Baijun Dong

Hypoxia‐induced downregulation of miR‐30c promotes epithelial‐mesenchymal transition in human renal cell carcinoma

MicroRNAs (miRNAs), which negatively regulate protein expression by binding protein‐coding mRNAs, have been integrated into cancer development and progression as either oncogenes or tumor suppressor genes. miR‐30c was reported to be downregulated in several types of cancer. However, its role in human renal cell carcinoma (RCC) remains largely unknown. Here, we show that miR‐30c is significantly downregulated in human RCC tissues and cell lines. We found that miR‐30c downregulation could be induced by hypoxia in RCC cells in a hypoxia‐inducible factors (HIFs) dependent manner. Repression of miR‐30c through its inhibitor resulted in reduction of E‐cadherin production and promotion of epithelial‐mesenchymal transition (EMT), while overexpression of miR‐30c inhibited EMT in RCC cells. We identified Slug as a direct target of miR‐30c in RCC cells. Slug was upregulated in RCC tissues and its expression could be induced by hypoxia, which is consistent with downregulation of miR‐30c by hypoxia. Forced overexpression of Slug in 786‐O cells reduced E‐cadherin production, and promoted EMT as well as cell migration. Moreover, Slug overexpression abrogated the inhibitory role of miR‐30c in regulating EMT and cell migration, indicating miR‐30c regulates EMT through Slug in RCC cells. Our findings propose a model that hypoxia induces EMT in RCC cells through downregulation of miR‐30c, which leads to subsequent increase of Slug expression and repression of E‐cadherin production, and suggest a potential application of miR‐30c in RCC treatment.

Effect of remote ischaemic preconditioning on renal protection in patients undergoing laparoscopic partial nephrectomy: a ‘blinded’ randomised controlled trial

To evaluate whether remote ischaemic preconditioning (RIPC) reduces renal injury in patients undergoing laparoscopic partial nephrectomy (LPN).

Downregulation of miR-221, -30d, and -15a contributes to pathogenesis of prostate cancer by targeting Bmi-1

Prostate cancer is the second leading cause of cancer-related deaths of men. Bmi-1, a member of PcG family of proteins, has been implicated in the pathogenesis of prostate cancer, and disturbed profile of microRNAs (miRNAs) has been found in prostate cancer tissues. How Bmi-1 is regulated by miRNAs is unclear. In this study, we screened 18 miRNAs that potentially repress the expression of Bmi-1 using a dual luciferase system and found that 12 miRNAs could bind with the 3′-untranslated region of Bmi-1 mRNA. Using qRT-PCR, we found that expression of miR-221, -15a, and -30d was significantly reduced in prostate cancer tissues. Subsequent functional study indicated that miR-221 and miR-30d can repress prostate cancer cell proliferation, and this effect can be partially rescued by Bmi-1 overexpression. Our study constructs the relation between downregulated miR-221 and miR-30d and prostate cancer pathogenesis. These results indicate that miR-221 and miR-30d are candidate tumor suppressor miRNAs in prostate cancer and therefore serve as potential clinical classification markers and therapeutic targets for human prostate cancer.

Monitoring laparoscopic radiofrequency renal lesions in real time using contrast-enhanced ultrasonography: An open-label, randomized, comparative pilot trial

BACKGROUND AND PURPOSE Radiofrequency ablation (RFA) has been considered as an important therapy for small renal lesions. The main limitation of RFA, however, is the lack of pathologic confirmation of complete tumor eradication. A single center, open label, randomized pilot study was designed to evaluate whether contrast-enhanced ultrasonography (CEUS) with Sonovue, performed in real time could allow us to determine the end point during laparoscopic radiofrequency ablation (LRFA) and the clinical outcome of this method. PATIENTS AND METHODS Ninety-six patients undergoing LRFA were randomly assigned to CEUS or a control group; finally, 38 and 40 patients with a pathologic diagnosis of renal-cell carcinoma completed a 3-month follow-up. CEUS was conducted in real time during the procedure to determine the end point in the CEUS group. The primary outcome was the incomplete ablation rate according to a radiographic image at 3 months after the procedure. The secondary outcome included the local tumor control rate and disease-free survival rate. RESULTS There were no differences in the incomplete ablation rate and disease-free survival rate between the two groups. Within a median 16-month follow-up period, three incomplete ablations and two local recurrences according to a radiographic image were found in the control group. Meanwhile, there was no incomplete ablation or recurrence but one lung metastasis in the CEUS group. The local tumor control rate was 87.5% (35/40) in the control group vs 100% (38/38) (P=0.073) in the CEUS group. CONCLUSION In patients undergoing LRFA, there were no differences in the incomplete ablation rate and local tumor control rate between the CEUS group and the control group in our study despite a nonsignificant trend in favor of CEUS. CEUS may have the potential to provide more effective renal tumor ablation. These novel data support the need for a larger study of CEUS during LRFA surgery.

AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis

Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.

