ErbB3 is required for hyperaminoacidemia-induced pancreatic α cell hyperplasia.

Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Construction of mRNA prognosis signature associated with differentially expressed genes in early stage of stomach adenocarcinomas based on TCGA and GEO datasets.

BACKGROUND: Stomach adenocarcinomas (STAD) are the most common malignancy of the human digestive system and represent the fourth leading cause of cancer-related deaths. As early-stage STAD are generally mild or asymptomatic, patients with advanced STAD have short overall survival. Early diagnosis of STAD has a considerable influence on clinical outcomes. METHODS: The mRNA expression data and clinical indicators of STAD and normal tissues were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The gene expression differences were analyzed by R packages, and gene function enrichment analysis was performed. Kaplan-Meier method and univariate Cox proportional risk regression analysis were used to screen differential expressed genes (DEGs) related to survival of STAD patients. Multivariate Cox proportional risk regression analysis was used to further screen and determine the prognostic DEGs in STAD patients, and to construct a multigene prognostic prediction signature. The accuracy of predictive signature was tested by receiver operating characteristic (ROC) curve software package, and the nomogram of patients with STAD was drawn. Cox regression was used to investigate the correlation between multigene prognostic signature and clinical factors. The predictive performance of this model was compared with two other models proposed in previous studies using KM survival analysis, ROC curve analysis, Harrell consistency index and decision curve analysis (DCA). qRT-PCR and Western blot were used to verify the expression levels of prognostic genes. The pathways and functions of possible involvement of features were predicted using the GSEA method. RESULTS: A total of 569 early-stage specific DEGs were retrieved from TCGA-STAD dataset, including 229 up-regulated genes and 340 down-regulated genes. Enrichment analysis showed that the early-stage specific DEGs were associated with cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and calcium signaling pathway. Multiple Cox regression algorithm was used to identify 10 early-stage specific DEGs associated with overall survival (P < 0.01) of STAD patients, and a multi-mRNA prognosis signature was established. The patients were divided into high-risk group and low-risk group according to the risk score. In the training set, the prognostic signature was positively correlated with tumor size and stage (P < 0.05), survival curve (P < 0.001) and time-dependent ROC (AUC = 0.625). In the training dataset and test dataset, the both signatures had good predictive efficiencies. Cox regression and DCA analysis revealed that the prognostic signature was an independent factor and had a better predict effect than the conventional TNM stage classification method and the earlier published biomarkers on the prognosis of STAD patients. CONCLUSION: In this study, based on the early-stage specifically expressed genes, the prognostic signature constructed through TCGA and GEO datasets may become an indicator for clinical prognosis assessment of STAD and a new strategy for targeted therapy in the future.

Association of ß-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Objectives: Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/ß-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods: The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results: The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that ß-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. ß-Catenin overexpression (HR: 0.137 (95% CI: 0.131-0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146-0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126-0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772-0.198)) also presented risk for shorter DFS. Conclusions: The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/ß-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.

Long-Lasting Proteinaceous Nanoformulation for Tumor Imaging and Therapy.

Nanodrugs have attracted increasing interest in drug delivery and disease treatment. However, the cumbersome preparation process and the poor biocompatibility of nanodrugs obstruct their clinical translation. In this study, we utilized a self-assembly strategy to develop a low-toxicity, long-lasting nanodrug for the effective treatment and real-time monitoring of bladder tumors. The accurate self-assembly of compatible raw materials allowed for an encapsulation rate of 43.7% for insoluble erdafitinib. Interestingly, robust therapeutic effects and reduced side effects could be realized simultaneously using this nanodrug, enabling broader scenarios for the clinical application of erdafitinib. Furthermore, the nanodrug exhibited a significantly prolonged in vivo half-life (14.4 h) and increased bioavailability (8.0 µg/mL·h), which were 8.3 times and 5.0 times higher than those of its nonformulated counterpart. Also, it is worth mentioning that the introduction of a fluorescent protein module into the nanodrug brought up a novel possibility for real-time feedback on the therapeutic response. In conclusion, this research revealed a versatile technique for developing low-toxicity, long-acting, and multifunctional nanoformulations, paving the way for multidimensional therapy of malignant tumors.

