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Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.

High prevalence and reoccurrence rate of nephrolithiasis bring about serious socioeconomic and healthcare burden, necessitating the need of effective therapeutic agents. Previous study revealed that gallic acid (GAL) alters the nucleation pathway of calcium oxalate (CaOx). On the other hand, it appears protective role against oxidative injury. Whether GAL could protect against crystal-induced lesion in vivo, and its underlying mechanism is yet unsolved.This study aims to investigate the protective effects of GAL on the crystal-induced renal injury and its underlying mechanism in the mouse model of stone formation induced by glyoxylic acid.The mouse model of stone formation was established via successive intraperitoneal injection of glyoxylate. Proximal tubular epithelial cell line HK-2 treated with calcium oxalate monohydrate (COM) was used as in vitro model. The protective role of GAL on nephrolithiasis was tested by determination of tubular injury, crystal deposition and adhesion, levels of inflammatory cytokines, macrophage infiltration and the redox status of kidney. In vitro, effect of GAL on the ROS level and oxidative tubular injury induced by COM were detected, as well as major antioxidant pathway Nrf2/HO-1.Administration of GAL alleviates the renal deposition and adhesion of CaOx stone. Meanwhile, GAL ameliorates the inflammation and renal tubular injury. Level of intracellular ROS, osteopontin and CD44 are reduced, either in the mouse model of stone formation or in the COM-treated HK-2 cells after treatment of GAL. Mechanistically, GAL activates Nrf2/HO-1 pathway in HK-2 cells. Silencing Nrf2 abrogates the protective effect of GAL on the oxidative injury and adhesion of COM in HK-2 cells.Taken together, our study demonstrates the protective effect of GAL on the deposition of kidney stone and consequent tubular injury. Induction of the antioxidant pathway Nrf2/HO-1 was found to decrease the level of ROS and oxidative injury, thus implying that GAL could be a potential therapeutic agent for the treatment of nephrolithiasis.

Background OTUB1 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding proteins)-mediated deubiquitination of FOXM1 (Forkhead box M1) participates in carcinogenesis of various tumors. We aim to investigate the effect and mechanism of OTUB1/FOXM1 on RCC (renal cell carcinoma) progression. Expression levels of OTUB1 in RCC tissues and cell lines were examined by qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. Cell proliferation was measured with CCK8 (Cell Counting Kit-8) and colony formation assays. Wound healing and transwell assays were used to determine cell migration and invasion, respectively. The effect of OTUB1 on FOXM1 ubiquitination was examined by Immunoprecipitation. Western blot was used to uncover the underlying mechanism. In vivo subcutaneous xenotransplanted tumor model combined with immunohistochemistry and western blot were used to examine the tumorigenic function of OTUB1. Results OTUB1 was up-regulated in RCC tissues and cell lines, and was associated with poor prognosis of RCC patients. Knockdown of OTUB1 inhibited cell viability and proliferation, as well as migration and invasion of RCC cells. Mechanistically, knockdown of OTUB1 down-regulated FOXM1 expression by promoting its ubiquitination. Down-regulation of FOXM1 inhibited ECT2 (epithelial cell transforming 2)-mediated Rho signaling. Moreover, the inhibition of RCC progression caused by OTUB1 knockdown was reversed by FOXM1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that knockdown of OTUB1 could suppress in vivo RCC growth via down-regulation of FOXM1-mediated ECT2 expression. Conclusions OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in RCC, providing a new potential therapeutic target for RCC treatment.

