poor prognosis of CDRCC. Finally, we pinpointed that PARP, PIGF, HDAC2, and FGFR inhibitors for effectively targeting CSCs may be the potential therapeutic strategies for CDRCC. Conclusion: The results of the present study may shed new light on the identification of CSCs, and help further understand the mechanism underlying drug resistance, differentiation and metastasis in human CDRCC.

At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China1, even more spread than SARS-CoV infection2. The entry of SARS-CoV into host cells mainly depends on the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion3,4. The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear5,6. Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

Recent advances in immunotherapy are raising hope to treat clear cell renal cell carcinoma (ccRCC) with PD-L1 inhibitors, but only a small portion of patients are PD-L1 positive. The heterogeneous expression pattern of PD-L1 in patient population suggests that PD-L1 expression is under the control of diverse regulatory mechanisms. Although recent studies have identified numerous novel PD-L1 regulators, reports on microRNAs which modulate PD-L1 expression are much scarce. In this study, we confirmed that PD-L1 expression was up-regulated in ccRCC compared to paired normal tissues. Using miRDB and miRTarBase, 11 microRNAs were predicted to target PD-L1. After measuring the microRNA panel with TaqMan assays, we found that microRNA-497-5p down-regulation was associated with PD-L1 up-regulation. In TCGA-KIRC dataset, microRNA-497-5p down-regulation was also associated with PD-L1 up-regulation as well as shorter survival. We further validated that PD-L1 was a direct target of microRNA-497-5p in two RCC cell lines. In addition, microRNA-497-5p inhibited cell proliferation, clone formation and migration, while promoted apoptosis in in-vitro assays. Our study reveals a novel regulatory mechanism of PD-L1 expression and the potential of miR-497-5p as therapeutic target and biomarker deserves further investigation.

Jian-Min Lv,1–3,* Lu Chen,1,* Yi Gao,1,* Hai Huang,1–3,* Xiu-Wu Pan,2,3,* Xi Liu,1 Ming Chen,2 Fa-Jun Qu,3 Lin Li,3 Jun-Kai Wang,2 Xin-Gang Cui,3,4,* Dan-Feng Xu1,* 1Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; 2Department of Urinary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 3Department of Urinary Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai 201805, China; 4Department of Urinary Surgery, Gongli Hospital, Second Military Medical University, Shanghai 200135, China *These authors contributed equally to this work Background: Prostate cancer (PCa) is one of the most common malignancies and a major leading cause of cancer-related deaths in males. And it is necessary to explore new molecular targets to enhance diagnosis and treatment level of the PCa. Serine/threonine protein phosphatase 5 (PPP5C) is a vital molecule that Involve in complex cell physiological activity. Purpose: The objective of this study was to detecte the expression level of PPP5C in the tissue of prostate cancer patients and further discussed the PPP5C biological function and mechanisms on the PCa. Methods: The expression level of PPP5C was analyzed by immunohistochemistry and ONCOMINE datasets. Lentivirus-mediated short hairpin RNA (shRNA) was constructed to silence the expression of PPP5C in prostate cancer cell. Cell viability and proliferation were measured using MTT and colony formation, and the cell cycle and apoptosis was analyszed by flow cytometry. The changes of downstream protein level and protein phosphorylation level were detected by western blot. Results: PPP5C was highly expressed in PCa tissue as analyzed by immunohistochemistry and ONCOMINE datasets. PPP5C Knockdown inhibited cell proliferation and colony formation in PCa cells. Flow cytometry analysis showed that DU145, PC3 and 22RV1 PCa cells deprived of PPP5C were arrested in G0/G1 phase and became apoptotic. Western blot analysis indicated that PPP5C knockdown could promote JNK and ERK phosphorylation. Conclusion: Our study indicated that the PPP5C may become a new potential diagnostic biomarker and therapeutic target for the PCa. Keywords: PPP5C, prostate cancer, tumorigenesis, JNK, ERK