The anti-inflammatory effect of Pien Tze Huang in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease that may progress to nonalcoholic steatohepatitis (NASH), hepatic tissue fibrosis, liver cirrhosis, and hepatocellular carcinoma. In this study, we investigated the effects of Pien Tze Huang (PTH), a well-known traditional Chinese herbal formula with liver protective effect, in methionine-choline deficient diet (MCD)- and high-fat diet (HFD)-induced NASH mouse models. Our results showed that PTH could exert hepatoprotective effects by improving liver weight and steatosis and reducing the fibrosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) in both animal models. The effects of PTH was accompanied with the reduction of infiltrated macrophages, the inhibition of the expression of cytokines, and the induction of adiponectin expression. Mechanistically, we found that PTH could inhibit the activation of proinflammatory transcription factor nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor of κBα (IκBα). These results demonstrate that PTH can improve NAFLD largely due to its suppression of the NF-κB inflammatory pathway.

Biomacromolecule-based photo-thermal agents for tumor treatment.

Cancer treatment has become one of the biggest challenges in modern medicine. Recently, many efforts have been devoted to treat tumors by surgical resection, radiotherapy, or chemotherapy. In comparison to these methods, photo-thermal therapy (PTT) with noninvasive, controllable, direct, and precise characteristics has received tremendous attention in eliminating tumor cells over the past decades. In particular, PTT based on biomacromolecule-based photo-thermal agents (PTAs) outperforms other systems with high photo-thermal efficiency, simple coating, and low immunogenicity. Considering the unique advantages of biomacromolecule-based PTAs in tumor treatment, it is necessary to summarize the recent progress in the field of biomacromolecule-based PTAs for tumor treatment. Herein, this minireview outlines recent progress in the fabrication and applications of biomacromolecule-based PTAs. Within this framework, various types of biomacromolecule-based PTAs are highlighted, including cell-based agents, protein-based agents, nucleotide-based agents, and polysaccharide-based PTAs. In each section, the functional design, photo-thermal effects, and potential clinical applications of each type of PTA are discussed. Finally, a brief perspective for the development of biomacromolecule-based PTAs is presented.

Discovery of new chalone adamantyl arotinoids having RXRα-modulating and anticancer activities.

In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 µM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 µM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.

Altered expression of striatin-4 is associated with poor prognosis in bladder transitional cell carcinoma.

Striatin-4 (STRN4 or Zinedin) is a scaffolding protein belonging to the mammalian STRN family of proteins and consists of multiple functional signaling domains. Due to its numerous signaling complexes, STRN4 has been reported to be involved in the tumorigenesis of various cancer types, including colon cancer, liver cancer and prostate cancer. However, few studies on STRN4 have been conducted in bladder cancer, and its prognostic role in bladder cancer remains unknown. The present study aimed to investigate the expression levels of STRN4 in bladder transitional cell carcinoma and evaluate the prognostic role of STRN4. STRN4 expression in clinical specimens was analyzed using immunohistochemistry and reverse transcription-quantitative PCR. It was demonstrated that STRN4 expression was significantly associated with clinical parameters such as tumor size, muscle invasion depth and pathological tumor grade. Abnormal STRN4 expression was typically associated with worse overall survival time and outcome when compared with the low STRN4 expression group. Using multivariate analysis, it was reported that STRN4 was an independent prognostic biomarker for survival time in bladder transitional cell carcinoma. Although the specific biological mechanisms of STRN4 in bladder cancer still remain to be elucidated, STRN4 expression could be a prognostic indicator in bladder cancer.

Minimally invasive surgery for appendiceal intussusception caused by mucocele of the appendix: case report and review of the literature.