Prediction and diagnosis of renal cell carcinoma using nuclear magnetic resonance-based serum metabolomics and self-organizing maps

Diagnosis of renal cell carcinoma (RCC) at an early stage is challenging, but it provides the best chance for cure. We aimed to develop a predictive diagnostic method for early-stage RCC based on a biomarker cluster using nuclear magnetic resonance (NMR)-based serum metabolomics and self-organizing maps (SOMs). We trained and validated the SOM model using serum metabolome data from 104 participants, including healthy individuals and early-stage RCC patients. To assess the predictive capability of the model, we analyzed an independent cohort of 22 subjects. We then used our method to evaluate changes in the metabolic patterns of 23 RCC patients before and after nephrectomy. A biomarker cluster of 7 metabolites (alanine, creatine, choline, isoleucine, lactate, leucine, and valine) was identified for the early diagnosis of RCC. The trained SOM model using a biomarker cluster was able to classify 22 test subjects into the appropriate categories. Following nephrectomy, all RCC patients were classified as healthy, which was indicative of metabolic recovery. But using a diagnostic criterion of 0.80, only 3 of the 23 subjects could not be confidently assessed as metabolically recovered after nephrectomy. We successfully followed-up 17 RCC patients for 8 years post-nephrectomy. Eleven of these patients who diagnosed as metabolic recovery remained healthy after 8 years. Our data suggest that a SOM model using a biomarker cluster from serum metabolome can accurately predict early RCC diagnosis and can be used to evaluate postoperative metabolic recovery.

Platelet to lymphocyte ratio as an independent prognostic indicator for prostate cancer patients receiving androgen deprivation therapy

BackgroundPlatelet to Lymphocyte ratio (PLR) is thought to be associated with a worse outcome in multiple types of cancer. However, the prognostic significance of PLR has not been investigated in the prostate cancer (PCa) patients receiving hormonal therapy. The objective of this study was to determine the prognostic value of PLR in PCa patients treated with androgen deprivation therapy (ADT).MethodsTwo-hundred-ninety prostate cancer patients who had undergone ADT as first-line therapy were retrospectively analyzed. The blood cell counts were performed at the time of diagnosis. PLR was calculated as the ratio of platelet count to lymphocyte count. Patients were categorized in two groups using a cut-off point of 117.58 as calculated by the receiver-operating curve analysis. Correlations between PLR and clinical characteristics were analyzed. Meanwhile, univariate and multivariate cox regression analyses were performed to determine the associations of PLR with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index.ResultsThe differences of age, serum prostate-specific antigen (PSA) level, Gleason score, risk stratification and incidence of metastasis between low PLR group (<117.58) and high PLR group (≥117.58) were not statistically significant (p > 0.05). Multivariate analyses identified PLR as an independent prognostic factor for PFS (hazard ratio (HR) = 1.581, p = 0.013), CSS (HR = 1.768, p = 0.037) and OS (HR = 1.650, p = 0.044). The addition of PLR to the final model improved predictive accuracy (c-index: 0.747, 0.801 and 0.768) for PFS, CSS and OS compared with the clinicopathological base model (c-index: 0.730, 0.778 and 0.746), which included Gleason score and incidence of metastasis.ConclusionsPLR might play a significant role in the prognosis of PCa patients treated with ADT. Thus, we recommend adding PLR to traditional prognostic model to improve the predictive accuracy.

Application of a standardized anatomical classification in a Chinese partial nephrectomy series.

Objective:  Preoperative aspects and dimensions used for an anatomical classification is a standardized system to assess the anatomical complexity of renal tumors and its impact on perioperative outcomes of partial nephrectomy. The objective is to apply the preoperative aspects and dimensions used for an anatomical classification in a series of Chinese patients undergoing open or laparoscopic partial nephrectomy.

RETRACTED ARTICLE: Cancer-associated fibroblasts promote renal cell carcinoma progression

The aim of this study was to determine the effect of cancer-associated fibroblasts (CAFs) on renal cell carcinoma (RCC) tumor proliferation, migration, and development of drug resistance, thus underlying their potential as therapeutic targets in RCC patients. CAFs were grown in primary cultures. The in vitro model of interaction of RCC cell lines with CAFs was established. The influence of CAFs on the proliferation and migration ability as well as sensitivity to everolimus of RCC cells was further analyzed. Furthermore, Western blotting analysis was performed to examine the mechanisms mediating the effect of CAFs on RCC cells. The results of the MTT assay showed that coculture with CAFs increased the proliferation activity of both 786-O and Caki-1 cells compared with serum-free medium controls. The migration ability of RCC cell lines was also significantly enhanced after coculture treatment compared with untreated control. The inhibition effect of everolimus on 786-O and Caki-1 cells abrogated in cocultures with CAFs. The sensitivity of both two cell lines to everolimus was dramatically decreased when cocultured with CAFs. RCC cells cocultured with CAFs resulted in the activation of both proliferation-related (Erks) and survival-related (Akt) pathways. These data indicate that CAFs have an important role in supporting and promoting RCC. The interaction of CAFs with RCC cell lines stimulates tumor cell proliferation and migration and induces resistance to everolimus in RCC cells, suggesting that target of the tumor microenvironment may be a novel targeted therapies for RCC.

Evaluation of expressed prostatic secretion and serum using surface-enhanced Raman spectroscopy for the noninvasive detection of prostate cancer, a preliminary study

Surface-enhanced Raman spectroscopy (SERS) involving expressed prostatic secretion (EPS) and serum was investigated; the objective was to determine if this approach could distinguish prostate cancer from benign prostatic hyperplasia. A total of 120 SERS spectra for EPS and 96 spectra for serum were gathered from patients within a prospective contemporary biopsy cohort. Significant differences in spectra between prostate cancer and benign prostatic hyperplasia were tentatively assigned to component changes in EPS and serum samples. Principal component analysis and linear discriminate analysis were utilized to evaluate the spectral data for EPS and serum, to build diagnostic algorithms. The leave-one-out cross-validation method was used to validate the diagnostic algorithms; it revealed diagnostic sensitivities of 75% and 60%, specificities of 75% and 76.5%, and accuracies of 75% and 68% for EPS and serum, respectively. The results suggest that EPS and serum SERS analysis could be a potential tool for prostate cancer detection.