Prostate cancer (PRAD) is associated with abnormal cholesterol metabolism and low-density lipoprotein (LDL) receptor-related protein (LRP) family is essential for the homeostasis of cholesterol. Immune check points like PD-L1 are vital for tumour cells to evade immune attack. However, the potential cross-talk between these two pathways has not been explored before in PRAD. Insight from the regulation mechanism of PD-L1 in PRAD may help to optimise PD-L1 based immunotherapy. In this study, we investigated a regulation network of LRP11/β-catenin/PD-L1 in PRAD. We showed that the expression of LRP11 and PD-L1 was up-regulated in PRAD compared to paired normal tissues. LRP11 expression was positively correlated to PD-L1 expression in PRAD tissues. Further experiments in two PRAD cell lines with LRP11 over-expression and knockdown showed that LRP11 induced PD-L1 expression through β-catenin signalling. In addition, LRP11 over-expression in PRAD cell line induced immunosuppression of Jurkat cell in in-vitro co-culture system. The effects of LRP11 could be blocked by neutralising LRP11 or PD-L1 antibody. Our results provide evidence for a novel regulation mechanism of PD-L1 expression in PRAD and LRP11 may be a potential therapeutic target in PRAD.

While the current standard first-line treatment for advanced renal cell carcinoma (RCC) is sunitinib, patients inevitably develop resistance to this drug. However, the rapid development of nanotechnology has provided emerging techniques for the treatment of advanced tumours, including RCC. In our previous research, cuprous oxide nanoparticles (CONPs) showed ideal anti-tumour effects and low systemic toxicity. While many inorganic nanomedicines, including CONPs, have similar pharmacological effects, their detailed mechanisms remain unknown. Copper chaperone proteins, which regulate the endocellular dosage and transport of copper, also play crucial roles in the progression of cancer. In this research, we discovered that CONPs can disrupt copper transportation by regulating the copper chaperone proteins ATOX1 and CCS in RCC cells and induce endoplasmic reticulum (ER) stress in vitro and in vivo by promoting the accumulation of intracellular calcium and reactive oxygen species (ROS). Furthermore, CONPs can initiate ER- and mitochondrial-dependent apoptosis by activating caspase-3, caspase-9 and caspase-12. In addition, CONPs downregulate the expression of AXL, MET, AKT, and ERK to recover sunitinib responsiveness in RCC cells with sunitinib resistance (SR) and may therefore facilitate the development of promising new pathways to treat patients with acquired SRRCC.

// Xi Liu 1, 3, * , Lu Chen 1, * , Hai Huang 1, 3, * , Jian-Min Lv 1, * , Ming Chen 3 , Fa-Jun Qu 2 , Xiu-Wu Pan 2 , Lin Li 2 , Lei Yin 3 , Xin-Gang Cui 2 , Yi Gao 1 and Dan-Feng Xu 1 1 Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China 2 Department of Urinary Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai 201805, China 3 Department of Urinary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China * These authors have contributed equally to this work Correspondence to: Xin-Gang Cui, email: xingangcui@126.com Yi Gao, email: gaoyismmu@163.com Dan-Feng Xu, email: danfengxu_urology@163.com Keywords: PDLIM5; epithelial-mesenchymal transition; prostate cancer; migration; AMPK Received: July 13, 2017 Accepted: August 27, 2017 Published: September 18, 2017 ABSTRACT PDZ and LIM domain 5 (PDLIM5) is a cytoskeleton-associated protein and has been shown to bind to a variety of proteins through its specific domain, thereby acting to regulate cell migration and tumor progression. Here, we found that PDLIM5 was abnormally upregulated in prostate cancer (PCa) tissues as compared with that in normal prostate tissue. ONCOMINE microarray data mining showed that PDLIM5 was closely correlated with the prognosis of PCa in terms of Gleason score, tumor metastasis and biochemical recurrence. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of PDLIM5 inhibited cell proliferation and colony formation, arrested hormone independent PCa cells DU145 and PC-3 in G2/M phase, and induced apoptosis. Meanwhile, silencing PDLIM5 inhibited migration and invasion of tumor cells by reversing the mesenchymal phenotype and a similar result was confirmed in a xenograft nude mouse model. Finally, we found PDLIM5 plays a crucial role in regulating malignant tumor cell proliferation, invasion and migration by binding to AMPK and affecting its activation and degradation, and may therefore prove to be a potential oncogenic gene in the development and progression of PCa.

