Ribosome production factor 2 homolog promotes migration and invasion of colorectal cancer cells by inducing epithelial-mesenchymal transition via AKT/Gsk-3ß signaling pathway.

Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract, and its prognosis is closely related to the degree of tumor invasion and metastasis. Ribosome production factor 2 homolog (RPF2) plays an important role in the process of ribosome biogenesis; however, its biological function in the progression of malignant tumors including CRC remains unknown. It was found that RPF2 expression was significantly higher in CRC tissues than in the adjacent normal tissue, using mRNA chip technology. This study aimed to explore the role of RPF2 in the invasion and migration of CRC cells and investigate its probable molecular mechanism. The results demonstrated that RPF2 is not only highly expressed in CRC tissues and cell lines but can also activate the AKT/GSK-3ß signaling pathway through direct interaction with CARM1, promoting epithelial-mesenchymal transition, and consequently enhancing the migration and invasion abilities of CRC cells in vitro and in vivo. Thus, we speculated that RPF2 may become a novel therapeutic target for suppression of local invasion and distant metastasis of CRC.

Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer.

Although the colorectal cancer (CRC) mortality rates are decreasing in virtue of CRC screening and improved therapeutic methods, CRC is still a leading cause of cancer deaths. One of the main causes is chemoresistance occurrence in CRC. Understanding of the molecular mechanisms of chemoresistance benefits to CRC diagnosis and treatment. In this study, gene expression was determined by western blot and qRT-PCR. The biological functions of genes in CRC cells were studied by knocking down or overexpressing the gene in CRC cells and then analyzing cell sensitivity to 5-Fu by the MTT assay and the flow cytometry, and analyzing cell migration and invasion by transwell assays. The luciferase reporter assay was used to examine microRNA regulation of target gene expression, and biotin pull-down assay was performed to detect interaction between RNA molecules. This study found that ferritin light chain (FTL) and long intergenic noncoding RNA Linc00467 were both upregulated in CRC tissues and cell lines, and inversely correlated to CRC patient survival. FTL and Linc00467 promoted CRC cells abilities to resistance against 5-fluor-ouracil (5-Fu), migration and invasion. These effects were compromised by miR-133b which targeted both FTL and Linc00467. miR-133b interacted with Linc00467 and miR-133b inhibitor prevented Linc00467 knockdown-induced alternations of FTL expression and biological functions. Both FTL and Linc00467 are oncogenes in CRC. FTL expression upregulated in CRC via Linc00467/ miR-133b axis, and leads to CRC cell resistance against 5-FU treatment and promotes CRC metastasis. FTL expression upregulated in CRC via Linc00467/miR-133b axis, and leads to CRC cell resistance to 5-FU treatment and promotes CRC metastasis.

Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance.

It has been reported that ursolic acid has anti-tumor activity and it enhances the therapeutic effect of oxaliplatin in colorectal cancer (CRC). However, the underlying mechanisms remain unknown. In the present study, the mechanisms of the enhancement of therapeutic effects through use of ursolic acid were investigated. We treated CRC cell lines HCT8 and SW480 with ursolic acid and oxaliplatin and monitored the effects on cell proliferation, apoptosis, reactive oxygen species (ROS) production and drug resistance gene production. We discovered that treatment with a combination of ursolic acid and oxaliplatin resulted in significant inhibition of cell proliferation, significantly increased apoptosis and ROS production, and significant inhibition of drug resistance gene expression. Our study provided evidence that ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by ROS-mediated inhibition of drug resistance.

Rapid assessment of malnutrition based on GLIM diagnosis in Crohn's disease.

Background and aims: Malnutrition is strongly linked to adverse outcomes in patients with Crohn's disease (CD). In this study, our objective was to validate the Global Leadership Initiative on Malnutrition (GLIM) criteria and develop a fast and accurate diagnostic approach for identifying malnutrition in CD patients. Methods: This study assessed 177 CD patients from four general hospitals. The efficacy of the GLIM criteria for the diagnosis of CD malnutrition was compared. By analyzing the independent factors, a nomogram model was derived and internally validated to predict the diagnosis of malnutrition in patients with CD. Model performance was assessed using discrimination and calibration, decision curves, and net benefit analyses. Results: Compared with the SGA criteria, the GLIM criteria was consistent in sensitivity (88.89%) and specificity (78.43%) [AUC = 0.84; 95% Confidence Interval (CI): 0.77-0.89]. The Harvey-Bradshaw index(HBI) score (OR: 1.58; 95% CI: 1.15-2.18), body mass index (OR: 0.41; 95% CI: 0.27-0.64), and mid-upper arm circumference (OR: 0.68; 95% CI: 0.47-0.9) were independent factors associated with malnutrition. The nomogram was developed based on these indicators showing good discrimination in malnutrition diagnosis (AUC = 0.953; 95% CI: 0.922-0.984), with agreement after calibration curve and decision curve analysis. Conclusion: The GLIM criteria are appropriate for diagnosing malnutrition in CD patients. The HBI score may be used to diagnose malnutrition in patients with CD and become a possible selection for the GLIM etiologic criteria of inflammation. The HBM nomogram could be a simple, rapid, and efficient method for diagnosing malnutrition in CD patients.

