Promoter hypomethylated PDZK1 acts as a tumorigenic gene in glioma by interacting with AKT1.

Glioma is the most frequently diagnosed primary brain tumor and typically has a poor prognosis because of malignant proliferation and invasion. It is urgent to elucidate the mechanisms driving glioma tumorigenesis and develop novel treatments to address this deadly disease. Here, we first revealed that PDZK1 is expressed at high levels in gliomas. Promoter hypomethylation may cause high expression of PDZK1 in glioma. Knockdown of PDZK1 inhibits glioma cell proliferation and invasion in vitro. Mechanistically, further investigations revealed that the loss of PDZK1 expression by siRNA inhibited the activation of the AKT/mTOR signaling pathway, leading to cell cycle arrest and apoptosis. Clinically, high expression of PDZK1 predicts a poorer prognosis for glioma patients than low expression of PDZK1. Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.

Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer.

Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC-/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.

Downregulated circPOKE promotes breast cancer metastasis through activation of the USP10-Snail axis.

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among females. Metastasis accounts for the majority of BC related deaths. One feasible strategy to solve this challenging problem is to disrupt the capabilities required for tumor metastasis. Herein, we verified a novel metastasis suppressive circRNA, circPOKE in BC. circPOKE was downregulated in primary and metastatic BC tissues and overexpression of circPOKE inhibited the metastatic potential but not the proliferative ability of BC cells in vitro and in vivo. Mechanistically, circPOKE competitively binds to USP10, and reduces its binding to Snail, a key transcriptional regulator of EMT, thereby inhibiting Snail stability via the protein-ubiquitination degradation pathway. In addition, we found that circPOKE could be secreted into the extracellular space via exosomes and that exosome-carried circPOKE significantly inhibited the invasive capabilities of BC cells in vitro and in vivo. Furthermore, the levels of circPOKE, USP10 and Snail are clinically relevant in BC, suggesting that circPOKE may be used as a potential therapeutic target for patients with BC metastasis.

Protein Phase Separation: New Insights into Carcinogenesis.

Phase separation is now acknowledged as an essential biologic mechanism wherein distinct activated molecules assemble into a different phase from the surrounding constituents of a cell. Condensates formed by phase separation play an essential role in the life activities of various organisms under normal physiological conditions, including the advanced structure and regulation of chromatin, autophagic degradation of incorrectly folded or unneeded proteins, and regulation of the actin cytoskeleton. During malignant transformation, abnormally altered condensate assemblies are often associated with the abnormal activation of oncogenes or inactivation of tumor suppressors, resulting in the promotion of the carcinogenic process. Thus, understanding the role of phase separation in various biological evolutionary processes will provide new ideas for the development of drugs targeting specific condensates, which is expected to be an effective cancer therapy strategy. However, the relationship between phase separation and cancer has not been fully elucidated. In this review, we mainly summarize the main processes and characteristics of phase separation and the main methods for detecting phase separation. In addition, we summarize the cancer proteins and signaling pathways involved in phase separation and discuss their promising future applications in addressing the unmet clinical therapeutic needs of people with cancer. Finally, we explain the means of targeted phase separation and cancer treatment.

Non-coding RNAs in breast cancer: Implications for programmed cell death.

Cell death is a necessary event in life and is crucial for the regulation of organismal development, homeostasis, aging and pathological conditions. There are different modes of cell death, i.e., regulated and nonregulated. Cell death induced by programmed cell death (PCD) has gained increasing attention in recent years. Abnormal control of PCD plays an important role in tumorigenesis. For example, tumor cells are relatively resistant to apoptosis, and the induction of cell death is also an important mechanism underlying the antitumor effects of current clinical chemotherapeutic agents. Recently, studies have revealed that noncoding RNAs (ncRNAs) are involved in regulating multiple biological processes of breast cancer, including PCD. NcRNAs can exert both protumorigenic and antitumorigenic effects, depending on their expression patterns. Therefore, constructing ncRNA-based therapies to target PCD may be a promising therapeutic strategy for breast cancer. Herein, this review discusses the function of various ncRNAs in regulating the PCD of breast cancer cells. In addition, given the recent trend of utilizing ncRNAs as cancer therapeutics, we also discuss the great potential applications of ncRNAs as biomarkers or activators of PCD in breast cancer.