Recent reports have shown a rapid rise in the incidence of renal cell carcinoma (RCC), and Wnt (Wingless-related integration site) signaling pathway is important in RCC. Frizzled 8 (FZD8) is a member of Frizzled (FZD) receptor family which could activate canonical or non-canonical Wnt/β-catenin pathways. Nevertheless, the role of FZD8 in RCC is poorly investigated. The immunohistochemical analysis showed high expression of FZD8 in RCC tissues compared with peri-tumor tissues. FZD8 knockdown decreased the ability of proliferation and metastasis of RCC cells. Research revealed that the FZD8 regulated the transcription of Cyclin D1, c-Myc, and could promote the epithelial to mesenchymal transition (EMT) by mediating Vimentin and Snail through the Wnt/β-catenin signaling pathway. In addition, the results of our experiment revealed that FZD8 is involved in the regulation of non-canonical Wnt signaling pathway. These data suggested that the expression of FZD8 may play an important role in the proliferation and metastasis of RCC, and serve as a putative promising drug target for human RCC therapy.

Serine/threonine protein phosphatase 5 (PPP5C) is a member of the protein serine/threonine phosphatase family and has been shown to participate in multiple signaling cascades and tumor progression. We found that PPP5C was highly expressed in bladder cancer tissues compared to normal urothelial tissues, and positively correlated to tumor stages through ONCOMINE microarray data mining. Knockdown of PPP5C via a lentivirus-mediated short hairpin RNA (shRNA) markedly inhibited cell proliferation and colony formation. Flow cytometric analysis showed that PPP5C-deficient T24 and BT5637 bladder cancer cells were arrested in G0/G1 phase and induced apoptosis. In addition, tumor growth was inhibited in vivo in a xenograft nude mouse model. Further studies indicated that knockdown of PPP5C downregulated c-myc and CDK4, whereas upregulated p27, BAD and Beclin1. These results suggest that PPP5C is associated with bladder cancer (BCa) and plays an oncogenic role in the development and progression of bladder cancer.

// Lu Chen 1, * , Xiu-Wu Pan 2, 3, * , Hai Huang 3, * , Yi Gao 3 , Qi-Wei Yang 2, 3 , Lin-Hui Wang 3 , Xin-Gang Cui 2 and Dan-Feng Xu 1 1 Department of Urinary Surgery of Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China 2 Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai 201805, China 3 Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, Shanghai 200003, China * These authors have contributed equally to this work Correspondence to: Xin-Gang Cui, email: xingangcui@126.com Dan-Feng Xu, email: nycnjc@126.com Keywords: GRO-α, CXCR2, bladder cancer, epithelial-mesenchymal transition, recurrence Received: March 24, 2016 Accepted: March 17, 2017 Published: April 03, 2017 ABSTRACT Non-muscle invasive bladder cancers (NMIBC) are typically treated by transurethral resection with intravesical chemotherapy. However, the post-therapeutic incidence of tumor recurrence and progression to muscle invasive disease is high, and the underlying mechanism(s) remains unknown. In this study, we observed that recurrent bladder cancer cells exhibit a mesenchymal phenotype, which is initiated by the autocrine GRO-α signaling. Mechanically, the chemotherapeutic drug epidoxorubicin induces GRO-α expression in primary bladder cancer cells at G1/S phase via p38-dependent activation of NF-κB. GRO-α phosphorylation of Snail on Ser246 supports Snail’s accumulation in the nucleus, and thereby promotes transcription repression activity of Snail from E-cadherin promoters. In accordance, disrupting the GRO-α-Snail axis in NMIBC represents a promising alternative to prevent post-therapeutic tumor progression and recurrence.

Structural maintenance of chromosome 1 alpha (SMC1A) gene has been reported to be related to tumor development in some types of human cancers. However, the misregulation of SMC1A and its functions in castration-resistant prostate cancer (CRPC) have not been well understood. In the present study, we found that SMC1A was elevated in androgen-independent PCa cell lines PC-3 and DU-145 compared to androgen sensitive LNCap and 22RV1 cells by qPCR and western blot assay. Knockdown of SMC1A inhibited cell growth, colony formation and cell migration abilities of PC-3 and DU145 cells by MTT, colony formation and transwell assays, and affected cell cycle progression in PC-3 and DU145 cells by flow cytometry. Moreover, SMC1A knockdown significantly reduced tumor growth in vivo in a nude mouse model. Additionally, we also found that the expression of SMC1A gene was higher in prostate cancer tissues than in the adjacent normal tissues by immunohistochemical staining, and was positively correlated to tumor metastasis and recurrence by Oncomine database mining. Taken together, the present study indicates that SMC1A may play an important role in malignant transformation of PCa under conditions of androgen deprivation and act as a new target for PCa diagnosis and treatment.