Multi-Omics Analyses Characterize the Gut Microbiome and Metabolome Signatures of Soldiers Under Sustained Military Training.

Exercise can directly alter the gut microbiome at the compositional and functional metabolic levels, which in turn may beneficially influence physical performance. However, data how the gut microbiome and fecal metabolome change, and how they interact in soldiers who commonly undergo sustained military training are limited. To address this issue, we first performed 16S rRNA sequencing to assess the gut microbial community patterns in a cohort of 80 soldiers separated into elite soldiers (ES, n = 40) and non-elite soldiers (N-ES, n = 40). We observed that the α-diversities of the ES group were higher than those of the N-ES group. As for both taxonomical structure and phenotypic compositions, elite soldiers were mainly characterized by an increased abundance of bacteria producing short-chain fatty acids (SCFAs), including Ruminococcaceae_UCG-005, Prevotella_9, and Veillonella, as well as a higher proportion of oxidative stress tolerant microbiota. The taxonomical signatures of the gut microbiome were significantly correlated with soldier performance. To further investigate the metabolic activities of the gut microbiome, using an untargeted metabolomic method, we found that the ES and N-ES groups displayed significantly different metabolic profiles and differential metabolites were primarily involved in the metabolic network of carbohydrates, energy, and amino acids, which might contribute to an enhanced exercise phenotype. Furthermore, these differences in metabolites were strongly correlated with the altered abundance of specific microbes. Finally, by integrating multi-omics data, we identified a shortlist of bacteria-metabolites associated with physical performance, following which a random forest classifier was established based on the combinatorial biomarkers capable of distinguishing between elite and non-elite soldiers with high accuracy. Our findings suggest possible future modalities for improving physical performance through targeting specific bacteria associated with more energetically efficient metabolic patterns.

Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

We investigated the immunogenic cell death provoked by oxaliplatin (OXA) and the involvement of OXA-induced immunosuppression in colorectal cancer. Immune-proficient or -deficient mice were employed to evaluate the therapeutic effects of OXA. Immunogenic cell death was characterized by cell-surface calreticulin, cytosol-translocated high migration rate group protein B1 (HMGB1), and secretory ATP content. Bone marrow-derived dendritic cell (BMDC) maturation and CD8+ T cell expansion were measured by flow cytometry. Expression of immunosuppressive genes was quantified by both RT-PCR and western blots. The proliferative and apoptotic indexes of xenograft tumors were evaluated by immunohistochemistry and TUNEL assays, respectively. The secretory cytokines were measured with ELISA. OXA induced immunogenic cell death of murine colorectal cancer, which greatly depended on the host immune response. OXA-pretreated CT26 cells promoted BMDC maturation and CD8+ T cell expansion. OXA significantly upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in patient-derived colorectal cancer cells and in combination with the IDO1-specific inhibitor, NLG919, suppressed tumor progression. Simultaneous administration with both OXA and NLG919 greatly promoted CD8+ T cell infiltration and decreased immunosuppressive cytokine transforming growth factor ß (TGF-ß) production, whereas increased immunostimulatory cytokines interleukin (IL)-12p70 and interferon (IFN)-γ. We demonstrated the upregulation of IDO1 by OXA, which combined with the IDO1 inhibitor, tremendously potentiated therapeutic effects of OXA against colorectal cancer.

Circ-SMARCA5 suppresses colorectal cancer progression via downregulating miR-39-3p and upregulating ARID4B.

BACKGROUND: Circular RNAs are crucial in tumorigenesis. However, little is known about their functions in colorectal cancer (CRC). Circ-SMARCA5 was found to be an oncogene or tumor suppresser in different types of cancers, but its exact role in CRC remains unknown. Here, we aim to identify the role of circ-SMARCA5 in CRC development. METHODS: Circ-SMARCA5 expression was determined by qRT-PCR. CRC cell proliferation, migration, and invasion were detected by CCK-8, wound healing, and Transwell assays, respectively. Bioinformatics analysis was performed to predict target genes. The interaction of microRNA (miR) with circ-SMARCA5 or target genes was detected using luciferase reporter assay. Xenograft model was established to determine the effect of circ-SMARCA5 on CRC tumor growth in vivo. RESULTS: Circ-SMARCA5 expression was dramatically decreased in CRC cell lines and tissues. Circ-SMARCA5 overexpression inhibited CRC cell proliferation, migration and invasion. MiR-93-3p was predicted as a target of circ-SMARCA5 and its overexpression attenuated the anti-tumor effect of circ-SMARCA5 on CRC cells. Furthermore, we predicted AT-rich interaction domain 4B (ARID4B) as the target of miR-39-3p. Functional analysis showed that circ-SMARCA5 upregulated ARID4B expression via miR-39-3p. Additionally, in vivo studies demonstrated that circ-SMARCA5 suppressed CRC tumor progression. CONCLUSION: Circ-SMARCA5 functions as a tumor suppressor by upregulating ARID4B expression via sponging miR-39-3p, and thereby inhibited CRC progression.

