Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression.

ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.

YTHDC1 positively regulates PTEN expression and plays a critical role in cisplatin resistance of bladder cancer.

Activation of PI3K/AKT signalling by PTEN loss significantly enhances chemoresistance in bladder cancer. This study aims to evaluate PTEN regulation and identify targets that could be used to relieve chemoresistance. Expression of YTHDC1, γ-H2AX and PTEN were detected by IHC assay. Cell Counting Kit-8 assay, colony formation assay and tumour xenograft experiment evaluated cisplatin response. Flow cytometry and comet assay estimated cell apoptosis, cell cycle distribution and DNA repair capability. Quantitative real-time polymerase chain reaction, Western blot and RIP assay assessed binding properties between PTEN mRNA and YTHDC1. Silencing YTHDC1 in bladder cancer cells reduced PTEN expression and activated PI3K/AKT signalling by destabilizing PTEN mRNA in an m6 A-dependent manner. Low YTHDC1 expression indicated poor cisplatin sensitivity in bladder cancer patients. Reducing YTHDC1 expression promoted drug resistance to cisplatin, while over-expressing YTHDC1 promoted cisplatin sensitivity. Reducing YTHDC1 expression activated DNA damage response, which includes quicker cell cycle recovery, apoptosis evasion and an enhanced DNA repair capability, whereas these effects were attenuated when MK2206, a PI3K/AKT inhibitor was applied. We provide novel evidence that PTEN/PI3K/AKT signalling pathway could be regulated by YTHDC1 in an m6 A-dependent manner and highlight a critical role of YTHDC1 in cisplatin resistance of bladder cancer.

Circular RNA circMBOAT2 promotes prostate cancer progression via a miR-1271-5p/mTOR axis.

Patients with advanced prostate cancer (PCa) have poor prognosis. Circular RNAs (circRNAs) regulate biological processes in a variety of cancers, but the precise roles of circRNAs in PCa are poorly understood. Herein, we identified a novel circRNA, termed circMBOAT2 (has_circ_0007334), which was significantly overexpressed in PCa tissues and cell lines. Overexpression of circMBOAT2 was associated with high Gleason score, advanced pathological T stage, and poor prognosis. Overexpression of circMBOAT2 promoted proliferation, migration, and invasion of PCa cells in vitro, and enhanced tumorigenesis and metastasis in vivo. Mechanistically, circMBOAT2 overexpression upregulated the expression of mTOR by acting as a decoy for miR-1271-5p, resulting in the activation of the PI3K/Akt pathway, ultimately promoting the progression of PCa. Importantly, application of an inhibitor of mTOR significantly antagonized circMBOAT2-mediated PCa tumorigenesis in vivo. circMBOAT2 promotes proliferation and metastasis of PCa through miR-1271-5p/mTOR axis-mediated activation of the PI3K/Akt pathway. In summary, our findings uncover a molecular mechanism in the progression of PCa and indicate that circMBOAT2 may be a useful prognostic biomarker and therapeutic target in PCa.

circRIP2 accelerates bladder cancer progression via miR-1305/Tgf-ß2/smad3 pathway.

BACKGROUND: Increasing evidences indicate that circular RNAs exert critical function in regulating bladder cancer progression. However, the expressive patterns and roles of circular RNAs in bladder cancer remain less investigated. METHODS: circRIP2 was identified and evaluated by RNA-sequencing and qPCR; in vitro effects of circRIP2 were determined by CCK8, clone forming, wound healing and trans-well assays; while mice subcutaneous tumor model was designed for in vivo analysis. Western blot, RNA pulldown assay, miRNA capture and dual luciferase assessment were applied for mechanistic studies. RESULTS: circRIP2 was identified as a conserved and dramatically repressed circular RNA in bladder cancer. Patients that displayed higher circRIP2 expression negatively associate with the grade, stage, metastasis as well as outcome of bladder cancer. In vitro and in vivo studies suggest that circRIP2 enables to promote bladder cancer progression via inducing EMT. Regarding the mechanism, we performed RNA-sequencing analysis, RNA pulldown with biotin-labeled circRIP2-specific probe, dual luciferase reporter assay. It was found that circRIP2 enables to sponge miR-1305 to elevate Tgf-ß2 in bladder cancer, and inducing EMT via Tgf-ß2/smad3 pathway. Blocking Tgf-ß2 in bladder cancer deprives circRIP2 induced cancer progression and EMT. CONCLUSIONS: Taken together, our study provides the first evidence that circRIP2 expresses differentially in bladder cancer and negatively along with the cancer progression; effective circRIP2 activity accelerates bladder cancer progression via inducing EMT by activating miR-1305/Tgf-ß2/smad3 pathway. The research implies that circRIP2 might be a potential biomarker and therapeutic target for bladder cancer patients.

ciRs-6 upregulates March1 to suppress bladder cancer growth by sponging miR-653.

