LncRNA UCA1 promotes renal cell carcinoma proliferation through epigenetically repressing p21 expression and negatively regulating miR-495.

Long non-coding RNAs have recently emerged as important regulators in the pathogenesis and progression of cancers. The long non-coding RNA urothelial carcinoma-associated 1 is reportedly upregulated and functions as an oncogene in some tumors. However, the role of urothelial carcinoma-associated 1 in renal cell carcinoma is not well elucidated so far. In this study, we found that urothelial carcinoma-associated 1 was overexpressed in renal cell carcinoma tissues compared with the adjacent normal tissues, and higher urothelial carcinoma-associated 1 expression levels were positively associated with advanced tumor stage and poor survival time in renal cell carcinoma patients. Further studies showed that knockdown of urothelial carcinoma-associated 1 suppressed renal cell carcinoma cell proliferation and S-phase cell number in vitro. Moreover, urothelial carcinoma-associated 1 was found to be associated with enhancer of zeste homolog 2, which suppressed p21 expression through histone methylation (H3K27me3) on p21 promoter. We also showed that knockdown of urothelial carcinoma-associated 1 increased the p21 protein expression through regulating enhancer of zeste homolog 2. In addition, bioinformatics analysis and dual-luciferase reporter assays confirmed that miR-495 was a target of urothelial carcinoma-associated 1 in renal cell carcinoma, and urothelial carcinoma-associated 1 promoted cell proliferation by negatively regulating miR-495. These findings illuminated that urothelial carcinoma-associated 1 promoted renal cell carcinoma progression through enhancer of zeste homolog 2 and interacted with miR-495. Overall, overexpression of urothelial carcinoma-associated 1 functions as an oncogene in renal cell carcinoma that may offer a novel therapeutic target for renal cell carcinoma patients.

Pin1 in cardiovascular dysfunction: A potential double-edge role.

BACKGROUNDS: Our lab focused on the structural and functional properties of Pin1, which is the only known cis-trans isomerase regulating pSer/pThr-Pro motifs in proteins and facilitates various signaling pathways. We are lucky enough to read the article, contributed by Costantino et al. in your esteemed journal, on the role of Pin1 in diabetes-induced vascular dysfunction. Pin1 regulates the production of nitric oxide (NO), which is a key physiological stimulator of blood vessels and promotes vascular relaxation responses significantly. However, the regulation of cardiovascular diseases by Pin1 is somewhat controversial. METHODS AND RESULTS: We compared the recent studies that support the down-regulation, as well as up-regulation, of NO production by Pin1 and tried to explore the underlying molecular mechanisms. We especially compared the different regulations of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) by Pin1, which is potentially the major reason leading to the controversial role of Pin1. Interestingly, the regulation of both eNOS and iNOS by Pin1 involves a double-edge effect, positively and negatively, contributing to paradoxical Pin1 functions in different animal models and cell lines. The extremely complex Pin1-regulated signaling networks might further exacerbate distinct cellular responses in vivo and influence NO production. CONCLUSIONS: Pin1 plays a dual role, both positive and negative, in regulating NO production and in mediating the pathogenesis of cardiovascular diseases. Pin1 functions may vary a lot under different circumstances. Future investigations should focus on eNOS as well as iNOS in order to increase authenticity and accuracy of results.

Expression of RKIP, E-cadherin and NF-kB p65 in esophageal squamous cell carcinoma and their correlations.

To detect the expression of RKIP, E-cadherin and NF-kB p65 in esophageal squamous cell carcinoma (ESCC) and study their correlations. Steptavidin-peroxidase (S-P) method was employed to detect the expressions of RKIP, E-cadherin and NF-kB p65 in ESCC tissues from 77 cases and paracancerous tissues from 77 cases. The correlations between their expressions and clinicopathological indices and between the expressions of these proteins themselves were analyzed. The expressions of RKIP and E-cadherin in ESCC tissues were obviously lower than those in the paracancerous tissues (P<0.01); the expressions in ESCC tissues from cases with lymph node metastasis were lower than those from cases without lymph node metastasis (P<0.01); the expression of RKIP was positively correlated with the expression of E-cadherin in ESCC tissues (P<0.01). The expression of NF-kB p65 in ESCC tissues was correlated with clinical staging, lymph node metastasis and tumor differentiation (P<0.01); the expression of RKIP was negatively correlated with the expression of NF-kB p65 in ESCC tissues (P<0.05). Downregulation or depletion of RKIP was related to the onset and progression of ESCC, and facilitated the invasion and metastasis of ESCC by downregulating E-cadherin and upregulating NF-kB p65.

Reduction behavior induced by HL010183, a metformin derivative against the growth of cutaneous squamous cell carcinoma.

Metformin is a biguanide widely prescribed as a first-line antidiabetic drug in type 2 diabetes mellitus patients. Animal and cellular studies support that metformin has a strong anti-proliferative effect on various cancers. Herein, we report that metformin derivative, HL010183 significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which in turn is associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. Enhanced apoptotic cell death and an increase in Bax: Bcl2 ratio supported the tumor growth reduction. The mechanism of the drug effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 together with decreased phosphorylation of NFkB inhibitory protein IKBa were also observed. Further, AKT signaling activation was evaluated by the reduced phosphorylation at Ser473. In addition, a concomitant decrease in mTOR signaling pathway was also estimated from the reduced phosphorylation at mTOR regulatory proteins p70S6K and 4E-BP-1. Along with this, decreased phosphorylation of GSK3b, which is carried out by AKT kinases was also observed. Overall results suggested that HL010183 interrupt SCC growth via NFkB and mTOR signaling pathways.