There are no effective therapies for advanced renal cell carcinoma (RCC), except for VEGFR inhibitors with only ~50% response rate. To identify novel targets and biomarkers for RCC is of great importance in treating RCC. In this study, we observed that eukaryotic initiation factor 3d (EIF3D) expression was significantly increased in RCC compared with paracarcinoma tissue using immunohistochemistry staining and western blot analysis. Furthermore, bioinformatics meta-analysis using ONCOMINE microarray datasets showed that EIF3D mRNA expressions in CCRCC tissue specimens were significantly higher than that in normal tissue specimens. In addition, RCC tissue microarray demonstrated that elevated EIF3D expression was positively correlated with TNM stage and tumor size. EIF3D silencing in human 786-O and ACHN CCRCC cell lines by RNA interference demonstrated that EIF3D knockdown obviously inhibited cell proliferation and colony formation, caused G2/M arrest through downregulation of Cyclin B1 and Cdk1 and upregulation of p21, and induced apoptosis shown by sub-G1 accumulation and RARP cleavage. Moreover, correlation analysis using ONCOMINE microarray datasets indicated that increased EIF3D mRNA expression was positively correlated to PCNA, Cyclin B1 and CDK1 mRNA expression in RCC. Collectively, these results provide reasonable evidences that EIF3D may function as a potential proto-oncogene that participates in the occurrence and progression of RCC.

// Yi Huang 1, 2, * , Xiu-Wu Pan 1, 3, * , Lin Li 1 , Lu Chen 1 , Xi Liu 1 , Jian-Lei Lu 4 , Xiao-Mei Zhu 4 , Hai Huang 1 , Qi-Wei Yang 1 , Jian-Qing Ye 3 , Si-Shun Gan 3 , Lin-Hui Wang 1 , Yi Hong 4 , Dan-Feng Xu 5 , Xin-Gang Cui 3 1 Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China 2 The 2nd Department of Oncology of Chenggong Hospital, Xiamen University, Xiamen, 361003, China 3 Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai, 201805, China 4 R & D Departmemt of DuruoBiotechnologies Inc., Shanghai, 200233, China 5 Department of Urinary Surgery of Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China * These authors have contributed equally to this work Correspondence to: Xin-Gang Cui, e-mail: xingangcui@126.com Dan-Feng Xu, e-mail: xu-danfeng@hotmail.com Yi Hong, e-mail: zandh@163.com Keywords: USP39, prostate cancer, prognosis, tumorigenesis, EGFR Received: January 15, 2016 Accepted: February 23, 2016 Published: March 03, 2016 ABSTRACT Castration resistance is a serious problem facing clinical treatment of prostate cancer (PCa). The underlying molecular mechanisms of acquired proliferation ability of tumor cells upon androgen deprivation are largely undetermined. In the present study, we identified that ubiquitin specific peptidase 39 (USP39) was significantly upregulated in PCa samples and cell lines. Elevated USP39 expression was positively correlated with Gleason score, predicted a poor outcome, and functioned as an independent risk factor for biochemical recurrence (BCR) especially in patients with a Gleason score ≤7. Our cell-based study showed that the expression level of USP39 was the highest in AR-negative PCa cell lines. Knockdown of USP39 in PCa cells inhibited cancer colony formation and tumor cell growth, and induced G2/M arrest and cell apoptosis. Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR. Silencing of USP39 inhibited the expression of EGFR 3′-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA. Oncomine datasets analysis showed that USP39 expression was positively correlated with EGFR level. The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of PCa and may prove to be a potential biomarker for predicting the prognosis of PCa patients.