Impact of Cyanocobalamin and Methylcobalamin on Inflammatory Bowel Disease and the Intestinal Microbiota Composition.

Patients with inflammatory bowel disease (IBD) are usually advised to supplement various types of vitamin B12, because vitamin B12 is generally absorbed in the colon. Thus, in the current study, the influence of cyanocobalamin (CNCBL) or methylcobalamin (MECBL) ingestion on IBD symptoms will be investigated. Then, whether and how the application of various cobalamins would modify the taxonomic and functional composition of the gut microbiome in mice will be examined carefully. Dextran-sulfate-sodium-induced IBD mice were treated with MECBL or CNCBL; disease activity index (DAI) scores and intestinal inflammatory conditions of mice were evaluated. Fecal samples were collected; microbiota composition was determined with a 16s rRNA analysis; functional profiles were predicted by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt); and short-chain fatty acids were measured. The consequence of higher relative abundances of Enterobacteriaceae and isomeric short-chain fatty acids by cobalamin treatment revealed that a high concentration of CNCBL but not MECBL supplementation obviously aggravated IBD. A microbial ecosystem rich in Escherichia/ Shigella and low in Lactobacillus, Blautia, and Clostridium XVIII was observed in IBD mice after a high concentration of CNCBL supplementation. In cobalamin-dependent enzymes, CNCBL was more efficient in the adenosylcobalamin system than MECBL and vice versa in the MECBL system. The distinct effects of various cobalamins were associated with the distribution and efficiency of vitamin-B12-dependent riboswitches. CNCBL had a strong inhibitory effect on all riboswitches, especially on btuB and pocR riboswitches from Enterobacteriaceae. CNCBL aggravated IBD via enhancing the proportion of Enterobacteriaceae organisms through riboswitch and enzyme systems. The present study provides a critical reference for offering a suitable amount and type of cobalamin during a symbiotic condition.

Stability of vitamin B12 with the protection of whey proteins and their effects on the gut microbiome.

Cobalamin degrades in the presence of light and heat, which causes spectral changes and loss of coenzyme activity. In the presence of beta-lactoglobulin or alpha-lactalbumin, the thermal- and photostabilities of adenosylcobalamin (ADCBL) and cyanocobalamin (CNCBL) are increased by 10-30%. Similarly, the stabilities of ADCBL and CNCBL are increased in the presence of whey proteins by 19.7% and 2.2%, respectively, when tested in gastric juice for 2 h. Due to the limited absorption of cobalamin during digestion, excess cobalamin can enter the colon and modulate the gut microbiome. In a colonic model in vitro, supplementation with cobalamin and whey enhanced the proportions of Firmicutes and Bacteroidetes spp. and reduced those of Proteobacteria spp., which includes pathogens such as Escherichia and Shigella spp., and Pseudomonas spp. Thus, while complex formation could improve the stability and bioavailability of cobalamin, these complexes might also mediate gut microecology to influence human nutrition and health.

Effect of Lactobacillus gasseri PA3 on gut microbiota in an in vitro colonic simulation.

It has been reported that Lactobacillus gasseri PA3 has an ability to absorb exogenous purines in the intestine to reduce a risk of gout and hyperuricemia. However, influences of this strain on gut microbiota and their metabolisms remain unclear. Herein, we aimed to investigate the effect of L. gasseri PA3 on microbiota composition and metabolisms. L. gasseri PA3 was isolated from yogurt and supplemented into a single-stage colonic fermentation in a culture volume of 30 ml and subjected to in vitro colonic simulation for 8 days. Microbiota composition was determined with 16S rRNA (V3 + V4) sequencing, and their metabolisms were predicted by PICRUSt. Short-chain fatty acids were measured by GC-MS. We found that L. gasseri PA3 reduced the diversity of microbiota, increased the relative abundances of Lactobacillus (73.5%) and Escherichia (36.5%), and decreased Bacterioides and Phascolarctobacterium. Total amount of short-chain fatty acids was found to decline. Fundamental metabolisms, especially nucleotide, was significantly higher after intervention with L. gasseri PA3, but the purine metabolism was lower, which means that PA3 might reduce uric acid concentrations by weakening purine metabolism. Our results indicated that L. gasseri PA3 can survive and play a role in the ascending colon environment. Therefore, the evaluation of the effect of L. gasseri PA3 on intestinal microbes and their metabolisms has great guiding significance for the development of treatment to prevent gout.

