Targeting Hypoxia and Autophagy Inhibition via Delivering Sonodynamic Nanoparticles With HIF-2α Inhibitor for Enhancing Immunotherapy in Renal Cell Carcinoma.

Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4'-azobisbenzenemethanol-PMDA)-mPEG5k, P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC.

m6A Methylation-Mediated Stabilization of LINC01106 Suppresses Bladder Cancer Progression by Regulating the miR-3148/DAB1 Axis.

BACKGROUND: The pivotal roles of long noncoding RNAs (lncRNAs) in the realm of cancer biology, inclusive of bladder cancer (BCa), have been substantiated through various studies. Remarkably, RNA methylation, especially m6A modification, has demonstrated its influence on both coding and noncoding RNAs. Nonetheless, the explicit impact of RNA methylation on lncRNAs and its subsequent contribution to the progression of BCa remains to be elucidated. METHODS: In the present investigation, we scrutinized the expression and m6A methylation status of LINC01106, employing quantitative real-time PCR (qRT-PCR) and methylated RNA immunoprecipitation (MeRIP)-qPCR. To decipher the regulatory mechanism underpinning LINC01106, we utilized RNA immunoprecipitation (RIP)-qPCR, methylated RNA immunoprecipitation (MeRIP) assays, and bioinformatic analysis. Furthermore, the CRISPR/dCas13b-METTL3-METTL14 system was implemented to probe the function of LINC01106. RESULTS: The findings of our study indicated that LINC01106 is under expressed and exhibits diminished m6A methylation levels in BCa tissues when compared those of normal controls. A diminished expression of LINC01106 was associated with a less favorable prognosis in BCa patients. Intriguingly, CRISPR-mediated hypermethylation of LINC01106, facilitated by dCas13b-M3-M14, abolished the malignant phenotype of the BCa cells, an effect that could be inverted by Disabled-1 (DAB1) knockdown. From a mechanistic standpoint, we identified an m6A modification site on LINC01106 and highlighted YTHDC1 as a potential reader protein implicated in this process. Additionally, a positive correlation between DAB1 and LINC01106 expression was observed, with miR-3148 potentially acting as a mediator in this relationship. CONCLUSIONS: In summary, our research unveils a suppressive regulatory role of the LINC01106/miR-3148/DAB1 axis in the progression of BCa and underscores the YTHDC1-mediated m6A modification mechanism in regards to LINC01106. These revelations propose a new therapeutic target for the management of BCa.

Comparative analysis of salvage partial nephrectomy versus radical nephrectomy after the failure of initial partial nephrectomy.

OBJECTIVES: To compare the oncologic outcomes and renal function discrepancy of salvage partial nephrectomy (sPN) and salvage radical nephrectomy (sRN) after an initial failed PN. MATERIALS AND METHODS: Retrospective data from multiple centers between 2008 and 2022 were analyzed in this study. Patients who received sPN or sRN after an initial failed PN were identified. Comparative analysis and propensity score matching (PSM) was performed and the RENAL score, tumor size, and pathological T stage at salvage surgery were used to match the 2 groups. Local recurrence-free survival (LRFS) and recurrence-free survival (RFS) were assessed using the Cox proportional hazards model and log-rank tests. Renal function after salvage surgery was assessed using the Wilcoxon rank sum test. RESULTS: A total of 140 patients who underwent salvage surgery were evaluated, of whom 60 were considered for PSM analysis after matching. At a median follow-up of 27.0 months, LRFS and RFS showed no significant difference between sPN and sRN, either before (LRFS, HR = 0.673 [95% CI: 0.171-2.644], P = 0.610; RFS, HR = 0.744 [95% CI: 0.271-1.344], P = 0.595) or after matching (LRFS, HR = 1.080 [95% CI: 0.067-17.30], P = 0.957; RFS, HR = 1.199 [95% CI: 0.241-5.983], P = 0.822). During long-term follow-up, sPN preserved renal function (after matching, eGFR, 71.4 vs. 54.0, P < 0.001) and prevented eGFR loss (after matching: 6.6% vs. 25.6%, P < 0.001). CONCLUSION: Salvage partial nephrectomy offers a better alternative than sRN for recurrence after initial PN, as sPN preserves renal function better while maintaining parallel tumor control and acceptable complication rates.

Development of Prognostic Biomarkers by TMB-Guided WSI Analysis: A Two-Step Approach.