Human Ataxin-3 protein was first identified as a transcript from patients with Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3). Recent studies have demonstrated that Ataxin-3 is involved in gastric cancer and lung cancer. However, the role of Ataxin-3 in testicular cancer (TC) remains poorly understood. This study aims to explore the significance of Ataxin-3 expression in TC. Firstly, we investigated 53 paired TC and para-tumor tissues and found that Ataxin-3 was overexpressed in TC tissues, and this overexpression of Ataxin-3 was correlated with tumor stages. Functionally, Ataxin-3 overexpression promoted cell proliferation, and Ataxin-3 knockdown inhibited cell proliferation. In addition, up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT/mTOR pathway. Conversely, inhibition of Ataxin-3 suppressed the expression of p-AKT and p-mTOR, and increased the expression of p-4EBP1. These findings may provide a better understanding about the mechanism of TC and suggest that Ataxin-3 may be a potential prognostic biomarker and therapeutic target for TC.

Prostate cancer (PCa) is one of the most commonly diagnosed urological malignancies. However, there are limited therapies for PCa patients who develop biochemical recurrence after androgen deprivation therapy (ADT). In the present study, we investigated the therapeutic efficacy and mechanism of α-Viniferin (KCV), an oligostilbene of trimeric resveratrol, against human PCa cells and found that it markedly inhibited the proliferation of LNCaP, DU145, and PC-3 cancer cells in a time- and dose-dependent manner, and had a strong cytotoxicity in non-androgen-dependent PCa cells. In addition, KCV inhibited AR downstream expression in LNCaP cells, and inhibited activation of GR signaling pathway in DU145 and PC-3. Further investigation indicated that KCV could induce cancer cell apoptosis through AMPK-mediated activation of autophagy, and inhibited GR expression in castration-resistant prostate cancer(CRPC). These findings suggest that KCV may prove to be a novel and effective therapeutic agent for the treatment of CRPC.

Background: The pervasive progression and drug-resistance of renal cell carcinoma (RCC) after treatments demands for more effective drugs with little side effects. Recently, extracts from natural resources have been reported to effectively suppress the progression of certain tumors. In this study, we examined the effects of degalactotigonin extracted from Solanum nigrum L. on the progression and sunitinib-resistance of RCC, and the underlying mechanisms. Methods: The in vitro effects of degalactotigonin on the proliferation, apoptosis, invasion, migration and sunitinib-resistance were assessed by CCK-8, flow cytometry, Western blot, Matrigel invasion and transwell migration assays. The in vivo effects were evaluated in murine models of subcutaneous and in situ tumor and lung metastasis. The related molecular characteristics were delineated by RNA-sequencing. Findings: Degalactotigonin induced apoptosis and suppressed proliferation, invasion, migration, and sunitinib-resistance of RCC cells in vitro in a dose-dependent manner. Furthermore, degalactotigonin effectively inhibited the tumorigenicity and lung metastasis of RCC cells in vivo. Mechanistically, RNA-sequencing revealed that inactivation of YAP signaling occurred in degalactotigonin-treated RCC cells with reduced expression of YAP and its target genes. We also observed that degalactotigonin activated p-LATS1/2 to phosphorylate YAP, which induced more YAP retention in the cytoplasm but less YAP entering the nucleus of RCC cells. Moreover, re-expressed YAP in degalactotigonin-treated RCC cells mediated the anti-tumor activities of degalactotigonin on RCC. Furthermore, degalactotigonin ameliorated sunitinib-resistance in an orthotopic RCC model. Interpretation: Degalactotigonin is an effective therapeutic agent in inhibiting the growth, progression and sunitinib-resistance of RCC. Funding Statement: National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Shanghai Natural Science Foundation of China (No. 13ZR1450700), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All experimental animal procedures were approved by the Animal Care and Use Committee of the Second Military Medical University (Shanghai, China).