Appendiceal intussusception caused by mucocele of the appendix is extremely rare. In the current study, a 32-year-old woman was admitted to the department of general surgery of our hospital, complaining of persistent right, lower quadrant pain without an obvious cause for 17 hours. Physical examination indicated significant pain and tenderness in the right, lower abdominal quadrant. Blood analysis indicated that leukocyte count, the percentage of neutrophils and the serum C-reactive protein were increased. Abdominal and pelvic computed tomography revealed a well-encapsulated cystic mass surrounded by the caecum and intussusception. The appendiceal intussusception caused by mucocele of the appendix was revealed during the laparoscopic exploration. Appendectomy and partial cecectomy were conducted using the laparoscopic approach. Postoperative pathological examinations showed ileocecal intussusception and chronic inflammation, appendiceal mucocele and acute suppurative appendicitis. The patient showed satisfactory recovery that was observed during 15-months of follow-ups. This case highlights that laparoscopic appendectomy and partial cecectomy may be a beneficial, minimally invasive approach for appendiceal intussusception caused by mucocele of the appendix.

Diagnostic Value of Combination of MicroRNA-192 in Urinary Sediment and B-Ultrasound for Bladder Cancer.

OBJECTIVE: We aimed to explore the diagnostic value of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. METHODS: A total of 118 patients with bladder cancer and 120 patients with benign urinary system diseases were selected for collection of urinary sediment. Real-time quantitative polymerase chain reaction was applied to detect the microRNA-192 expression (normalized to U6 level) in urinary sediment. Besides, the relationship between microRNA-192 expression and clinicopathological characteristics was analyzed. Furthermore, receiver operating characteristic curve was performed to analyze clinical value of microRNA-192 expression alone and microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. RESULTS: MicroRNA-192 expression was significantly downregulated in urinary sediment of patients with bladder cancer, which was related to tumor stage and tumor size (P < .05). The results of receiver operating characteristic curve analysis showed that the best critical value of microRNA-192 expression in urinary sediment for the diagnosis of bladder cancer was 0.785 with the sensitivity and specificity of 76.7% and 78.0%, respectively. The sensitivity and specificity of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer were 93.2% and 76.7%, respectively. The sensitivity of combined diagnosis (93.2%) was not significantly different from that of cystoscopy (93.2%; P > 0.05). There were significant differences between the expression of microRNA-192 in urinary sediment and the sensitivity of B-ultrasound examination alone with cystoscopy (P < .05). CONCLUSION: The downregulation of microRNA-192 expression in urinary sediment of patients with bladder cancer may be related to tumor progression. The microRNA-192 expression in urinary sediment is valuable in the diagnosis of bladder cancer, which shows high sensitivity in diagnosis of bladder cancer when combined with B-ultrasound.

Bioinspired red blood cell membrane-encapsulated biomimetic nanoconstructs for synergistic and efficacious chemo-photothermal therapy.

Recently, the fabrication of nanotechnology-based co-delivery systems has garnered enormous interest for efficacious cancer therapy. However, these systems still face certain challenges such as codelivery of drugs with different chemistries, inadequate loading efficiency, immune rejection resulting in rapid clearance and substantially poor bioavailability in vivo. To address the challenges, we have developed a biomimetic and stable design based on bovine serum albumin (BSA) nanoparticles that are encapsulated with a hydrophilic photothermal agent, indocyanine green (ICG), as well as a hydrophobic agent, gambogic acid (GA), via the desolvation method. Furthermore, these nanoconstructs have been coated with the red blood cell membranes (RBCm), which exhibit pronounced long-term circulation in addition to avoiding premature leakage of drugs. RBCm-coated BSA nanoparticles show a higher affinity towards both GA and ICG (RmGIB NPs), resulting in high loading efficiencies of 24.3 ±â€¯1.2 % and 25.0 ±â€¯1.2 %, respectively. Moreover, the bio-efficacy investigations of these biomimetic constructs (RmGIB NPs) in cells in vitro as well as in tumor-bearing mice in vivo confirm augmented inhibition, demonstrating potential synergistic chemo-photothermal therapeutic efficacy. Altogether, we provide an efficient delivery platform for designing and constructing BSA nanovehicles toward synergistic and effective co-delivery of therapeutics.

