Xiangyu Che

MicroRNA-21 (miR-21) Post-Transcriptionally Downregulates Tumor Suppressor PDCD4 and Promotes Cell Transformation, Proliferation, and Metastasis in Renal Cell Carcinoma

Objectives: MiR-21 induces neoplastic transformation, cell proliferation, and metastasis and downregulates programmed cell death4 (PDCD4) in some cancers. The aim of this study was to investigate the roles and interactions of PDCD4 and miR-21 in human renal cell carcinoma (RCC). Materials and Methods: A total of 32 paired tumor and normal tissue specimens from RCC patients as well as three renal cancer cell lines (786-O, A498, caki-1) and one normal epithelial kidney cell line (HK-2) were studied. The expression levels of PDCD4 (protein and mRNA) and miR-21 were examined by Western blot analysis and by qRT-PCR and luciferase reporter assays. Furthermore, we transfected 786-O cells with pre-miR-21 (mimics) and anti-miR-21 (inhibitor) and then again analyzed the expression of PDCD4 protein and mRNA, and determined cell proliferation and transformation capabilities by EDU and soft agar colony formation assay. Results: MiR-21 expression was significantly upregulated in RCC, metastatic RCC specimens and renal cancer cell lines (A498, 786-O, caki-1) compared to normal non-metastatic RCC specimens and HK-2 cells (P<0.05). In contrast, PDCD4 protein expression significantly decreased (P<0.05), whereas PDCD4 mRNA expression remained unaltered (P>0.05). Moreover, we observed a significant reduction in PDCD4 protein levels in miR-21mimic-transfected cells, but a significant increase in miR-21inhibitor-transfected cells (P<0.05), whereas PDCD4 mRNA was practically unaltered (P>0.05). Furthermore, miR-21mimic-transfected cells exhibited increased cell proliferation and transformation capacity according to EDU analysis and soft agar formation assay, whereas miR-21inhibitor-transfected cells exhibited the opposite phenomenon(P<0.05). Conclusions: MiR-21 not only promoted cancer cell hyperplasia and contributed to tumor cell transformation and metastasis, but also post-transcriptionally downregulated PDCD4 protein expression. PDCD4 and miR-21 expression levels potentially play an important role in renal cell cancer.

Can tamsulosin facilitate expulsion of ureteral stones? A meta‐analysis of randomized controlled trials

To determine the efficacy and safety of the adrenergic alpha‐antagonist tamsulosin in facilitating ureteral stones expulsion.

Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients.

PURPOSE To evaluate the tumor-related expression profile of cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein (cIAP2) in patients with bladder cell carcinoma (BCC) and to investigate its potential prognostic value. METHODS The expression of cIAP1 and cIAP2 was examined immunohistochemically in archival bladder specimens from 32 normal controls and 102 consecutive patients who underwent surgical operations at our department from January 2004 through December 2005. Cytoplasm cIAP1 and cIAP2 expression was scored as 0 (negative), +1 (weak), +2 (medium), and +3 (strong). Nuclear cIAP1 expression was scored as 0 (0%), +1 (1%-25%), +2 (26%-50%), and +3 (>50%). Proliferation was determined by Ki67 staining as percentage of positive cells. RESULTS cIAP1 and cIAP2 expression were significantly increased in bladder cancer compared with normal bladder urothelium (cIAP1-C: P < 0.01, cIAP2-C: P = 0.017, cIAP1-N: P < 0.01). Nuclear staining of cIAP1 (cIAP1-N) was significantly associated with tumor stage (muscle invasive vs. non-muscle invasive, P = 0.03) and tumor grade (low vs. high, P = 0.01). Both the mean overall survival and mean recurrence-free survival were significantly decreased in the high cIAP1-N group compared to the low cIAP1-N group (low cIAP1-N: mean overall survival 62.7 months, high cIAP1-N: mean overall survival 45.6 months, P < 0.01; low cIAP1-N: mean recurrence-free survival 44.2 months, high cIAP1-N: mean recurrence-free survival 30.1 months, P < 0.01). cIAP1-N expression correlated strongly with KI67 expression (r = 0.744, P < 0.01). CONCLUSION Nuclear cIAP-1 expression strongly correlated to bladder cancer stage, tumor grade, tumor recurrence and tumor related death. This marker expression was also appears to be a marker in bladder cancer prognosis.