Background: In the clinic, how to stratify renal cell carcinoma (RCC) patients with different risks and to accurately predict their prognostic outcome remains a crucial issue. There is a lack of relevant and reliable biomarkers. In this study, we examined the expression and prognostic value of gankyrin in RCC patients. Methods: The expression of gankyrin in RCC specimens was examined in public database, and validated in specimens in our institution. The clinical practice of gankyrin (or combined with other current clinical parameters) in RCC patients was evaluated in two independent cohorts of RCC patients. Findings: Analyses based on public TCGA, GEO and ONCOMINE databases revealed that gankyrin expression was up-regulated in RCC specimens, which was also confirmed in RCC patients from two independent cohorts. In addition, high gankyrin expression positively associated with disease progression, metastasis and sunitinib-resistance of RCC patients. Kaplan-Meier analysis revealed that patients with higher gankyrin expression presented worse prognosis of RCC patients in the two cohorts. Gankyrin served as an independent prognostic factor for RCC patients even after multivariable adjustment by clinical variables. Furthermore, time-dependent AUC and Harrell's c-index analysis both presented that the incorporation of the gankyrin classifier into the current clinical prognostic parameters such as TNM stage, Furman nuclear grade or SSIGN score achieves a greater accuracy than without it in predicting prognosis of RCC patients. All these results were confirmed in randomized training and validation sets from the above two cohorts of patients. Interpretation: Gankyrin can serve as a reliable biomarker for disease progression and for prognosis of RCC patients. Combining gankyrin with the current clinical parameters may help clinical management for RCC patients. Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Shanghai Natural Science Foundation of China (No. 13ZR1450700), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200) and Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (No.PWR12016-05). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: The present study was followed the reporting recommendations for tumor marker prognostic studies (REMARK), and was approved by the institutional ethical review boards from all hospitals, and written informed consent was obtained from all patients.

We conducted this study to report on our initial experience and assess the safety, feasibility, and efficacy of extraperitoneal single plus one port laparoscopic radical prostatectomy (SPOPL-RP), and determine whether it shows any objective advantage over standard laparoscopic radical prostatectomy. From June 2009 to September 2011, 15 extraperitoneal SPOPL-RPs were performed through a 2–3-cm subumbilical longitudinal incision and another 5-mm trocar placed at the McBurney point. This cohort was compared with 37 contemporary patients who underwent standard extraperitoneal laparoscopic radical prostatectomy performed by the same urologist. Peri- and postoperative outcomes, including continence, potency, and scar length, were statistically analyzed. The two groups were comparable with respect to patient demographics, estimated blood loss, drainage time, duration of catheterization, catheterization rate >14 days, complication rate, postoperative hospitalization, and postoperative functional and oncologic outcomes ( p > 0.05). The SPOPL-RP procedures had a longer mean operative time (170.1 minutes vs. 139.5 minutes, p = 0.005), but with fewer patients requiring analgesics (20% vs. 54.1%, p = 0.038) and earlier resumption of oral intake (20.7 hours vs. 26.8 hours, p = 0.037). The mean scar length in the SPOPL-RP group was much smaller (3.4 cm vs. 5.8 cm, p = 0.000) owing to the significant reduction of the skin incision. The peri- and postoperative outcomes of SPOPL-RP for low-risk prostate cancer are comparable to those with the standard laparoscopic approach. In addition, SPOPL-RP provides better postoperative pain control, faster recovery of bowel function, and smaller scar length than standard laparoscopy, albeit with a longer operative time.

Background Health-related quality-of-life (HRQoL) is an important consideration after radical cystectomy (RC). Lack of effective ways to assess HRQoL after RC and unawareness of disease-specific problems related to ileal conduit (IC) and orthotopic ileal neobladder (OIN) are serious problems. The present study was to evaluate and compare morbidity and HRQoL between IC and OIN after RC, and examine their unmet needs in the two groups. Methods A retrospective analysis was made of 294 patients treated with RC in our hospital between 2007 and 2013. Matched pair analysis was used to determine the patients of IC and OIN groups. Patient HRQoL between IC and OIN groups was assessed using the bladder-specific bladder cancer index (BCI) and European Organization for Research and Treatment of Cancer Body Image scale (BIS) questionnaires. Unmet information of patients undergoing these two urinary diversions was recorded through individual interviews. Results Of the 117 included patients, 39 patients were treated with OIN and the other 78 matched patients with IC as controls for matched pair analysis. There was no significant difference in baseline characteristics between the two groups. OIN patients showed significantly better BIS scores in terms of HRQoL outcomes after RC at a short-term (1 year) follow-up level between the two groups. Interestingly, urinary bother (UB) and urinary function (UF) were poor in OIN patients at the one-year follow-up level, but there was no significant difference in UB between the two groups at the long term follow-up level. Unmet needs analysis showed that OIN patients had a more positive attitude towards treatment and participated in physical and social activities more positively, although they may have more urine leakage problems. Conclusions The mean BIS score in OIN group patients was significantly better than that in IC group patients at the one-year follow-up level, but there was no significant difference at the long-term follow-up level. Due attention should be paid to some particular unmet needs in individual patients in managing the two UD modalities. Electronic supplementary material The online version of this article (doi:10.1186/s12894-015-0113-7) contains supplementary material, which is available to authorized users.