Comprehensive Gene Expression Analysis in NMIBC Using RNA-seq Reveals New Therapy Strategies.

Non-muscle invasive bladder cancer (NMIBC) patients often have fewer treatment options, and suffer the progression of disease due to mechanisms that are not clear, as well as due to its diversity. This study was designed to explore the molecular mechanism of bladder cancer through an RNA-seq. In addition to conventional analyses, we also simplified the network through modularization using the WGCNA algorithm, with the help of the topological overlapping matrix and hierarchical cluster tree, which are based on the PPI network of STRING. Furthermore, the hub genes were confirmed through survival analyses in the independent cohorts (n = 431). Among them, 15 genes were significantly associated with poor prognosis. Finally, we validated the results at mRNA and protein level using qRT-PCR, IHC and western blotting. Taken together, our research is important for the prediction, as well as the prospective clinical development of drug targets and biomarkers.

Alisol B 23-acetate-induced HepG2 hepatoma cell death through mTOR signaling-initiated G1 cell cycle arrest and apoptosis: A quantitative proteomic study.

OBJECTIVE: The present study aimed to investigate the molecular events in alisol B 23-acetate (ABA) cytotoxic activity against a liver cancer cell line. METHODS: First, we employed a quantitative proteomics approach based on stable isotope labeling by amino acids in cell culture (SILAC) to identify the different proteins expressed in HepG2 liver cancer cells upon exposure to ABA. Next, bioinformatics analyses through DAVID and STRING on-line tools were used to predict the pathways involved. Finally, we applied functional validation including cell cycle analysis and Western blotting for apoptosis and mTOR pathway-related proteins to confirm the bioinformatics predictions. RESULTS: We identified 330 different proteins with the SILAC-based quantitative proteomics approach. The bioinformatics analysis and the functional validation revealed that the mTOR pathway, ribosome biogenesis, cell cycle, and apoptosis pathways were differentially regulated by ABA. G1 cell cycle arrest, apoptosis and mTOR inhibition were confirmed. CONCLUSIONS: ABA, a potential mTOR inhibitor, induces the disruption of ribosomal biogenesis. It also affects the mTOR-MRP axis to cause G1 cell cycle arrest and finally leads to cancer cell apoptosis.

Pro-oncogene Pokemon Promotes Prostate Cancer Progression by Inducing STRN4 Expression.

Pokemon, also known as leukemia/lymphoma-related factor (LRF) is a pro-oncogenic protein highly expressed in several cancers. There have been few in vitro and animal studies about its malignant biological behavior and function, however, its role especially in prostate cancer has not been completely elucidated. Therefore, in this study, we identified that Pokemon is overexpressed in human prostate cancer tissue samples, and its suppression inhibits proliferation of prostate cancer cells, along with promotion of apoptosis. Furthermore, to explore the mechanism by which Pokemon promotes tumor progression, we observed that it binds to the promoter of STRN4 (striatin 4), a downstream target, and subsequently regulates its expression. In conclusion, our study indicated that Pokemon through stimulation of STRN4 expression promotes prostate tumor progression via a Pokemon /STRN4 axis.

MiR-873-5p suppresses cell proliferation and epithelial-mesenchymal transition via directly targeting Jumonji domain-containing protein 8 through the NF-κB pathway in colorectal cancer.

