Kuo Yang

Vasculogenic mimicry is a marker of poor prognosis in prostate cancer.

We investigated the role of vasculogenic mimicry (VM) in the progression of prostate cancer (PCa). Ninety-six patients who had undergone prostatectomy for treatment of PCa and for whom a complete record of clinical and follow-up data were available were reviewed. VM and matrix metalloproteinase-2 (MMP-2) were detected by immunohistochemical staining in frozen tissue sections. Relationship between VM and clinicopathological variables was analyzed statistically. Multivariate analyses were performed to assess the prognostic significance of VM. Results showed that out of the 96 PCa cases studied here, VM was detectable in 24 (25%) and was positively correlated with preoperative prostate-specific antigen (PSA) level, Gleason score, pathological stage, lymph node metastasis, seminal vesicle invasion, distant metastasis and PSA doubling time (PSADT). Univariate analysis showed that VM, PSA level, Gleason score, distant metastasis and PSADT were correlated with overall survival (OS), while VM, Gleason score, distant metastasis, local recurrence and PSADT were correlated with disease-free survival (DFS). Multivariable analysis indicated that the presence of VM, higher Gleason score and distant metastasis were the adverse predictors of OS and DFS. A higher widespread staining for MMP-2 was correlated with the VM-positive subgroup. In conclusion, VM mainly exists in the high risk PCa patients and is an independent marker of poor prognosis.

Double-targeted and double-enhanced suicide gene therapy mediated by generation 5 polyamidoamine dendrimers for prostate cancer.

Herpes simplex virus (HSV)‐thymidine kinase (TK)/ganciclovir (GCV) system is one of the most widely used and efficient suicide gene therapy for prostate cancer, but the lack of favorable gene vector and target limits its application. In this study, we established a novel system using nonviral gene vector G5‐PAMAM‐D to express HSV‐TK and connexin43 (Cx43) gene driven by prostate‐specific membrane antigen (PSMA) promoter, and evaluated the anti‐tumor effect of this system. G5‐PAMAM‐D delivered PSMAe/p‐TK‐Cx43 showed expression of TK and Cx43 only in LNCaP cells, but not in PC‐3 and other cells. The transfection efficiency of this system was comparable to lipofectamine 2000 by propidium iodide staining assay. With gemcitabine, folate‐G5‐PAMAM‐D delivered PSMAe/p‐TK‐Cx43 (folate‐G5‐PAMAM‐D/PSMAe/p‐TK‐Cx43) significantly decreased prostate cancer LNCaP cell proliferation and promoted apoptosis in vitro. With gemcitabine, the systemic deliver of folate‐G5‐PAMAM‐D/PSMAe/p‐TK‐Cx43 significantly inhibited tumor growth in the LNCaP xenograft animal model. Our study demonstrates that this double‐targeted and double‐enhanced system is effective in inducing cell growth inhibition and apoptosis in vitro and suppressing tumor growth in vivo. In conclusion, Cx43 and gemcitabine combined with HSV‐TK/GCV gene therapy using nonviral vector G5‐PAMAM‐D hold great potential as a novel approach for the gene therapy of prostate cancer.

PIM-1 gene RNA interference induces growth inhibition and apoptosis of prostate cancer cells and suppresses tumor progression in vivo†

The goal of this study was to investigate the roles of PIM‐1 in prostate cancer (CaP) cell proliferation and apoptosis, and to assess the potential of PIM‐1 as a target for CaP therapy.

miR-486-5p suppresses prostate cancer metastasis by targeting Snail and regulating epithelial–mesenchymal transition

The most common cause of death from prostate cancer (PCa) is metastases. There is an increasing body of evidence that microRNAs play an important role in the development of PCa by regulating target genes involved in tumor metastasis. Here, we identified that expression of miR-486-5p was decreased in metastatic C4-2 cells compared to non-metastatic LNCaP cells. Further validation in clinical samples showed that miR-486-5p expression was significantly decreased in metastatic PCa tissues compared to localized PCa tissues. Functional studies demonstrated that increased miR-486-5p expression can suppress cell migration and the invasive ability of C4-2 cells. Moreover, Snail, a key regulator of the epithelial–mesenchymal transition, was verified as a target gene of miR-486-5p. In conclusion, these findings suggest that miR-486-5p plays a suppressive role in mediating the migration and invasion of PCa by directly suppressing the protein expression of Snail and may provide a potential therapeutic target for the disease.