GPR137 belongs to the G protein-coupled receptor family involving the regulation of transmembrane signal transduction that launches pivotal cellular functions. However, its function in prostate cancer (PCa) has been rarely reported. It was found in this study that GPR137 was upregulated in PCa tissues as compared with that in paracancerous tissues. To see whether GPR137 could serve as a potential therapeutic target for PCa, GPR137 was knocked down to verify its biological function in PCa cells. Lentivirus-introduced short hairpin RNA (shRNA) was designed to silence GPR137 gene. It was found that silencing of GPR137 gene suppressed the proliferation and colony formation of PCa cell lines PC-3 and DU145. Further study indicated that growth inhibition by GPR137 knockdown was associated with cell cycle arrest at G0/G1 phase. Furthermore, silencing of GPR137 repressed the invasion and migration abilities of PC-3 cells via downregulating slug and snail and upregulating E-cadherin. Collectively, these findings imply that GPR137 plays an important role in the occurrence and progression of PCa and may prove to be a potential therapeutic target for the treatment of advanced PCa.

Microvascular invasion (MVI), an omen of potential hematogenous spread of tumor cells, has been identified as an accepted risk factor for poor prognosis in some solid tumors. But its prognostic value in renal cell carcinoma (RCC) remains disputable. In order to address this question rigorously, we performed a systematical review of the published literature on MVI and RCC prognosis. According to the PRISMA statement, we searched PubMed, Web of science, and Cochrane Library database and identified 33 cohort articles that met the eligibility criteria and involved 14,946 patients (48-2596 per study) in this meta-analysis. Using the random effects model, the association between MVI and four generally recognized end points were estimated, including cancer-specific survival (CSS), recurrence-free survival (RFS), metastasis-free survival (MFS) and overall survival (OS). The presence of MVI was detected in 14.4% of the pathological specimens. A higher incidence of MVI was associated with some acknowledged prognostic risk factors such as higher pathological TNM stages and higher tumor grades. Statistical significance of the combined hazard ratio (HR) was detected for CSS (HR, 2.090; 95% CI, 1.530-2.857), RFS (HR = 2.749; 95% CI, 1.974-3.828), MFS (HR = 1.621; 95% CI, 1.095-2.400). However, the association between MVI and worse overall survival did not address statistical significance (HR = 1.371; 95% CI, 0.978-1.923). These findings suggest that the presence of MVI has a detrimental effect on clinicopathological features of RCC and could serve as a poor prognostic factor for patient with RCC.

To evaluate the feasibility and therapeutic outcome of a personalized laparoscopic partial nephrectomy (LPN) selection scheme designed according to tumor characteristics.We included 187 patients in this study with clinical T1 renal tumors who were diagnosed between March 2012 and February 2014. 93 patients underwent the personalized LPN on the basis of tumor characteristics (Group A, n = 93), including no renal arterial clamping LPN, selective renal arterial clamping LPN and main renal arterial clamping LPN, and the other 94 patients underwent LPN with main renal arterial clamping (Group B, n = 94). Patient characteristics, tumor characteristics, perioperative data and renal function parameters were collected prospectively.85 patients in Group A and 90 patients in Group B completed the designed surgery without conversion. Compared with Group B, the operation time was longer in Group A (110.2 vs. 122.3 min, p = 0.001), intraoperative blood loss was increased (127.8 vs. 151.1 ml, p = 0.017), and there was less reduction in GFR 12 months postoperative (7.6 vs. 5.1 ml/min, p0.001). The study was limited by the relatively small sample size and long-term postoperative renal function is still awaited.The result of our study showed that, although the intraoperative blood loss was greater, there was a less decrease in GFR 12 months postoperative in personalized LPN group.