Colorectal cancer (CRC) is one of the most common leading causes of cancer-related deaths in the world. Recent studies showed that microRNAs (miRNAs) play important roles in the development of diseases, such as CRC. However, the role of miR-873-5p in CRC remains unclear. In this study, we found that miR-873-5p expression was down-regulated in CRC tissues and cell lines, and the down-regulation of miR-873-5p expression was associated with poor survival in patients with CRC. MiR-873-5p could function as a tumour suppressor in CRC. It could inhibit the growth, proliferation, migration and invasion of CRC cells; influence the cell cycle and enhance apoptosis of CRC cells. Bioinformatics and luciferase reporter analyses demonstrated that Jumonji domain-containing protein 8 (JMJD8) was a target of miR-873-5p that could directly target the 3'UTR of JMJD8 and significantly inhibit its expression in CRC cells. This study also verified that JMJD8 functioned as an oncogene in CRC cells. The over-expression of JMJD8 could partly save the harmful effects induced by miR-873-5p in CRC cells, demonstrating that miR-873-5p suppressed carcinogenesis by targeting JMJD8 in CRC. We also verified that miR-873-5p over-expression could suppress CRC cell growth by inhibiting JMJD8 and its downstream NF-κB pathway in CRC. Hence, miR-873-5p inhibited tumour growth, and it may be a potential biomarker and a promising treatment for CRC.

RETRACTED: lncRNA PEG10 promotes cell survival, invasion and migration by sponging miR-134 in human bladder cancer.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief as unusual similarity between the background of various Western Blots have been detected post-publication. Also, quadrants within various FACS plots appear similar to each other in Figure 2E. Panels from Figures 2C,D, 4C,D and 6D,E appear similar to panels from Figures 1B,C, 2D,E, 3D,E and 5C,D of the article that Zhiliang Guo, Lanlan Li, Yu Gao, Xiaoyun Zhang and Min Cheng have published in the Artificial Cells, Nanomedicine, and Biotechnology 47 (2019) 2624-2633 https://doi.org/10.1080/21691401.2019.1629953. Although this article was published earlier than the other article, the Editor decided to retract this article given concerns about the reliability of the data.

LncRNA FAL1 promotes carcinogenesis by regulation of miR-637/NUPR1 pathway in colorectal cancer.

LncRNA FAL1 has been demonstrated to play an important role in promoting carcinogenesis via the ceRNA mechanism in several types of cancer. However, the role and the mechanism of lncRNA FAL1 in CRC remain unclear. Here our results demonstrate that lncRNA FAL1 is markedly upregulated in CRC tissues and cells, and lncRNA FAL1 promotes proliferation ability, migration and invasion in CRC cells. Additionally, we demonstrate that lncRNA FAL1 acts as a sponge of miR-637, which functions as a suppressor via targeting and downregulation of NUPR1 expression. Moreover, we demonstrate that lncRNA FAL1 promotes carcinogenesis of CRC cells via regulation of the miR-637/NUPR1 pathway. Taken together, our findings underscore the crucial roles of lncRNA FAL1 in CRC carcinogenesis and its potential prognostic and therapeutic value.

Dendrimer-like mesoporous silica nanospheres with suitable surface functionality to combat the multidrug resistance.

Multidrug resistance (MDR), as a major obstacle in cancer therapy, has resulted in over 90% of cancer chemotherapeutic failure. Mesoporous silica nanospheres (MSNs) have been demonstrated to be tuned with large pore sizes, mediating the MDR-reversal effects. However, the study that surface functionality of the large pore sized-MSNs affects the MDR-overcoming effects hasn't been extensively studied. In this study, we developed a new dendrimer-like MSNs delivery system based on a rational synthesis strategy and further modified MSNs with various surface functionalities to evaluate their roles in overcoming cancer MDR. Our results showed that the small particle sized-MSNs could be fabricated with dendrimer-like internal structure, resulting in the large pore size of 9 nm. Surface functionality of MSNs, especially hydroxylation and carboxylation, largely improved the intra-nuclear delivery and therapeutic efficiency of DOX for MCF7/ADR cells, which was not up to inhibiting P-gp expression but significantly increasing the intracellular drug accumulation of over 90% even under the strong drug efflux. This study indicates that surface functionality design strategy may display the potential of the large pore sized-MSNs as the efficient chemotherapeutic carriers to combat MDR.