The rapid development of computational pathology has brought new opportunities for prognosis prediction using histopathological images. However, the existing deep learning frameworks lack exploration of the relationship between images and other prognostic information, resulting in poor interpretability. Tumor mutation burden (TMB) is a promising biomarker for predicting the survival outcomes of cancer patients, but its measurement is costly. Its heterogeneity may be reflected in histopathological images. Here, we report a two-step framework for prognostic prediction using whole-slide images (WSIs). First, the framework adopts a deep residual network to encode the phenotype of WSIs and classifies patient-level TMB by the deep features after aggregation and dimensionality reduction. Then, the patients' prognosis is stratified by the TMB-related information obtained during the classification model development. Deep learning feature extraction and TMB classification model construction are performed on an in-house dataset of 295 Haematoxylin & Eosin stained WSIs of clear cell renal cell carcinoma (ccRCC). The development and evaluation of prognostic biomarkers are performed on The Cancer Genome Atlas-Kidney ccRCC (TCGA-KIRC) project with 304 WSIs. Our framework achieves good performance for TMB classification with an area under the receiver operating characteristic curve (AUC) of 0.813 on the validation set. Through survival analysis, our proposed prognostic biomarkers can achieve significant stratification of patients' overall survival (P 0.05) and outperform the original TMB signature in risk stratification of patients with advanced disease. The results indicate the feasibility of mining TMB-related information from WSI to achieve stepwise prognosis prediction.

Concomitant Treatment of Ureteropelvic Junction Obstruction Complicated by Renal Calculi with Laparoscopic Pyeloplasty and Pyelolithotomy via 19.5F Rigid Nephroscope: A Report of 12 Cases.

Objective: To introduce our experience of concomitant laparoscopic pyeloplasty (LP) and pyelolithotomy via 19.5 F rigid nephroscope to treat ureteropelvic junction obstruction (UPJO) complicated with renal calculi.Methods: The data of 42 patients with UPJO who underwent LP from June 2016 to August 2019 were retrospectively reviewed. Twelve patients with ipsilateral renal calculi underwent LP and concomitant pyelolithotomy via 19.5 F rigid nephroscope. Perioperative data of this group were compared with other 12 matched patients without calculi who underwent LP only.Results: Of 12 patients with renal calculi, only 4 patients had simple stone and the other 8 patients suffered complex stones. Anatomical solitary kidney was found in 2 patients. The mean diameter of the largest stone was 1.1 cm (ranged from 0.6 to 1.7). The mean operative time was 171 min, the mean time of nephroscopic management was 17.2 min, 7 patients received pyelolithotomy by forceps, 3 patients received pyelolithotomy and ultrasonic lithotripsy, 1 patient received ultrasonic lithotripsy, the mean number of stones retrieved was 8.9 (ranged from 0-53), in one case the calculus was inaccessible because it was located in a narrow neck caliceal diverticulum. Overall stone-free rate was 91.7% (11/12). No difference in operative time, postoperative hemoglobin drop, postoperative hospital stay and incidence of complications was observed between the 2 groups. At the mean follow-up of 17.9 months, no patients had obstruction or recurrent stones.Conclusion: LP and concomitant pyelolithotomy via 19.5 F rigid nephroscope is a safe and feasible option to treat UPJO with renal calculi, with acceptable success rate and stone-free rate.

The Clinicopathological Features and Prognosis in Patients With Papillary Renal Cell Carcinoma: A Multicenter Retrospective Study in Chinese Population.