Formation of vasculogenic mimicry in bone metastasis of prostate cancer: Correlation with cell apoptosis and senescence regulation pathways

Vasculogenic mimicry (VM) has been found in prostate cancer (PCa) as an independent marker of poor prognosis. To investigate the correlation between VM and bone metastasis in PCa, a total of 80 cases were analyzed by CD31 and PAS dual-staining as well as the follow-up data. All cases were divided into two groups: VM-positive and VM-negative (VM-pos/VM-neg). Immunohistochemical staining for investigating the expression of Casepase-3, Bcl-2/Bax, and SA-β-gal was performed. 28 of the 80 PCa cases exhibited VM structure (35.0%). The incidence of bone metastasis in the VM-pos and VM-neg was 67.9% (19/28) and 38.5% (20/52), respectively. The positive rate of Casepase-3 and Bcl-2 expression was significantly different of the two groups (Caspases-3: VM-pos 71.4%, 20/28 vs VM-neg 42.3%, 22/52; Bcl-2: VM-pos 35.7%, 10/28 vs VM-neg 65.4%, 34/52). Bcl-2/Bax ratio of the VM-pos (0.71±0.22) was lower than that of the VM-pos (0.89±0.13). In addition, a higher frequency of SA-β-gal was detected in VM-pos (64.29±86.42) than in VM-neg (25.37±72.21). Taken together, our findings demonstrate that PCa with VM has the tendency to develop bone metastasis. Activations of cell apoptosis and senescence regulation pathways may play important roles in the formation process of VM structure.

Metformin Prevents Renal Stone Formation through an Antioxidant Mechanism In Vitro and In Vivo.

Oxidative stress is a causal factor and key promoter of urolithiasis associated with renal tubular epithelium cell injury. The present study was designed to investigate the preventive effects of metformin on renal tubular cell injury induced by oxalate and stone formation in a hyperoxaluric rat model. MTT assays were carried out to determine the protection of metformin from oxalate-induced cytotoxicity. The intracellular superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured in vitro. Male Sprague-Dawley rats were divided into control group, ethylene glycol (EG) treated group, and EG + metformin treated group. Oxidative stress and crystal formations were evaluated in renal tissues after 8-week treatment. Metformin significantly inhibited the decrease of the viability in MDCK cells and HK-2 cells induced by oxalate. Besides, metformin markedly prevented the increased concentration of MDA and the decreased tendency of SOD in oxalate-induced MDCK cells and HK-2 cells. In vivo, the increased MDA levels and the reduction of SOD activity were detected in the EG treated group compared with controls, while these parameters reversed in the EG + metformin treated group. Kidney crystal formation in the EG + metformin treated group was decreased significantly compared with the EG treated group. Metformin suppressed urinary crystal deposit formation through renal tubular cell protection and antioxidative effects.

Bone marrow mesenchymal stem cells participate in prostate carcinogenesis and promote growth of prostate cancer by cell fusion in vivo

The tumor microenvironment is comprised of diverse stromal cells that contribute towards tumor progression. As a result, there has been a growing interest in the role of bone marrow derived cells (BMDCs) in cancer progression. However, the role of BMDCs in prostate cancer (PCa) progression still remains unclear. In this study, we established GFP bone marrow transplanted TRAMP and MUN-induced prostate cancer models, in order to investigate the role of BMDCs in prostate cancer progression. By tracing GFP positive cells, we observed that BMDCS were recruited into mouse prostate tissues during tumorigenesis. GFP+/Sca-1+/CD45− BMDCs were significantly increased in the MNU-induced PCa group, as compared to the citrated-treated control group (2.67 ± 0.25% vs 0.67 ± 0.31%, p = 0.006). However, there were no significant differences found in GFP+/Sca-1+/CD45+ cell populations between the two groups (0.27 ± 0.15% vs 0.10 ± 0.10%, p = 0.334). Moreover, co-grafting of bone marrow mesenchymal stem cells (BMMSCs) and RM1 cells were found to promote RM1 tumor growth in vivo, and cell fusion was observed in RM-1+BMMSCs xenografts. Therefore, the data suggests that BMDCs can be recruited to the prostate during carcinogenesis, and that BMMSCs may promote the growth of PCa.

