Xiancheng Li

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 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.

Livin mediates tumor cell invasion in the DU-145 cell line via NF-κB

Livin is a member of the family of inhibitors of apoptosis proteins (IAPs) and tumor cell invasion is a general property of multiple IAPs. Livin is highly expressed in prostate cancer (PCa) tissues. Livin overexpressing cells are more resistant to apoptotic stimuli than normal cells. Thus, aberrantly increased cell survival is an invariable requirement of metastasis. In this study, we investigated whether livin signaling affects metastasis by transfecting siRNA targeting livin into the DU-145 prostate cancer cell line to confirm the anti-invasion effect and blockade of the livin gene. We found that livin knockdown inhibited DU-145 prostate carcinoma cell invasion. We investigated how livin promotes tumor cell invasion, and found that livin induction of fibronectin contributed to tumor cell invasion. In addition, we found that livin induction of fibronectin regulates tumor cell invasion via nuclear factor κB (NF-κB) signaling. These data showed that livin, as a gene directly promoting metastasis, can be useful for therapeutic intervention against advanced and disseminated PCa.

Low extracellular lysyl oxidase expression is associated with poor prognosis in patients with prostate cancer

Remodeling of the extracellular matrix (ECM), which is induced by lysyl oxidase (LOX), has been demonstrated to accompany tumor progression; however, the association between LOX expression levels and the malignant behavior of prostate cancer (Pca) remains unclear. The present study aimed to analyze the tumor-associated expression profile of LOX in patients with Pca and to evaluate its potential prognostic value. In the form of a retrospective study, the expression patterns of LOX and collagen I were analyzed in patients with benign prostate hyperplasia and Pca by immunohistochemical examination. The results demonstrated that, with the initiation and progression of Pca, the expression levels of LOX and collagen I were closely associated with Gleason score and tumor stage. In addition, although LOX was expressed in cancer and non-cancer tissues, the differential expression pattern observed in the ECM of Pca cells may indicate that LOX is an important molecule that affects the progression of this disease. Therefore, LOX expression level in the ECM may function as an independent predictor of Pca.

Nodal activates smad and extracellular signal-regulated kinases 1/2 pathways promoting renal cell carcinoma proliferation.

Expression of the nodal gene is high in a number of tumor cell types and may promote tumor growth. The expression of lefty, an inhibitor of nodal is often reduced in tumor cells. To the best of our knowledge, few studies have investigated the expression of nodal and lefty in renal cell carcinoma (RCC) cells. In the present study, quantitative polymerase chain reaction assays demonstrated that the level of nodal expression in RCC cells was high compared with that of adjacent non-tumor tissue cells, while the opposite pattern was observed for the level of lefty expression. Furthermore, lefty overexpression in RCC cells inhibited the expression of nodal. Nodal overexpression promoted RCC cell proliferation and invasion, and inhibited RCC cell apoptosis. Nodal downregulation and lefty overexpression led to similar observations: The inhibition of RCC cell proliferation and invasion, and the promotion of RCC cell apoptosis. The results of the present study suggested that the expression of nodal promoted RCC growth by activating the smad and extracellular signal-regulated kinases 1/2 pathways. The expression of lefty in RCC cells was lower than that in adjacent non-tumor cells, which may result in the overexpression of nodal, thereby promoting the growth of RCC. The results of the present study may therefore be useful for the development of novel biomarkers for RCC tumor diagnosis, and suggest a potential target gene for the treatment of RCC.