BACKGROUND: Circular RNAs have been widely explored as potential biomarkers and therapeutic targets in bladder cancer; however, few have been functionally characterized. RESULTS: ciRs-6 is expressed at low levels in cancer tissues and advanced tumor grades and stages, and its expression correlates with better outcomes for bladder cancer patients. In vitro and in vivo, ciRs-6 was shown to suppress bladder cancer growth by sponging miR-653 to elevate March1 levels. March1 is an E3 ubiquitin ligase that has been proven to suppress bladder cancer growth; knocking down March1 in ciRs-6 overexpressed bladder cancer cells reversed the tumor suppressive effect of ciRs-6. CONCLUSIONS: Our study identifies an oncogenic role of ciRs-6 and suggests its usefulness as a novel biomarker for bladder cancer diagnosis and prognosis and as a therapeutic target for bladder cancer. METHODS: ciRs-6 was identified by RNA-seq and qPCR; CCK8 assays, clone forming assays and cell cycle analyses were performed to evaluate the in vitro effect of ciRs-6 in bladder cancer; further, a mouse subcutaneous tumor model was designed for in vivo analysis. RNA pulldown assays, miRNA capture experiments and dual luciferase assessments were applied for mechanistic studies.

circ5912 suppresses cancer progression via inducing MET in bladder cancer.

BACKGROUND: Increasing evidence suggests that circular RNAs play a key role in regulating bladder cancer progression. However, this remains to be fully elucidated. RESULTS: In this study, we reanalyzed our previous RNA sequence, and circ5912 was found to downregulate significantly in bladder cancer tissues compared with normal control. Expression of circ5912 inversely correlates with bladder cancer grade, stage, metastasis, and better patient outcomes. In vitro and in vivo, circ5912 has been shown to repress transforming growth factor ß signaling, which suppresses proliferation, invasion and migration of bladder cancer induced by mesenchymal-to epithelial transition. CONCLUSIONS: Our study firstly demonstrate that circ5912 regulates mesenchymal-to epithelial transition pathway to suppress bladder cancer progression and propose new therapeutic targets and biomarkers for bladder cancer. MATERIALS AND METHODS: Clinical values of circ5912 in human bladder cancer were examined in a cohort of 58 patients by qPCR. 2 bladder cancer cell lines, T24 and SW780, were used for biological evaluation of circ5912. CCK8, clone formation, wound healing and trans-well assays were performed to determine the in vivo effect of circ5912; a mouse subcutaneous model was designed for in vivo analysis. Western blotting, RNA pulldown assays and florescent in situ hybridization were applied for mechanistic analysis.

Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis.

BACKGROUND: Circular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. However, the aberrant expression profile and dysfunction of circRNAs in human bladder cancer remain to be investigated. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer. METHODS: circACVR2A (hsa_circ_0001073) was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. The role of circACVR2A in bladder cancer was assessed both in vitro and in vivo. Biotin-coupled probe pull down assay, biotin-coupled microRNA capture, dual-luciferase reporter assay, and fluorescence in situ hybridization were conducted to evaluate the interaction between circACVR2A and microRNAs. RESULTS: The expression of circACVR2A was lower in bladder cancer tissues and cell lines. The down-regulation of circACVR2A was positively correlated with aggressive clinicopathological characteristics, and circACVR2A served as an independent risk factor for overall survival in bladder cancer patients after cystectomy. Our in vivo and in vitro data indicated that circACVR2A suppressed the proliferation, migration and invasion of bladder cancer cells. Mechanistically, we found that circACVR2A could directly interact with miR-626 and act as a miRNA sponge to regulate EYA4 expression. CONCLUSIONS: circACVR2A functions as a tumor suppressor to inhibit bladder cancer cell proliferation and metastasis through miR-626/EYA4 axis, suggesting that circACVR2A is a potential prognostic biomarker and therapeutic target for bladder cancer.

Hypoxia-elevated circELP3 contributes to bladder cancer progression and cisplatin resistance.

