Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.

BK-type K + channels are activated by voltage and intracellular Ca 2+ , which is important in modulating muscle contraction, neural transmission, and circadian pacemaker output. Previous studies suggest that the cytosolic domain of BK channels contains two different Ca 2+ binding sites, but the molecular composition of one of the sites is not completely known. Here we report, by systematic mutagenesis studies, the identification of E535 as part of this Ca 2+ binding site. This site is specific for binding to Ca 2+ but not Cd 2+. Experimental results and molecular modeling based on the X-ray crystallographic structures of the BK channel cytosolic domain suggest that the binding of Ca 2+ by the side chains of E535 and the previously identified D367 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, providing a basis to understand how Ca 2+ binding at this site opens the activation gate of the channel that is remotely located in the membrane. ] i . Because of this function, BK channels are important modulators of muscle contraction (1), neuronal spike frequency adaptation (2), neurotransmitter release (3), and circadian pacemaker output (4). BK channels are formed by four Slo1 subunits (5, 6). Each Slo1 contains a membrane-spanning domain, which comprises the pore-gate domain (PGD) and the voltage sensing domain (VSD), and a cytosolic domain (CTD) (7,8), which is made of two regulating domains for K + conductance (RCK1 and RCK2) (9, 10). Intracellular Ca 2+ binds to the CTD to activate the channel by enhancing the open probability of the activation gate located in the membrane-spanning PGD.Previous studies have identified two putative Ca 2+ binding sites in the CTD of BK channels, one is the Ca 2+ bowl located in the RCK2 domain (10-13) and the other is located in the RCK1 domain including the residue D367 (14). The existence of two distinctively different high-affinity Ca 2+ binding sites that are responsible for Ca 2+ -dependent activation of BK channels has been demonstrated in various experimental studies (15). These studies demonstrated that Ca 2+ binding to the two sites activates channel independently with only a small cooperativity (14,16,17), and the two sites show differences in various properties including affinities for Ca 2+ (14, 17), voltage dependence (17), and the molecular mechanisms of coupling to the activation gate (18). The distinction between the properties of the two putative Ca 2+ binding sites may lead to different physiological roles of these sites. For instance, a mutation in Slo1 that is associated with epilepsy and dyskinesia in human (19) specifically enhances the coupling of the RCK1 site to the activation gate to increase Ca 2+ sensitivity of channel activation (18). Although previous studies showed that the Ca 2+ binding site in RCK1 is important for physiological functions, its molecular identity is less certain than that of the Ca 2+ bowl. In the Ca 2+ bowl, previous mutagenesis studies (13) and a recently published X-ray cr...

Endometrial cancer is one of the most common cancers of the female reproductive system. Although surgery, radiotherapy, chemotherapy, and hormone therapy can significantly improve the survival of patients, the treatment of patients with very early lesions and a strong desire to retain reproductive function or late recurrence is still in the early stages. Metabolic syndrome (MS) is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Obesity, diabetes and hypertension often coexist in patients with endometrial cancer, which increases the risk of endometrial cancer, also known as the “triple syndrome of endometrial cancer.” In recent years, epidemiological and clinical studies have found that MS associated with metabolic diseases is closely related to the incidence of endometrial cancer. However, the key molecular mechanisms underlying the induction of endometrial cancer by MS have not been elucidated to date. Characterizing the tumor metabolism microenvironment will be advantageous for achieving a comprehensive view of the molecular mechanism of metabolic syndrome associated with endometrial cancer and for providing a new target for the treatment of endometrial cancer. This review focuses on recent advances in determining the role of metabolic syndrome-related factors and mechanisms in the pathogenesis of endometrial cancer. We suggest that interfering with the tumor metabolic microenvironment-related molecular signals may inhibit the occurrence of endometrial cancer.