To assess the efficacy and tolerability of sunitinib dosing schedule of 2 weeks on and 1 week off (schedule 2/1) vs. the traditional schedule of 4 weeks on and 2 week off (schedule 4/2) and its influence on health-related quality of life (HRQoL) in Chinese patients with metastatic renal cell carcinoma (mRCC).A retrospective analysis of 108 patients with mRCC who were treated with sunitinib regimens (50mg daily) between January 2009 and July 2013 was undertaken. Overall, 3 groups of patients were studied according to the dosing schedule they received: schedule 4/2 (n = 50), transitional schedule 2/1 (T2/1; patients switched from schedule 4/2 to 2/1; n = 26), and initial schedule 2/1 (I2/1; n = 32). The tumor response, progression-free survival (PFS) time, adverse events, and HRQoL were assessed and compared among the groups.The incidences of diarrhea, fatigue, hand-foot syndrome, and neutropenia induced by the treatment of sunitinib were all significantly less common with schedule I2/1 and T2/1 than with schedule 4/2 (P0.05). Although there was no statistically significant difference in the tumor response among the 3 groups, the median PFS time was significantly longer with schedule I2/1 than with schedules T2/1 and 4/2 (11.2 vs. 9.4 and 9.5mo, respectively, P = 0.030), and HRQoL (as determined by 19-item Functional Assessment of Cancer Therapy Kidney Symptom Index scores) was better.Treatment with sunitinib 50mg daily using a 2/1 dosing schedule can provide better tolerability and a longer PFS with better HRQoL in Chinese patients with mRCC than the traditional schedule 4/2.

EIF3 is the largest multi-protein complex, and several studies have revealed the oncogenic roles of its subunits in many human cancers. However, the roles of EIF3D in the development and progression of PCa remain uncovered. In the present study, the expression of EIF3D in prostate cancer and paracarcinoma tissues, as well as PCa cell lines, was examined. In PCa tissues, the expression of EIF3D was up-regulated compared to that in paracarcinoma tissues. In order to investigate whether EIF3D could serve as potential therapeutic target for prostate cancer, EIF3D was knocked down to verify its functional role in prostate cancer cells. After EIF3D knockdown in PC-3 and DU145 cells, cell proliferation, invasion and colony formation were significantly inhibited; meanwhile, cell cycle analysis revealed cell cycle arrest at G2/M phase. EIF3D is associated with PCa, and silencing EIF3D will result in decreased proliferation, and migration, as well as G2/M arrest in DU145 and PC-3 cells. These results suggest that EIF3D plays an oncogenic role in PCa development and progression.

Open retropubic radical prostatectomy (ORP) remains the “gold standard” for surgical treatment of clinically localized prostate cancer (PCa). Robot-assisted radical prostatectomy (RARP) is a robotic surgery used worldwide. The aim of this study is to collect the data available in the literature on RARP and ORP, and further evaluate the overall safety and efficacy of RARP vs. ORP for the treatment of clinically localized PCa. A literature search was performed using electronic databases between January 2009 and October 2013. Clinical data such as operation duration, transfusion rate, positive surgical margins (PSM), nerve sparing, 3- and 12-month urinary continence, and potency were pooled to carry out meta-analysis. Six studies were enrolled for this meta-analysis. The operation duration of RARP group was longer than that of ORP group (weighted mean difference = 64.84). There was no statistically significant difference in the transfusion rate, PSM rate, and between RARP and ORP (transfusion rate, OR = 0.30; PSM rate, OR = 0.94). No significant difference was seen in 3- and 12-month urinary continence recovery (3 months, OR = 1.32; 12 months, OR = 1.30). There was a statistically significant difference in potency between the 3- and 12-month groups (3 months, OR = 2.80; 12 months, OR = 1.70). RARP is a safe and feasible surgical technique for the treatment of clinically localized PCa owing to the advantages of fewer perioperative complications and quicker patency recovery.

Nin one binding-1 protein (NOB1) is a kind of zinc protein involved in ribosome biogenesis and controlled proteolysis. To explore the function of NOB1 in human prostate malignancy, we analyzed the expression of NOB1 in prostate cancer and found that NOB1 was elevated in prostate cancer tissues compared to the adjacent normal tissues. Knockdown of NOB1 by lentivirus-shRNA inhibited the proliferation and colony-formation ability of PC-3 and DU145 prostate cancer cells. Cell cycle analysis showed that silencing of NOB1 caused G0/G1 phase arrest and a slight decrease in S phase (P < 0.05). Furthermore, knockdown of NOB1 significantly suppressed the mobility of PC-3 and DU145 prostate cancer cells (P < 0.05). Collectively, these findings suggested that NOB1 might be involved in tumorigenecity of prostate cancer, and could be a potential molecular target for prostate cancer gene therapy.