GATA3-driven expression of miR-503 inhibits prostate cancer progression by repressing ZNF217 expression.

Although increasing evidence demonstrated that deregulation of mircoRNA-503 (miRNA-503) contributes to tumorigenesis, little is known about the biological role and intrinsic regulatory mechanisms of miR-503 in prostate cancer (PCa). In present study, we found that miR-503 was significantly downregulated in advanced PCa tissues and cell lines. Downregulation of miR-503 was strongly associated with aggressive clinical-pathological features and poor prognosis in PCa patients. Ectopic expression of miR-503 significantly inhibited tumor cells growth, cell migration and invasion in vitro and in vivo. Mechanistic studies revealed that ZNF217 was a direct target downstream target of miR-503. Knockdown of ZNF217 mimicked the tumor-suppressive effects of miR-503 overexpression on PCa invasion, whereas ZNF217 overexpression attenuated the tumor-suppressive function of miR-503. Subsequently, miR-503 further modulated the activation of ZNF217-downstream epithelial-mesenchymal transition (EMT) genes. Besides, we also found that GATA3 directly increased miR-503 expression and thus decreased ZNF217 expression, indicating the involvement of GATA3/miR-503/ZNF217 signaling in EMT process. Collectively, our results demonstrated that GATA3-driven expression of miR-503 inhibits PCa progression by repressing ZNF217 expression, and also implicated the potential application of miR-503 in PCa therapy.

CtBP2 Overexpression is associated with tumorigenesis and poor clinical outcome of prostate cancer

Introduction The aim of the study was to evaluate the expression of CtBP2 in prostate cancer and to determine its relationship with clinicopathologic parameters. Material and methods The expression of CtBP2 in 119 prostate cancer tissues and 41 normal tissues was examined by qPCR and Western blot analysis, and the results were correlated with clinicopathologic parameters. Results CtBP2 expression in prostate cancer tissues was higher than that in normal samples. CtBP2 overexpression was closely correlated with serum prostatic specific antigen (PSA) (p = 0.018), advanced tumor stage (T3) (p = 0.025), higher Gleason scores (p = 0.019), positive extraprostatic extension (p = 0.012), positive vascular invasion (p = 0.011) and perineural invasion (p = 0.035). However, no significant association was found between CtBP2 abnormal expression and other parameters, including age (p = 0.776), positive lymph node (p = 0.872) and positive surgical margin (p = 0.37). Moreover, CtBP2 overexpression was significantly associated with poor clinical outcome of prostate cancer (p = 0.0168). Conclusions CtBP2 is overexpressed in prostate cancer, and its increased expression is closely associated with tumor progression and the outcome of prostate cancer.

Laparoscopic simple enucleation and coagulation on tumor bed using argon beam coagulator for treating small renal cell carcinomas: An animal study followed by clinical application

Summary Background The aim of our study was to evaluate the feasibility and clinical effect of laparoscopic simple enucleation and coagulation on tumor bed using an argon beam coagulator for treating small renal cell carcinomas. Material/Methods The animal experiments of coagulation therapy on the wound tissue bed during partial nephrectomy with an argon beam coagulator were performed on 16 rabbits, which were randomly divided into 4 groups. Groups A and B had renal artery occlusion; the treatment time of coagulation was 4 seconds and 6 seconds, respectively. Groups C and D did not have renal artery occlusion; the treatment time of coagulation was 2 seconds and 4 seconds, respectively. Then 30 clinical operations of laparoscopic simple enucleation and coagulation on tumor bed using an argon beam coagulator were performed. Results All 16 rabbits successfully underwent the operation. By the histological examination, the scab depth of the wound tissue bed in groups A, B, C, and D were 2.76±0.17 mm, 3.15±0.15 mm, 2.28±0.16 mm and 2.75±0.06 mm, respectively. Group A differed significantly from groups B and C (P=0.012, 0.007), and group D differed significantly from groups B and C (P=0.002, 0.002). In the clinical study, all 30 patients successfully underwent the operation. The mean operative time was 182 minutes, and the mean blood loss was 280 ml. With a median follow-up time of 37 months, neither local recurrence nor distant metastasis was found by computerized tomography scan. Conclusions Laparoscopic simple enucleation and coagulation on tumor bed using an argon beam coagulator can be considered for treating small renal cell carcinomas. However, the indication of this procedure should be highly selected.