Jiwei Huang

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).

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.

Renal mucinous tubular and spindle cell carcinoma: a report of 8 cases and review of the literature

BackgroundMucinous tubular and spindle cell carcinoma of kidney (MTSCC-K) is a rare variant of renal tumor. The current data show most of MTSCCs are of low malignant potential and rare cases metastatic to lymph nodes have been reported; however, the recorded computed tomography (CT) and follow up data are limited.Material and methodIn the present study, we retrospectively analyzed CT and clinicopathological data of eight patients with renal MTSCC-K.ResultsA total of eight cases, including six females and two males, were included in this analysis with a mean age of 48.4 (range 25 to 81) years. Mean tumor size was 4.2 (range 2.5 to 10.0) cm. Preoperative CT demonstrated that all tumors were slightly enhanced on both corticomedullary and nephrographic phase, which was different from many other renal cell carcinomas. Three of them were treated with open radical nephrectomy, three with laparoscopic radical nephrectomy and the other two with laparoscopic partial nephrectomy. No postoperative therapy was applied. Patients were followed up for 15 to 64 months and there was no evidence of recurrence and metastasis.ConclusionsThe MTSCC-K has special clinicopathological characteristics, low degree of malignancy and relative good prognosis. The diagnosis mainly depends on the histopathological examination and CT may help to differentiate with papillary renal cell carcinoma. Surgical treatment is recommended and additional therapies are not necessary.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8435581771088249.

Preoperative serum pre-albumin as an independent prognostic indicator in patients with localized upper tract urothelial carcinoma after radical nephroureterectomy

Purpose To investigate the prognostic value of preoperative pre-albumin and albumin level in patients with localized upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy. Methods and Materials Between January 2003 and June 2013, we evaluated data on 425 patients with nonmetastatic UTUC (Ta-4N0/+M0) who underwent radical nephroureterectomy at our institution. Low pre-albumin level was defined as <20 mg/dl, while hypoalbuminemia was defined as albumin <35 g/L. The associations of preoperative low pre-albumin level and hypoalbuminemia with clinical and pathologic variables were assessed. Univariable and multivariable analyses using the Cox regression model were performed to determine prognostic factors that were associated with cancer specific survival (CSS) and overall survival (OS). The Harrell concordance index with variables only or combined pre-albumin data were used to evaluate the prognostic accuracy. Results Compared with patients with high pre-albumin level, patients with low pre-albumin level were more likely to have older age, higher tumor stage, higher rate of diabetes, regional lymph node metastasis and lymphovascular invasion. Meanwhile, hypoalbuminemia was only associated with diabetes. Multivariate analysis identified decreased preoperative pre-albumin level as an independent prognostic factor for CSS (HR 1.85, 95% CI 1.14-3.00, p=0.013) and OS (HR 1.73, 95% CI 1.12-2.70, p=0.015), but not preoperative hypoalbuminemia. The estimated c-index of the multivariate model for CSS and OS increased from 0.771 and 0.760 without pre-albumin to 0.775 and 0.765 when pre-albumin added. Conclusions Low preoperative pre-albumin level but not preoperative hypoalbuminemia is a negative independent prognostic factor for survival outcome in patients with UTUC undergoing radical nephroureterectomy.

Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression

Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.

Prognostic value of preoperative plasma fibrinogen level and platelet-to-lymphocyte ratio (F-PLR) in patients with localized upper tract urothelial carcinoma

Purpose Hemostatic factors is thought to have a potentially significant role in progression and metastasis of malignant tumors. We investigated the prognostic value of preoperative plasma fibrinogen level and platelet-to-lymphocyte ratio (PLR) in localized upper tract urothelial carcinoma (UTUC). Materials and Methods A total of 481 patients who underwent radical nephroureterectomy for localized UTUC (pTa-4N0M0) were identified between January 2002 and June 2013. Patients were assigned a F-PLR score of 0, 1, or 2 based upon the presence of elevated plasma fibrinogen level, an elevated PLR, or both. The association between F-PLR score and clinicopathological variables was analysed. Results The optimal cut-off value of plasma fibrinogen and PLR for overall survival stratification was determined to be 4.22 and 241.2. Kaplan–Meier analysis revealed significant differences in cancer specific survival (CSS) and overall survival (OS) among patients with F–PLR scores of 0, 1 and 2. Multivariate analysis identified higher F–PLR score as an independent risk factor for CSS (P < 0.001) and OS (P < 0.001). The estimated c-index of the multivariate model for CSS and OS increased from 0.772 and 0.756 to 0.799 and 0.784 when F–PLR score added, which was higher than fibrinogen level, PLR or neutrophil-to-lymphocyte ratio added. Conclusions Preoperative F-PLR score is a negative independent prognostic factor for survival outcomes in patients with localized upper tract urothelial carcinoma. Preoperative F-PLR score may become a useful biomarker, particularly because of its low associated cost and easy accessibility.

The selective MEK1 inhibitor Selumetinib enhances the antitumor activity of everolimus against renal cell carcinoma in vitro and in vivo

Renal cell carcinoma (RCC) is a urologic malignant cancer and often diagnosed at an advanced stage, which results in high mortality. Targeted therapy may improve the quality of life and survival of patients who are not suitable for nephrectomy. Everolimus, an mTOR inhibitor, is currently used as sequential or second-line therapy for RCC refractory to Sunitinib or sorafenib. However, its efficiency is palliative. In this study, we evaluated whether the antitumor activity of everolimus against RCC is enhanced by selumetinib, a selective MEK1 inhibitor. We discovered that everolimus in combination with selumetinib synergistically inhibited the proliferation of Caki-1, 786-O and 769-P cells in vitro. Mechanistically, this combination decreased p-RPS6 and p-4E-BP1 dramatically, which causes G1 cell cycle arrest and prevents reactivation of AKT and ERK. In vivo, the antitumor efficacy and pharmacodynamic biomarkers of the combination therapy were recapitulated in Caki-1 xenograft model. In addition, this combination treatment potently inhibited angiogenesis in xenograft models by impairing VEGF secretion from tumor cells. Our findings provide a sound evidence that combination of everolimus and selumetinib is a potential dual-targeted strategy for renal cell carcinoma.

TIKI2 is upregulated and plays an oncogenic role in renal cell carcinoma.

TIKI2 is a negative regulator of the Wnt family. Although many Wnt antagonists play important roles in renal cell carcinoma (RCC), the molecular function of TIKI2 in human RCC has not been fully elucidated. Here, we analyzed TIKI2 mRNA level in RCC specimens, the corresponding non-tumor tissues, RCC cell lines, and human proximal tubule epithelial cell line HK-2 using qPCR. We demonstrated that TIKI2 was highly expressed in RCC tissue (P < 0.05) and most RCC cell lines. In vitro, TIKI2 knockdown significantly inhibited proliferation, invasion, and clone formation ability of 769-P cells compared with controls, while ectopic TIKI2 expression enhanced A498 cell proliferation, invasion, and clone formation ability. In vivo, the average tumor volume was significantly increased in mice injected with A498-Tiki2 cells (P < 0.05). In the 769-P cell TIKI2 knockdown group, the average tumor volume was not significantly different compared to that of the control group (P = 0.08). Moreover, Wnt/β-catenin signaling was not affected by TIKI2 knockdown or overexpression. Results of the present study indicate that TIKI2 is upregulated in RCC tissues and plays an oncogenic role in RCC.