WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription; however, its role in bladder cancer remains largely unknown. Our study investigated the role of WDR5 in bladder cancer and demonstrated that WDR5 was upregulated in bladder cancer tissues, and elevated WDR5 protein levels positively correlated with advanced tumor stage and poor survival. Through gain or loss of function, we demonstrated that WDR5 promoted proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro, and tumor growth in vivo. Mechanistically, WDR5 regulated various functions in bladder cancer by mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1, BIRC3 and Nanog by histone H3 lysine 4 trimethylation. Therefore, we have discovered that WDR5 plays an important role in bladder cancer suggesting that WDR5 is a potential biomarker and a promising target in the treatment of bladder cancer.

MicroRNAs (miRNAs) have emerged as post-transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Recently, cyclin-dependent kinase 6 (CDK6) is found to be up-regulated in several types of human tumors and has been implicated in cancer initiation and progression. We have identified miR-107 as a potential regulator of CDK6 expression. A bioinformatics search revealed a putative target site for miR-107 within the CDK6 3' untranslated region. Expression of miR-107 in gastric cancer cell lines was found inversely correlated with CDK6 expression. miR-107 could significantly suppress CDK6 3' UTR luciferase reporter activity, and this effect was not detectable when the putative 3' UTR target site was mutated. Consistent with the results of the reporter assay, ectopic expression of miR-107 reduced both mRNA and protein expression levels of CDK6, inhibited proliferation, induced G1 cell cycle arrest, and blocked invasion of the gastric cancer cells. Our results suggest that miR-107 may have a tumor suppressor function by directly targeting CDK6 to inhibit the proliferation and invasion activities of gastric cancer cells.

Polyacrylamide (PAM) is a water-soluble polymer that is widely used as a flocculant in sewage treatment. The accumulation of PAM affects the formation of dewatered sludge and potentially produces hazardous monomers. In the present study, the bacterial strain HI47 was isolated from dewatered sludge. This strain could metabolize PAM as its sole nutrient source and was subsequently identified as Pseudomonas putida. The efficiency of PAM degradation was 31.1% in 7 days and exceeded 45% under optimum culture condition (pH 7.2, 39 °C and 100 rpm). The addition of yeast extract and glucose improved the bacterial growth and PAM degradation. The degraded PAM samples were analyzed by gel-filtration chromatography, Fourier transform infrared and high-performance liquid chromatography. The results showed that high-molecular-weight PAM was partly cleaved to small molecular oligomer derivatives and part of the amide groups of PAM had been converted to carboxyl groups. The biodegradation did not accumulate acrylamide monomers. Based on the SDS-PAGE and N-terminal sequencing results, the PAM amide groups were converted into carboxyl groups by a PAM-induced extracellular enzyme from the aliphatic amidase family.

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Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop.

LMX1A is epigenetically inactivated in cervical cancer. However, the expression and methylation status of LMX1A in gastric cancer tissues remains unknown. In the present study, we found that the expression of LMX1A was significantly decreased in gastric cancer tissues compared with normal tissues. A statistically significant inverse association was found between the LMX1A methylation status and expression of LMX1A in tumor tissues (P = 0.008). Restoration of LMX1A induced cell apoptosis and suppressed anchorage-independent growth, suggesting LMX1A may be a potential biomarker for gastric cancer. (Cancer Sci 2011; 102: 361-366) T he LIM homeobox transcription factor 1, alpha (LMX1A) gene maps to 1q24.1 and is one of the group of LIM homeobox-containing genes that encode LIM-homeodomain (LIM-HD).(1,2) It is proven that LMX1A is a critical regulator of cell-fate decisions using genetic fate mapping in wild-type and LMX1A () ⁄ )) mice.(3) LMX1A also plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells. In the developing cerebellum, loss of LMX1A completely abolishes roof plate induction in the spinal cord.(4) Recently, evidence for the role of LMX1A in cancers has been found. For example, LMX1A was identified as a metastasis suppressor in cervical cancer.(5) It is well known that hypermethylation of CpG islands in their promoter regions is an important mechanism for loss of function of several tumor suppressor genes. (6,7) Like most tumor suppressors, LMX1A is methylated more frequently in squamous cell carcinoma tissues than in the normal cervix.(8) It was also reported that the methylation of LMX1A genes correlated with recurrence and overall survival of ovarian cancer patients.(8) Methylation of LMX1A was observed in a colon cancer cell line (HCT-116), and was demethylated in the DKO cell line genetically disrupted in DNMT1 and DNMT3B. (9) To characterize the role of LMX1A in gastric cancer, we examined a series of primary gastric cancers and control tissues for LMX1A expression and promoter methylation. Our results confirm frequent downregulation of LMX1A expression in primary gastric cancers and identify hypermethylation of the LMX1A gene as a common epigenetic aberration in these tumors. Materials and MethodsPatient samples and cell lines. Tumor samples were collected from surgical specimens from 50 patients with gastric cancer at the Department of Pathology, Minhang District Central Hospital, Shanghai, China. Non-tumor samples from the macroscopic tumor margin were isolated at the same time and used as the matched adjacent non-neoplastic tissues (>5 cm). Tissue samples were collected, immediately snap frozen in liquid nitrogen and stored at )80°C until RNA extraction. Informed consent was obtained for all samples and the institutional review board of Minhang District Central Hospital approved the study. All patients obtained a confirmed diagnosis of gastric carcinoma after resection. The five different established human gastric cancer cell lines used in the present study (AGS...

MicroRNA-155 (miR-155) is dysregulated in human cancers. In this study, we reported that miR-155 was over-expressed in bladder cancer tissues. We found that miR-155 promoted cell proliferation in vitro and tumorigenesis in vivo. MiR-155 directly reduced the expression of the tumor suppressor DMTF1. The expression of DMTF1 was decreased in bladder cancer tissues. Similar to the restoring miR-155 expression, knockdown of DMTF1 promoted cell growth and cell cycle progression, whereas DMTF1 over-expression rescued the effect of miR-155. Moreover, we investigated DMTF1-Arf-p53 pathway and found that DMTF1 worked in both p53-dependent and p53-independent manners. Taken together, our findings suggested that miR-155 functions as a tumor promoter in bladder cancer, which is partially through repressing DMTF1 expression. The identification of miR-155 and its novel target DMTF1 will be valuable in developing diagnostic markers and therapeutic applications for bladder cancer.

The ability of human embryonic stem cells (hESCs) to differentiate into skeletal muscle cells is an important criterion in using them as a cell source to ameliorate skeletal muscle impairments. However, differentiation of hESCs into skeletal muscle cells still remains a challenge, often requiring introduction of transgenes. Here, we describe the use of WNT3A protein to promote in vitro myogenic commitment of hESC-derived cells and their subsequent in vivo function. Our findings show that the presence of WNT3A in culture medium significantly promotes myogenic commitment of hESC-derived progenitors expressing a mesodermal marker, platelet-derived growth factor receptor-α (PDGFRA), as evident from the expression of myogenic markers, including DES, MYOG, MYH1, and MF20. In vivo transplantation of these committed cells into cardiotoxin-injured skeletal muscles of NOD/SCID mice reveals survival and engraftment of the donor cells. The cells contributed to the regeneration of damaged muscle fibers and the satellite cell compartment. In lieu of the limited cell source for treating skeletal muscle defects, the hESC-derived PDGFRA+ cells exhibit significant in vitro expansion while maintaining their myogenic potential. The results described in this study provide a proof-of-principle that myogenic progenitor cells with in vivo engraftment potential can be derived from hESCs without genetic manipulation.