Expression of the IAP protein family acts cooperatively to predict prognosis in human bladder cancer patients

The inhibitors of apoptosis (IAPs) are a group of anti-apoptotic factors in the apoptotic pathway that render cancer cells insensitive to apoptotic stimulation. Recently, several members of the IAP family have been investigated in the context of bladder cancer, and some of these have been associated with specific clinical and pathological tumor features, and with prognosis. These data suggested that the expression of an individual nuclear IAP has an important relationship with the progression of bladder cancer. To date, there are no studies concerning the overall tendencies of IAPs and their comparative therapeutic values in bladder cancer. In this study, we investigated the overall expression trends of the five tumor-related proteins, Survivin, cIAP1, cIAP2, XIAP and Livin, in normal bladder tissues and bladder cancer tissues. We classified and compared the gene expression data of these IAPs with the corresponding clinical and pathological tumor features, and with prognosis, in the development and progression of bladder cancer. The differences in IAP expression levels between archival bladder specimens from 36 normal controls and 105 patients who underwent surgery at our facility were examined using western blot analysis. The localization and expression level of each protein in low- and high-grade bladder cancer tissues were examined through immunohistochemistry. The cytoplasmic expression levels of each protein were scored as 0 (negative), +1 (weak), +2 (medium) or +3 (strong). The nuclear expression levels of cIAP1 and Survivin were scored as 0 (0%), +1 (1–25%), +2 (26–50%) or +3 (>50%). The results demonstrated that the expression of IAPs acted cooperatively to predict prognosis in human bladder cancer patients.

Livin-α promotes cell proliferation by regulating G1-S cell cycle transition in prostate cancer.

Prostate cancer is the third most common cancer and the second leading cause of cancer death for males in US. Livin has recently been described as a cancer‐associated member of inhibitor of apoptosis proteins family, highly expressed in prostate cancer. Livin gene encodes two splicing variants, termed Livin‐α and Livin‐β. We hypothesized that deregulation of proliferation could be due in part to Livin expression.

Effect of lymph node dissection on the outcomes of upper tract urothelial carcinomas: a meta-analysis

A systematic search was conducted in PubMed, Cochrane Library. 6032 patients were included. There was no significant difference in survival between LND and NLND (non-lymph node dissection) among the patients. However, the patients in the LND group had more advanced tumour stages and grades (p < 0.001). In addition, among the muscle-invasive patients, LND demonstrated remarkable CSS improvement compared with NLND (HR: 2.19; 95% CI: 1.26–3.80; p = 0.005). Moreover, subgroup analyses found that patients with muscle-invasive UTUC had better CSS (HR: 1.22; 95% CI: 1.02–1.45; p < 0.001) than those patients with pN0 compared to pNx (NLND). In terms of RFS, the results showed no difference in the survival rates between pN0 and pNx patients in the subgroup of patients with muscle-invasive UTUC (HR: 1.40; 95% CI: 0.84–2.23; p = 0.19). Our meta-analysis supports that LND may prolong the CSS and RFS of UTUC, especially for patients with muscle-invasive UTUC.

Suppression of Livin Gene Expression by siRNA Leads to Growth Inhibition and Apoptosis Induction in Human Bladder Cancer T24 Cells

Apoptosis deficiency is a hallmark of many cancer cells. Functional suppression of specific antiapoptotic factors might provide a feasible strategy in cancer gene therapy. Livin, the latest found inhibitor of apoptosis protein (IAP) family member, plays important role in cell growth and apoptosis. It has been reported that Livin is highly expressed in bladder cancer tissues. In this study, we found that, unlike other cancer cell lines, there was only Livin-α not Livin-β expression in bladder cancer cell lines. We further investigated the effects of Livin knockdown on human bladder cancer T24 cell growth and apoptosis. We found that small interfering RNA (siRNA) mediated Livin suppression significantly inhibited T24 cell proliferation and colony formation ability. Livin knockdown dramatically increased the T24 cell apoptotic rate in response to different proapoptotic stimuli, such as Mitomycin and TNF-alpha, and this was associated with caspase-3 and caspase-9 activation. These results suggest that Livin knockdown can inhibit cell growth and increase sensitivity to apoptotic stimuli, and might serve as a potent target in bladder cancer gene therapy.