// Yuanyuan Zhang 1, * , Haixing Mai 2, * , Gang Guo 3 , Guofang Bi 1 , Guangtao Hao 1 , Yuanyuan Li 1 , Xiaofang Wang 1 , Longmei Cheng 1 , Jing Wang 1 , Ruihua Dong 1 , Zeyuan Liu 1 , Lijun Chen 2 and Hengyan Qu 1 1 Department of Clinical Pharmacology, Academy of Military Medical Sciences Affiliated Hospital, 307 Clinical College, Anhui Medical University, Beijing 100071, China 2 Department of Urology Department, Academy of Military Medical Sciences Affiliated Hospital, Beijing 100071, China 3 Department of Urology Department, The General Hospital of the People's Liberation Army, Beijing 100853, China * These authors contributed equally to this work Correspondence to: Hengyan Qu, email: quhengyan@hotmail.com Keywords: single-nucleotide polymorphisms; cell-free DNA; pharmacokinetics; sunitinib; renal-cell carcinoma Received: December 27, 2016 Accepted: November 11, 2017 Epub: January 03, 2018 Published: March 06, 2018 ABSTRACT Background: Sunitinib is a tyrosine kinase inhibitor with effective therapeutic outcomes in patients with renal-cell carcinoma. The study were to analyze the association of single-nucleotide polymorphisms present in cell-free DNA and pharmacokinetics with sunitinib treatment-emergent adverse events in Chinese patients with renal-cell carcinoma. Materials and Methods: We genotyped 8 keys SNPs in 6 candidate genes. The plasma concentrations of sunitinib and N-desethyl sunitinib were measured using a high performance liquid chromatography-tandam mass spectrometry method. Correlations between the single-nucleotide polymorphisms and adverse events were investigated by univariate and multivariate logistic regression and we quantitatively evaluated the effect of single-nucleotide polymorphisms on the pharmacokinetics of sunitinib by using a population PK model. Results: Necessary dose reductions of sunitinib were significantly correlated with SNP rs1933437 in FLT3 . A higher severity of AEs were collected with SNP rs2032582 in ABCB1 and rs1800812 in PDGFRα . Thrombocytopenia was collected with rs1800812 in PDGFRα . Our study provides a population PK model of sunitinib with the ABCB1 genotype as a predictive covariate for apparent oral clearance. Conclusions: Our study preliminarily confirmed the hypothesis that the pharmacokinetics of sunitinib is affected by the SNPs of enzyme in Chinese renal-cell carcinoma patients, and this affects the different distribution and severity of adverse events of sunitinib.

This single-center, observational study analyzed the association between plasma concentration of sorafenib and its safety and efficacy in Chinese patients with metastatic renal cell carcinoma (mRCC). Adult patients with RCC (n = 94), treated with sorafenib were enrolled between January 2014 and January 2015. Sorafenib plasma concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety and efficacy variables were evaluated using National Cancer Institute-Common Toxicity Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors criteria. Association of plasma concentration with safety and efficacy was analyzed. The steady state plasma concentration of sorafenib after 2 weeks of treatment ranged from 881 to 12,526 ng/mL. Major adverse reactions (ADRs) included diarrhea (76.5%), hand-foot syndrome (HFS; 68.99%) and fatigue (55.32%). Significant association was reported between plasma concentration and all the ADRs except rash. At 6 weeks, complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) was reported in 3.1%, 13.82%, 52.2% and 13.82% patients, respectively. Objective response and disease control rates were 17.02% and 69.14%. Plasma concentration of sorafenib was >10,000 ng/mL in patients with severe ADRs, which decreased with reduction in dose or discontinuation of treatment. After 21.2 weeks follow-up, median progression free survival was 12.3 months. CR, PR, SD and PD were reported in 1%, 46%, 33% and 19% patients. In conclusion, plasma concentration of sorafenib was associated with its safety and efficacy in Chinese patients with mRCC.

Summary Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo . SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.

Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP) was shown to be crucial during the development and progression of a variety of tumors. However, the role of HPIP in renal cell carcinoma (RCC) is unknown. Here we report that HPIP is upregulated in most RCC patients, positively correlates with tumor size, high Fuhrman grade and preoperative metastasis, and predicts poor clinical outcomes. Mechanistically, we identified casein kinase 1α (CK1α), a critical regulator of tumorigenesis and metastasis, as a novel HPIP-interacting protein. HPIP facilitates RCC cell growth, migration, invasion and epithelial–mesenchymal transition depending on its interaction with CK1α. Activation of mammalian target of rapamycin pathways by HPIP is partly dependent on CK1α and is required for HPIP modulation of RCC cell proliferation and migration. HPIP knockdown suppresses renal tumor growth and metastasis in nude mice through CK1α. Moreover, expression of CK1α is positively correlated with HPIP in RCC samples, and also predicts poor clinical outcome-like expression of HPIP. Taken together, our data demonstrate the critical regulatory role of the HPIP–CK1α interaction in RCC, and suggest that HPIP and CK1α may be potential targets for RCC therapy.