Correlations of Promoter Methylation in WIF-1, RASSF1A, and CDH13 Genes with the Risk and Prognosis of Esophageal Cancer.

BACKGROUND This study was designed to explore the correlations of promoter methylation in Wnt inhibitory factor-1 (WIF-1), ras-association domain family member 1A (RASSF1A), and Cadherin 13 (CDH13) genes with the risk and prognosis of esophageal cancer (EC). MATERIAL AND METHODS A total of 71 EC tissues from resection and 35 adjacent normal tissues were collected. Methylation status in the promoter region was detected by methylation- and non-methylation-specific primers. Corresponding mRNA levels were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Correlations between the methylations of these 3 genes and clinicopathologic characteristics were analyzed. Kaplan-Meier method and Cox regression model were used to investigate the relationships between WIF-1, RASSF1A, and CDH13 promoter methylations and the prognosis of EC. RESULTS Compared with adjacent normal tissues, the methylation frequencies of WIF-1, RASSF1A, and CDH13 genes were significantly higher but the mRNA levels of these 3 genes were significantly lower in EC tissues (all P<0.05). WIF-1 and CDH13 promoter methylations were associated with the degree of tumor differentiation and WIF-1 and RASSF1A promoter methylations were associated with age (all P<0.05). The survival rates of patients with WIF-1, RASSF1A, and CDH13 methylations were significantly lower than those of patients without methylation (all P<0.05). WIF-1, RASSF1A, and CDH13 promoter methylations were independent risk factors affecting the prognosis of EC (all P<0.05). CONCLUSIONS WIF-1, RASSF1A, and CDH13 promoter methylations are associated with EC. The methylation levels are negatively related with the prognosis in EC.

Effects of Minimally Invasive Esophagectomy and Open Esophagectomy on Circulating Tumor Cell Level in Elderly Patients with Esophageal Cancer.

OBJECTIVE: To investigate the effects of minimally invasive esophagectomy (MIE) and open esophagectomy (OE) on circulating tumor cell (CTC) level of elderly patients with esophageal cancer (EC). METHODS: A total of 78 elderly EC patients who aged over 64 years were divided into the MIE group (n = 40) and the OE group (n = 38). CTC enrichment was performed through CD326 (EpCAM) immunomagnetic beads positive sorting, and then labeled by CK-PE and CD45. The quantity of CTCs was measured by multiparameter flow cytometry. Double antibody sandwich enzyme-linked immuno sorbent assay ELISA (DAS-ELISA) was used for detecting the levels of IL-6, IL-10, and IFN-γ. RESULTS: Among the 78 elderly EC patients, CTC level after the surgery was higher than that during the surgery, and CTC level during surgery was higher than that before the surgery (both P < 0.05). Postoperative CTC level in the MIE group was lower than that in the OE group, and the variation of CTC level from pre-operation to intra-operation in the MIE group was also lower than that in the OE group (both P < 0.05). Furthermore, there was significant difference in the incidences of intra-operative and postoperative complications between the MIE group and the OE group (17 cases vs. 31 cases, P < 0.05), and the CTC levels of the patients with complications in either group were significantly higher than the patients without complications (both P < 0.05). IL-6 and IL-10 levels significantly increased, while IFN-γ level decreased in both groups during the surgery and 3 days after the surgery compared to those before the surgery; 2 weeks after the surgery, IL-6 and IL-10 levels in the MIE group recovered to the pre-operative levels (all P < 0.05). However, in the OE group, IL-6 and IL-10 levels 2 weeks after the surgery were still significantly higher than those before the surgery (all P < 0.05); IFN-γ levels in both groups recovered to the pre-operative levels, with higher level in the MIE group than that in the OE group (P < 0.05). CONCLUSION: MIE helped to reduce the survival rate of tumor cells in peripheral blood at the early period of postoperation, and dynamic monitoring CTC level could be used to evaluate the prognosis of EC patients.