Livin regulates prostate cancer cell invasion by impacting the NF-κB signaling pathway and the expression of FN and CXCR4

Prostate cancer (PCa) has the second highest mortality rate of all tumor‐related diseases for males in Western countries, and the incidence of PCa in China is increasing. Previous studies have proven that inhibitor of apoptosis proteins (IAPs) can regulate tumor cell invasion and metastasis. Livin is the most recently identified IAP. Our previous study showed that Livin might play an important role in the initiation of human PCa and that Livin‐α might promote cell proliferation by regulating the G1–S cell cycle transition. However, whether Livin, as an IAP, can regulate the invasive ability of PCa cells remains unknown. In this study, we found that the expression of Livin was higher in metastatic PCa tissues than in nonmetastatic tissues and that the expression of Livin was downregulated/upregulated by small interfering RNA/vector, which could inhibit/promote PC‐3/LNCaP cell invasion. This action was related to the impact of Livin on nuclear factor‐κB (NF‐κB) and its downstream signaling pathway, including FN and CXCR4. Together, our findings suggested that Livin might regulate tumor cell invasion in PCa directly, and that Livin might be an ideal candidate for preventing tumor cell invasion.

Alterations in mechanical properties are associated with prostate cancer progression

Abstract Cancer progression and metastasis have been shown to be accompanied by alterations in the mechanical properties of tissues, but the relationship between the mechanical properties and malignant behavior in prostate cancer (Pca) is less clear. The aims of this study were to detect the mechanical properties of benign prostatic hyperplasia (BPH) and Pca tissues on both the macro- and micro-scales, to explore the relationships between mechanical properties and malignant behavior and, finally, to identify the important molecules in the mechanotransduction signaling pathway. We demonstrated that the strain index of Pca tissue was significantly higher than that of BPH tissue on the macro-scale but the Young’s modulus of the Pca tissues, especially in advanced Pca, was lower than that of BPH tissues on the micro-scale. These two seemingly contradictory results can be explained by the excessive proliferation of tumor cells (Ki-67) and the degradation of scaffold proteins (collagens). These data indicate that alterations of the macro- and micro-mechanical properties of Pca tissues with malignant behavior are contradictory. The mechanical properties of tissues might be useful as a new risk factor for malignancy and metastasis in Pca. Furthermore, collagens, matrix metalloproteinase, fibronectin, and integrins might be the important molecules in the mechanotransduction signaling pathway.

Zinc sensitizes prostate cancer cells to sorafenib and regulates the expression of Livin

In prostate carcinogenesis, normal zinc-accumulating epithelial cells are transformed into malignant cells that do not accumulate zinc. Increased levels of zinc have been shown to induce apoptosis through a caspase-dependent mechanism with down-regulated anti-apoptotic proteins in prostate cancer cells. Our previous study showed that, as a member of the inhibitor of apoptosis proteins (IAPs) family, Livin could play an important role in the initiation of human prostate cancer and promote cell proliferation by altering the G1-S cell cycle transition. In the present study, we measured the apoptosis sensitivity of prostate cancer cells to zinc and sorafenib and found that zinc sensitized prostate cancer cells to sorafenib-induced apoptosis. Surprisingly, we also found that, unlike its counterparts Survivin and cIAP2, Livin was not decreased all the time; instead, it was compensatively increased in zinc-mediated apoptosis at 48 h in prostate cancer cells. Our results offer potential treatment combinations that may augment the effect of sorafenib, and also reveal, for the first time, that increased Livin expression may play a role in the early cell death response of prostate cancer cells to zinc.