OBJECTIVE: The purpose of this study was to compare the clinicopathological characteristics of type 1 and type 2 papillary renal cell carcinoma (PRCC) and to explore the prognostic factors of PRCC in the Chinese population. METHODS: A total of 242 patients with PRCC from five Chinese medical centers were retrospectively included. From them, 82 were type 1 PRCC and 160 were type 2 PRCC. Clinicopathological features and oncologic outcomes were reviewed. The Kaplan-Meier analysis and log-rank test were performed to describe the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic factors of PRCC. RESULTS: Of the 242 patients, the average age at surgery was 55.3 ± 13.1 years. The mean tumor size was 5.1 ± 3.1 cm. Compared with type 1 PRCC patients, type 2 PRCC patients had a larger tumor size and were more likely to undergo radical nephrectomy. Besides, type 2 PRCC patients had higher tumor stage (p < 0.001) and WHO International Society of Urological Pathology (WHO/ISUP) grading (p < 0.001). Furthermore, tumor necrosis was more common in type 2 PRCC than type 1 PRCC (p = 0.030). The Kaplan-Meier survival analysis showed that the PFS and OS of type 1 PRCC patients were significantly better than those of type 2 PRCC patients (p = 0.0032 and p = 0.0385, respectively). Univariate analysis showed that tumor size, surgical procedures, pT stage, WHO/ISUP grading, and microvascular invasion were significant predictors of PFS and OS for type 2 PRCC patients. In the multivariate analysis, only pT stage (p = 0.004) and WHO/ISUP grading (p = 0.010) were the independent risk factors. Among type 2 PRCC patients with pT1 stage, no significant difference was found in PFS and OS between the partial nephrectomy and radical nephrectomy groups (p = 0.159 and p = 0.239, respectively). CONCLUSION: This multi-institutional study reveals the significant differences in clinicopathological variables and oncologic outcomes between type 1 and 2 PRCC. For type 2 PRCC in pT1 stage, the prognosis of partial nephrectomy is not inferior to that of radical nephrectomy, and nephron-sparing surgery can be considered.

Deep Learning with Quantitative Features of Magnetic Resonance Images to Predict Biochemical Recurrence of Radical Prostatectomy: A Multi-Center Study.

Biochemical recurrence (BCR) occurs in up to 27% of patients after radical prostatectomy (RP) and often compromises oncologic survival. To determine whether imaging signatures on clinical prostate magnetic resonance imaging (MRI) could noninvasively characterize biochemical recurrence and optimize treatment. We retrospectively enrolled 485 patients underwent RP from 2010 to 2017 in three institutions. Quantitative and interpretable features were extracted from T2 delineated tumors. Deep learning-based survival analysis was then applied to develop the deep-radiomic signature (DRS-BCR). The model's performance was further evaluated, in comparison with conventional clinical models. The model achieved C-index of 0.802 in both primary and validating cohorts, outweighed the CAPRA-S score (0.677), NCCN model (0.586) and Gleason grade group systems (0.583). With application analysis, DRS-BCR model can significantly reduce false-positive predictions, so that nearly one-third of patients could benefit from the model by avoiding overtreatments. The deep learning-based survival analysis assisted quantitative image features from MRI performed well in prediction for BCR and has significant potential in optimizing systemic neoadjuvant or adjuvant therapies for prostate cancer patients.

CRDet: Improving Signet Ring Cell Detection by Reinforcing the Classification Branch.

Detecting signet ring cells on histopathologic images is a critical computer-aided diagnostic task that is highly relevant to cancer grading and patients' survival rates. However, the cells are densely distributed and exhibit diverse and complex visual patterns in the image, together with the commonly observed incomplete annotation issue, posing a significant barrier to accurate detection. In this article, we propose to mitigate the detection difficulty from a model reinforcement point of view. Specifically, we devise a Classification Reinforcement Detection Network (CRDet). It is featured by adding a dedicated Classification Reinforcement Branch (CRB) on top of the architecture of Cascade RCNN. The proposed CRB consists of a context pooling module to perform a more robust feature representation by fully making use of context information, and a feature enhancement classifier to generate a superior feature by leveraging the deconvolution and attention mechanism. With the enhanced feature, the small-sized cell can be better characterized and CRDet enjoys a more accurate signet ring cell identification. We validate our proposal on a large-scale real clinical signet ring cell data set. It is shown that CRDet outperforms several popular convolutional neural network-based object detection models on this particular task.

Patient-Level Prediction of Multi-Classification Task at Prostate MRI Based on End-to-End Framework Learning From Diagnostic Logic of Radiologists.