Hypoxia plays a critical role in cancer biology. It induces genomic instability, which in turn helps cancer cells respond adaptively to meet the needs of carcinogenesis, cancer progression and relapse. Circular RNA has not been reported among the variety of downstream factors in this adaptive response. Although a few studies have demonstrated the important role of circular RNAs in driving human bladder cancer progression, their carcinogenic roles are still under investigated. Here, we identified a hypoxia-elevated circular RNA, circELP3, that contributes to bladder cancer progression and cisplatin resistance. Decreasing the level of circELP3 via siRNA clearly reduced the in vitro proliferation and cisplatin resistance of bladder cancer cells and promoted apoptosis. Interfering with circELP3 suppressed tumor xenograft growth in nude mice in vivo. In addition, lower circELP3-expressing bladder cancer cells displayed poorer self-renewal capacity, as demonstrated by lower levels of sphere formation and stem cell marker expression. Furthermore, in human bladder cancer patients, strong correlations between a high circELP3 level and advanced tumor grade and lymph node metastasis were observed. In summary, we provide the first direct evidence that circular RNA participates in the adaptive response to hypoxia and may play a role in the progression and drug resistance of bladder cancer.

Circular RNA, a novel marker for cancer determination (Review).

Circular RNAs are abundant and conserved endogenous RNAs that are formed by exon skipping or back­splicing events and occur in all forms of life. They have been proven to exhibit tissue­ or cell­type specificity and to be able to regulate cell behavior through multiple pathways. In cancer research, numerous studies have indicated that circular RNAs serve as potential biomarkers and therapeutic targets. Furthermore, differential expression of certain circular RNAs clearly predicts the clinical outcomes of cancer patients. Circular RNAs regulate carcinogenesis and cancer progression by acting as a microRNA sponge, coding for proteins and interacting with proteins. The present review mainly focuses on the recent literature regarding the role of circular RNAs in cancer, which may suggest novel strategies for cancer prognosis, diagnosis and clinical treatment.

Bariatric surgery: beta cells in type 2 diabetes remission.

Bariatric surgery is a new emerging treatment that demonstrates a favourable effect on type 2 diabetes, although its underlying mechanisms still remain unknown. After receiving bariatric surgery, beta cells undergo the process of rebirth, which involves apoptosis evasion, regeneration and improved beta-cell function. Therefore, further studies are necessary to elucidate how bariatric surgery can resolve type 2 diabetes. Here, our review focuses mainly on beta cells, the insulin-generating cells, whose biological features change dramatically after bariatric surgery. Copyright © 2015 John Wiley & Sons, Ltd.

Circulating Long Noncoding RNA as a Potential Target for Prostate Cancer.

Prostate cancer is considered the second most common visceral malignancy in men in Western countries. Its emergence is largely due to the coordination of a malignant network, and long noncoding RNA has been recently demonstrated to play a critical role in prostate carcinogenesis. The aberrant expression of long noncoding RNA in prostate cancer patients is strongly associated with diagnosis, risk stratification and carcinogenesis, information that provides new insight into the complicated intracellular milieu of prostate cancer. This review focuses mainly on literature evidence for the role of long noncoding RNA in prostate cancer, which may suggest novel strategies for its prognosis, diagnosis and clinical treatment.

Characterization of casein hydrolysates derived from enzymatic hydrolysis.

BACKGROUND: Casein is the main proteinaceous component of milk and has made us interest due to its wide applications in the food, drug, and cosmetic industries as well as to its importance as an investigation material for elucidating essential questions regarding the protein chemistry. Enzymatic hydrolysis is an important method commonly used in the modification of protein structure in order to enhance the functional properties of proteins. The relationship between enzymatic hydrolysis and structure change of casein need to make more study. RESULTS: During hydrolysis, degree of hydrolysis in the casein hydrolysates increased rapidly in the initial 20 minutes, reached a plateau after 45 minutes, and then kept relative constant for the rest of the hydrolysis. The relative percentage of the released peptides with molecular weight of over 50 kD significantly decreased with hydrolyzation, while those with MW of 30-50 kD and below 20 kD increased significantly. The contents of a-helix and ß-turn in the hydrolysates increased compared to the original casein. Moreover, the molecular flexibilities of the casein hydrolysates, estimated by the ratio of α-helix to ß-structure, were lower than that of original casein protein. CONCLUSIONS: The significant changes in molecular weight distribution and structure characteristics of casein hydrolysates were found compared to the control sample. This change should be the basis of enhancement of functional properties.

Peanut Allergy, Allergen Composition, and Methods of Reducing Allergenicity: A Review.

Peanut allergy affects 1-2% of the world's population. It is dangerous, and usually lifelong, and it greatly decreases the life quality of peanut-allergic individuals and their families. In a word, peanut allergy has become a major health concern worldwide. Thirteen peanut allergens are identified, and they are briefly introduced in this paper. Although there is no feasible solution to peanut allergy at present, many methods have shown great promise. This paper reviews methods of reducing peanut allergenicity, including physical methods (heat and pressure, PUV), chemical methods (tannic acid and magnetic beads), and biological methods (conventional breeding, irradiation breeding, genetic engineering, enzymatic treatment, and fermentation).