Over the last several decades, increased agricultural production has been driven by improved agronomic practices and a dramatic increase in the use of nitrogen-containing fertilizers to maximize the yield potential of crops. To reduce input costs and to minimize the potential environmental impacts of nitrogen fertilizer that has been used to optimize yield, an increased understanding of the molecular responses to nitrogen under field conditions is critical for our ability to further improve agricultural sustainability. Using maize (Zea mays) as a model, we have characterized the transcriptional response of plants grown under limiting and sufficient nitrogen conditions and during the recovery of nitrogen-starved plants. We show that a large percentage (approximately 7%) of the maize transcriptome is nitrogen responsive, similar to previous observations in other plant species. Furthermore, we have used statistical approaches to identify a small set of genes whose expression profiles can quantitatively assess the response of plants to varying nitrogen conditions. Using a composite gene expression scoring system, this single set of biomarker genes can accurately assess nitrogen responses independently of genotype, developmental stage, tissue type, or environment, including in plants grown under controlled environments or in the field. Importantly, the biomarker composite expression response is much more rapid and quantitative than phenotypic observations. Consequently, we have successfully used these biomarkers to monitor nitrogen status in real-time assays of field-grown maize plants under typical production conditions. Our results suggest that biomarkers have the potential to be used as agronomic tools to monitor and optimize nitrogen fertilizer usage to help achieve maximal crop yields.

A large proportion of swine and humans in close contact with those swine were infected with M suis in Shanghai, China. The close phylogenetic relationship between swine and human isolates of M suis suggested possible interspecies transmission; however, additional research is required to better assess that possibility.

To date, the useful markers of hepatocellular carcinoma (HCC) remains incompletely developed. Here, we show that annexin A2 complement alpha-fetoprotein (AFP), a widely used liver cancer marker, in the serologically surveillance and early detection of HCC. First, differentially expressed proteins in HCC were identified using a subcellular proteomic approach. Annexin A2 was then selected for further verification. It was found to be overexpressed in HCC tissues (60.7%, 136/224). Using a self-estabished sandwich enzyme-linked immunosorbent assay, we found that annexin A2 significantly increased in the sera of HCC (n = 175, median, 24.75ng/µl) compared with the healthy (n = 49, median, 16.69ng/µl), benign tumors (n = 19, median, 19.92ng/µl), hepatitis (n = 23, median, 6.48ng/µl) and cirrhosis (n = 51, median, 7.39ng/µl) controls and other malignant tumors (n = 87). Importantly, raised concentrations of annexin A2 were observed in 83.2% (79/95) of early stage (median, 24.32ng/µl) and 78.4% (58/74) of AFP-negative (median, 24.09ng/µl) patients. Annexin A2 alone had a better area under the receiver-operating characteristic curve (AUC = 0.79, 95% confidence interval: 0.73–0.85) in comparison with AFP (AUC = 0.73, 95% confidence interval: 0.66–0.80) in detecting of early stage HCC. Combining both markers notably improved the diagnostic efficiency of early HCC with an achieved sensitivity of 87.4%. Additionally, the expression characteristics of annexin A2 during hepatocarcinogenesis were detected in p21-HBx gene knockin transgenic mice model. The results showed that annexin A2 expression was substantially elevated in HCC-bearing mice, in accordance with the finding in human samples. In conclusion, annexin A2 may be an independent serological candidate for hepatitis B virus–related HCC, especially in the early stage cases with normal serum AFP.

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

Lettuce is an important leafy vegetable that represents a significant dietary source of antioxidants and bioactive compounds. However, the levels of metabolites in different lettuce cultivars are poorly characterized. In this study, we used combined GC × GC-TOF/MS and UPLC-IMS-QTOF/MS to detect and relatively quantify metabolites in 30 lettuce cultivars representing large genetic diversity. Comparison with online databases, the published literature, standards as well using collision cross-section values enabled putative identification of 171 metabolites. Sixteen of these 171 metabolites (including phenolic acid derivatives, glycosylated flavonoids, and one iridoid) were present at significantly different levels in leaf and head type lettuces, which suggested the significant metabolomic variations between the leaf and head types of lettuce are related to secondary metabolism. A combination of the results and metabolic network analysis techniques suggested that leaf and head type lettuces contain not only different levels of metabolites but also have significant variations in the corresponding associated metabolic networks. The novel lettuce metabolite library and novel non-targeted metabolomics strategy devised in this study could be used to further characterize metabolic variations between lettuce cultivars or other plants. Moreover, the findings of this study provide important insight into metabolic adaptations due to natural and human selection, which could stimulate further research to potentially improve lettuce quality, yield, and nutritional value.