The grade groups (GGs) of Gleason scores (Gs) is the most critical indicator in the clinical diagnosis and treatment system of prostate cancer. End-to-end method for stratifying the patient-level pathological appearance of prostate cancer (PCa) in magnetic resonance (MRI) are of high demand for clinical decision. Existing methods typically employ a statistical method for integrating slice-level results to a patient-level result, which ignores the asymmetric use of ground truth (GT) and overall optimization. Therefore, more domain knowledge (e.g., diagnostic logic of radiologists) needs to be incorporated into the design of the framework. The patient-level GT is necessary to be logically assigned to each slice of a MRI to achieve joint optimization between slice-level analysis and patient-level decision-making. In this paper, we propose a framework (PCa-GGNet-v2) that learns from radiologists to capture signs in a separate two-dimensional (2-D) space of MRI and further associate them for the overall decision, where all steps are optimized jointly in an end-to-end trainable way. In the training phase, patient-level prediction is transferred from weak supervision to supervision with GT. An association route records the attentional slice for reweighting loss of MRI slices and interpretability. We evaluate our method in an in-house multi-center dataset (N = 570) and PROSTATEx (N = 204), which yields five-classification accuracy over 80% and AUC of 0.804 at patient-level respectively. Our method reveals the state-of-the-art performance for patient-level multi-classification task to personalized medicine.

Crossing vessels with suspension versus transposition in laparoscopic pyeloplasty of patients with ureteropelvic junction obstruction: a retrospective study.

PURPOSE: To compare the effects of two different methods of laparoscopic pyeloplasty for the treatment of crossing vessels. METHODS: From January 2016 to August 2019, 33 patients with ureteropelvic junction obstruction (UPJO) underwent laparoscopic pyeloplasty at our center, including 21 men and 12 women, ranging from 14 to 66 years of age. There were 20 and 13 cases on the left and right sides, respectively. Patients underwent laparoscopic pyeloplasty (Anderson-Hynes operation). During the operation, either a Hem-o-lok clip suspension or transposition was used to treat the crossing vessels. The double-J stent was removed 8 weeks after the operation. The clinical data of patients were collected and follow-ups were regularly performed after the operation. RESULTS: All the crossing vessels were successfully preserved, and none of them were severed during the operation. The average operation time was 210.6 ± 58.9 min in this group and the average time to manage the crossing vessel was 8.0 ± 3.5 min, 5.9 ± 1.4 min in the suspension group, and 11.7 ± 3.0 min in the transposition group. The dilation of the affected side was 4.8 ± 1.5 cm before operation and 1.2 ± 1.3 cm 3 months after operation. The difference was statistically significant (P < 0.05). Follow-up to February 2020 showed no significant changes in the kidney size in all patients and hydronephrosis was relieved. CONCLUSION: For UPJO patients with crossing vessel compression, the method of Hem-o-lok suspension or vascular transposition can be used to relieve crossing vascular compression and improve the success of pyeloplasty.

CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. METHODS: BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing. RESULTS: We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity. CONCLUSIONS: We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.

CREPT is required for murine stem cell maintenance during intestinal regeneration.

Intestinal stem cells (ISCs) residing in the crypts are critical for the continual self-renewal and rapid recovery of the intestinal epithelium. The regulatory mechanism of ISCs is not fully understood. Here we report that CREPT, a recently identified tumor-promoting protein, is required for the maintenance of murine ISCs. CREPT is preferably expressed in the crypts but not in the villi. Deletion of CREPT in the intestinal epithelium of mice (Vil-CREPTKO) results in lower body weight and slow migration of epithelial cells in the intestine. Vil-CREPTKO intestine fails to regenerate after X-ray irradiation and dextran sulfate sodium (DSS) treatment. Accordingly, the deletion of CREPT decreases the expression of genes related to the proliferation and differentiation of ISCs and reduces Lgr5+ cell numbers at homeostasis. We identify that CREPT deficiency downregulates Wnt signaling by impairing ß-catenin accumulation in the nucleus of the crypt cells during regeneration. Our study provides a previously undefined regulator of ISCs.

m6A-mRNA Methylation Regulates Gene Expression and Programmable m6A Modification of Cellular RNAs With CRISPR-Cas13b in Renal Cell Carcinoma.

Background: N6-methyladenosine (m6A) is the most extensive messenger RNA modification. Despite recent advances in the biological roles of m6A, its role in the development and progression of renal cell carcinoma (RCC) remains unclear. Methods: In this study, we gained the transcriptome-wide m6A profile and gene expression pattern in RCC and paired adjacent peritumoral tissues by meRIP-seq and RNA-seq. m6A modifications of mRNAs were validated by meRIP-qPCR in tissues, and targeted methylation or demethylation was validated by using a CRISPR-Cas13b-based tool in RCC cell lines. Results: Our findings showed that there were 13,805 m6A peaks among 5,568 coding gene transcripts (mRNAs) in adjacent tissues and 24,730 m6A peaks among 6,866 mRNAs in tumor tissues. Furthermore, m6A modification sites were usually located in the coding sequences (CDS), and some near the start and stop codons. Gene Ontology analysis revealed that coding genes had differential N6-methyladenosine sites and were enriched in kidney development and cancer-related signaling pathways. We also found that different levels of m6A modifications could regulate gene expression. Conclusion: In summary, our results provided evidence for studying the potential function of RNA m6A modification and m6A-mediated gene expression regulation in human RCC.

