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The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson’s trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin. In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis-related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis-related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin–mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway. [ABSTRACT FROM AUTHOR]

This study aims to investigate the biological role of RhoB in clear cell renal cell carcinoma (ccRCC). The expression of RhoB was examined in specimens of patients and cell lines by Western blot and Immunohistochemistry. The correlation between RhoB expression and clinicopathologic variables was also analyzed. The effects of RhoB on cell proliferation, cell cycle, cell apoptosis, and invasion/migration were detected by over-expression and knockdown of RhoB level in ccRCC cells via plasmids and RNAi. The results showed that RhoB was low-expressed in ccRCC surgical specimens and cell lines compared with adjacent normal renal tissues and normal human renal proximal tubular epithelial cell lines (HKC), and its protein expression level was significantly associated with the tumor pathologic parameter embracing tumor size(P = 0.0157), pT stage(P = 0.0035), TNM stage(P = 0.0024) and Fuhrman tumor grade(P = 0.0008). Further, over-expression of RhoB remarkably inhibited the cancer cell proliferation, colony formation and promoted cancer cell apoptosis, and aslo reduced the invasion and migration ability of ccRCC cells. Interestingly, up-regulation of RhoB could induce cell cycle arrest in G2/M phase and led to cell cycle regulators(CyclineB1,CDK1) and pro-apoptotic protein(casp3,casp9) aberrant expression. Moreover, knockdown of RhoB in HKC cells promoted cell proliferation and migration. Taken together, our study indicates that RhoB expression is decreased in ccRCC carcinogenesis and progression. Up-regulation of RhoB significantly inhibits ccRCC cell malignant phenotype. These findings show that RhoB may play a tumor suppressive role in ccRCC cells, raising its potential value in futural therapeutic target for the patients of ccRCC. [ABSTRACT FROM AUTHOR]

In this study, we investigated a potential regulatory role of FBI-1 in transcription factor activity of ETS-1. The protein interaction was identified between ETS-1 and FBI-1 in lovo cells. The accumulating data showed that FBI-1 promoted the recruitment of ETS-1 to endogenous promoter of its target genes and increase ETS-1 accumulation in the nuclear. Our work also indicated that the FBI-1 enhances ETS-1 transcription factor activity via down-regulating p53-mediated inhibition on ETS-1. Further, FBI-1 plays a role in regulation of colorectal carcinoma cells proliferation. These findings supported that FBI-1 might be a potential molecule target for treating colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Krüppel-like factor 4 (KLF4) is a transcription factor with diverse functions in various cancer types; however, the function of KLF4 in clear cell renal cell carcinoma (ccRCC) carcinogenesis remains unknown. In this study, we initially examined KLF4 expression by using a cohort of surgically removed ccRCC specimens and cell lines. Results indicated that the transcription and translation of KLF4 were lower in ccRCC tissues than in patient-matched normal tissues. Furthermore, the KLF4 expression was significantly downregulated in the five ccRCC cell lines at protein and mRNA levels compared with that in normal renal proximal tubular epithelial cell lines (HKC). KLF4 downregulation was significantly correlated with tumor stage and tumor diameter. Promoter hypermethylation may contribute to its low expression. In addition, in vitro studies indicated that the KLF4 overexpression significantly inhibited proliferation in human ccRCC cell lines 786-O and ACHN. Moreover, the KLF4 overexpression arrested the cell cycle progress at the G1/S phase transition by upregulating p21WAF1/CIP1 expression and downregulating cyclin D1 expression, KLF4 knockdown in HKC cells did the opposite. In vivo studies confirmed the anti-proliferative effect of KLF4. Our results suggested that KLF4 had an important function in suppressing the growth of ccRCC. [ABSTRACT FROM AUTHOR]

Background:Transcription factor E2F1 exerts effects on many types of cancers. As an upstream regulator of a host of genes, E2F1 can trigger diverse aberrant transcription processes that may dominate malignancy. Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma which displays high malignancy and has a shortage of biomarkers in clinics. Our study aimed to explore the function of E2F1 in ccRCC and its correlation with clinicopathological parameters. Methodology/Principle Findings:Transcription factor E2F1 was mainly distributed in cancer cell nucleus and mRNA expression significantly increased in 72 cases of clear cell renal cell carcinoma (ccRCC) tissues compared with adjacent non-cancerous kidney tissues (p<0.001). The protein expression was consistent with mRNA expression. Further analysis in 92 cases indicated that E2F1 mRNA level expression was associated with the tumor pathologic parameters embracing diameter, Fuhrman tumor grade, pT stage, TNM stage grouping and macrovascular infiltration (MAVI). These surgical specimens had high grade tumors accompanied with an elevated E2F1 expression. Moreover, E2F1 transfection was found to contribute significantly to cancer cell proliferation, migration and invasion in vitro. Conclusions/Significance:Overexpression of E2F1 may be a key event in the local and vascular infiltration of ccRCC indicated by the activation of matrix metalloproteinase (MMP) 2 and MMP9. These findings highlighted the implication of E2F1’s function in the metastatic process. Furthermore, the clinical relevance of E2F1 in ccRCC pointed to a potential new therapeutic target. [ABSTRACT FROM AUTHOR]