Challenges and management of laparoscopic treatment of pyonephrosis caused by calculi.

BACKGROUND: Calculous pyonephrosis is a disease characterized by infectious hydronephrosis associated with pyogenic destruction of the renal parenchyma, with complete or almost complete loss of renal function. METHODS: The clinical data of laparoscopic nephrolithotomy performed at Peking University People's Hospital from May 2017 to June 2020 were analyzed retrospectively. Eight patients (2 men; 6 women) aged 27 to 65 years (average age, 45.8 years) were included. Among them, 7 patients were treated with retroperitoneal approach and 1 patient by transperitoneal approach. All patients had received more than one endoscopic lithotripsy before nephrectomy. Renal dynamic imaging and computed tomography revealed the absence of function in pyonephrosis before nephrectomy. General clinical data and perioperative data were recorded. All nephrectomies were performed by the same physician. RESULTS: Laparoscopic surgery was successfully performed in 7 patients; however, 1 patient underwent open surgery because of bleeding. The operation time, average operation time, and blood loss were 1.5-4.5 h, 3.4 h, and 100-1000 ml (average, 300 ml), respectively. The postoperative pathology showed inflammatory renal disease in 6 patients, xanthogranulomatous pyelonephritis in 1 patient, and high-grade urothelial cancer in 1 patient. The average postoperative hospital stay was 5.3 days. One patient had a Clavien-Dindo Grade IIIb complication (severe hematuria), which required laparotomy, and was found that there was bleeding of ureteral stump. None of the patients experienced poor healing of endoscopic wounds. CONCLUSION: For patients with complicated calculous pyonephrosis, renal inflammation could not be effectively controlled, and renal function was seriously damaged. Thus, kidneys should be immediately resected. With laparoscopy, patients may recover quickly, but surgeons require enough experience when performing laparoscopy to achieve safety.

Radiologist-like artificial intelligence for grade group prediction of radical prostatectomy for reducing upgrading and downgrading from biopsy.

Rationale: To reduce upgrading and downgrading between needle biopsy (NB) and radical prostatectomy (RP) by predicting patient-level Gleason grade groups (GGs) of RP to avoid over- and under-treatment. Methods: In this study, we retrospectively enrolled 575 patients from two medical institutions. All patients received prebiopsy magnetic resonance (MR) examinations, and pathological evaluations of NB and RP were available. A total of 12,708 slices of original male pelvic MR images (T2-weighted sequences with fat suppression, T2WI-FS) containing 5405 slices of prostate tissue, and 2,753 tumor annotations (only T2WI-FS were annotated using RP pathological sections as ground truth) were analyzed for the prediction of patient-level RP GGs. We present a prostate cancer (PCa) framework, PCa-GGNet, that mimics radiologist behavior based on deep reinforcement learning (DRL). We developed and validated it using a multi-center format. Results: Accuracy (ACC) of our model outweighed NB results (0.815 [95% confidence interval (CI): 0.773-0.857] vs. 0.437 [95% CI: 0.335-0.539]). The PCa-GGNet scored higher (kappa value: 0.761) than NB (kappa value: 0.289). Our model significantly reduced the upgrading rate by 27.9% (P < 0.001) and downgrading rate by 6.4% (P = 0.029). Conclusions: DRL using MRI can be applied to the prediction of patient-level RP GGs to reduce upgrading and downgrading from biopsy, potentially improving the clinical benefits of prostate cancer oncologic controls.

Microultrasonic Probe Combined with Ultrasound-Guided Minipercutaneous Nephrolithotomy in the Treatment of Upper Ureteral and Renal Stones: A Consecutive Cohort Study.

Objectives: We conduct a study to assess the outcome of microultrasonic probe combined with ultrasound (US)-guided minipercutaneous nephrolithotomy (PCNL) for upper ureteral and renal stones. Patients and Methods: Data of 119 patients (123 kidney units) who underwent microultrasonic lithotripsy combined with mini-PCNL were retrospectively reviewed. The group included 96 men and 23 women. All procedure of puncture and dilatation were guided by US solely. Data were analyzed by SPSS. Results: The mean operation time was 32.6 minutes (range, 10-110 minutes). The mean time of lithotripsy and stone removal was 14.5 minutes (3-100 minutes). The mean postoperative length of stay was 2.7 days (1-7 days). Besides, stone-free rate (SFR) at discharge was 95.9% (118/123). The mean hemoglobin drop was 11.6 mg/dL (range 1-26 mg/dL). Grades I, II, and IIIa complications were observed in four, one, and one patients, respectively. Subgroup analysis was done to compare the outcomes of 20 mm or less vs 21 mm or more calculi. There was a longer operation duration (40 vs 29 minutes) and lower SFR in the 21 mm or more calculi subgroup. Conclusions: Microultrasonic probe combined with US-guided mini-PCNL is an effective and safe procedure to treat patients with upper ureteral and renal stones with higher SFR but lower complications.

Expression of CREPT is associated with poor prognosis of patients with renal cell carcinoma.

Cell-cycle-associated and expression-elevated protein in tumor (CREPT) functions as a cell cycle modulator that enhances the transcription of cyclin D1 by interacting with RNA polymerase II. CREPT has been identified to be overexpressed in various human cancer types; however, the expression and significance of CREPT in renal cell carcinoma (RCC) has remained largely elusive. In the present study, increased expression of CREPT was identified in 46.7% RCC tissues compared with adjacent normal tissue (31.1%; P=0.032) using immunohistochemistry. Furthermore, overexpression of CREPT was significantly associated with the Tumor-Node-Metastasis stage (χ2=11.967, P=0.001) and Fuhrman grade (χ2=15.453, P<0.001). In addition, increased expression of CREPT was associated with poor overall survival (P=0.021) and disease-free survival (P=0.015) of patients according to Kaplan-Meier analysis. Cellular function assays demonstrated that knockdown of CREPT in the 786-O and 769P RCC cell lines suppressed their proliferative, colony formation, migratory and invasive capacity and led to cell cycle arrest in the G1 phase. In addition, the western blotting analysis demonstrated that CREPT may control the cell cycle through downregulation of cyclin D1 and c-myc. Collectively, the overexpression of CREPT was indicated to be a negative prognostic factor for RCC, and CREPT may serve as a novel therapeutic target for the treatment of RCC.

MicroRNA-218 inhibits the cell proliferation and migration in clear cell renal cell carcinoma through targeting cancerous inhibitor of protein phosphatase 2A.

MicroRNAs (miRs) have emerged as critical modulators of tumor initiation and progression in numerous types of human cancer, including clear cell renal cell carcinoma (ccRCC), which is the most common subtype of renal cell carcinoma. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a newly characterized oncoprotein and its overexpression has been reported to promote cellular epithelial-mesenchymal transition and the tumor progression of ccRCC. The present study examined the effects of miR-218 on CIP2A expression in ccRCC cells. The results demonstrated that the expression level of miR-218 was lower in ccRCC tissues compared with that in adjacent non-tumor renal tissues. In addition, it was identified that miR-128 could directly bind to the 3'-untranslated region of CIP2A. Furthermore, a negative correlation between the expression levels of miR-218 and CIP2A was detected in ccRCC. Additionally, the downregulation of CIP2A or overexpression of miR-218 in ccRCC cells was revealed to inhibit cell proliferation and migration. In summary, these data suggest that miR-218 serves a role in the regulation of CIP2A and elucidate its consequences on tumor progression, tumor cell proliferation and migration. These results indicate that miR-218 may exhibit potential as a molecular target for the treatment of ccRCC.

The physiological roles of autophagy in the mammalian life cycle.

Autophagy is primarily an efficient intracellular catabolic pathway used for degradation of abnormal cellular protein aggregates and damaged organelles. Although autophagy was initially proposed to be a cellular stress responder, increasing evidence suggests that it carries out normal physiological roles in multiple biological processes. To date, autophagy has been identified in most organs and at many different developmental stages, indicating that it is not only essential for cellular homeostasis and renovation, but is also important for organ development. Herein, we summarize our current understanding of the functions of autophagy (which here refers to macroautophagy) in the mammalian life cycle.