MiR-4319 suppresses colorectal cancer progression by targeting ABTB1.

Background: Colorectal cancer is one of the highly malignant cancers with a poor prognosis. The exact mechanism of colorectal cancer progression is not completely known. Recently, microRNAs (miRNAs, miRs) were suggested to participate in the regulation of multiple cancer development, including colorectal cancer. Methods: MiR-4319 expression in colorectal cancer patient samples was detected by real-time polymerase chain reaction. MiR-4319 was knocked down in the colorectal cancer cells by siRNA transfection to study the role of miR-4319 in the cell cycle and proliferation of colorectal cancer cells. Results: MiR-4319 expression was found to be inverse correlated with survival in colorectal cancer patients. Overexpression of miR-4319 markedly reduced the proliferation of colorectal cancer cells and altered cell cycle distribution. A further experiment showed that ABTB1 is the target gene of miR-4319. MiR-4319 was regulated by PLZF. Conclusion: Our studies indicated that reduced expression of miR-4319 was correlated with poor prognosis in colorectal cancer patients; miR-4319 also suppressed colorectal cancer cell proliferation by targeting ABTB1. ABTB1 might become an excellent therapeutic target for colorectal cancer treatment.

A new biosensor detection system to overcome the Debye screening effect: dialysis-silicon nanowire field effect transistor.

Background: A silicon nanowire field effect transistor biosensor has four advantages in the detection of small biomolecules. It is mark-free, immediately responsive, highly sensitive, and specific. However, because of environments with a high salt concentration, the Debye screening effect has been a major issue in biological detection. Objective: To overcome Debye screening effect, realize the clinical application of silicon nanowire field effect transistor and verify its specificity and sensitivity. Materials and methods: The test solution was desalted by miniature blood dialyzer, and then the tumor markers were detected by silicon nanowire field effect transistor. Results: Tumor markers in serum were detected successfully and their sensitivity and specificity were verified. Conclusion: This method was found to effectively promote the development of semiconductor materials in biological solution detection.

EZH2 is involved in silencing of WNT5A during epithelial-mesenchymal transition of colon cancer cell line.

PURPOSE: Transforming growth factor-ß (TGF-ß) induction of epithelial-mesenchymal transition (EMT) in SW480 was established as a system for studies of colon cancer metastasis. However, the epigenetic mechanisms underlying this process remain unknown. In mammal, polycomb repressive complex-2 (PRC2) is a highly conserved histone methyltransferase involved in epigenetic regulations. Enhancer of zeste Homolog 2 (EZH2) is the catalytic subunit of PRC2, which catalyzes methylation of lysine 27 of histone H3 (H3K27). METHODS: An inducible EMT system in colorectal cancer was utilized to study its mechanistic and phenotypic changes. Particularly, gene expression analysis was studied after immunoprecipitation. RESULTS: In this study, we reported that EZH2 is significantly enriched in the promoter region of WNT5A after TGF-ß induction in SW480 colon cancer cell line, which in turn silenced the expression of WNT5A. Furthermore, EZH2 inhibitor antagonized the TGF-ß-induced morphological conversion associated with epithelial-mesenchymal transition (EMT). Conversely, inhibition of histone H3K27me3 reader CBX does not affect the WNT5A expression level during TGF-ß-induced EMT. CONCLUSIONS: Our results indicate that EZH2 was essential for the silencing of WNT5A during TGF-ß-induced epithelial-mesenchymal transition of colon cancer cells.

Curcumin Suppresses the Colon Cancer Proliferation by Inhibiting Wnt/ß-Catenin Pathways via miR-130a.

Curcumin exhibits anti-tumor effects in several cancers, including colorectal carcinoma (CRC), but the detailed mechanisms are still unclear. Here we studied the mechanisms underlying the anti-tumor effect of curcumin in colon cancer cells. SW480 cells were injected into mice to establish the xenograft tumor model, followed by evaluation of survival rate with the treatment of curcumin. The expression levels of ß-catenin, Axin and TCF4 were measured in the SW480 cells in the absence or presence of curcumin. Moreover, miRNAs related to the curcumin treatment were also detected in vitro. Curcumin could suppress the growth of colon cancer cells in the mouse model. This anti-tumor activity of curcumin was exerted by inhibiting cell proliferation rather than promoting cell apoptosis. Further study suggested that curcumin inhibited cell proliferation by suppressing the Wnt/ß-catenin pathway. MiR-130a was down-regulated by curcumin treatment, and overexpressing miR-130a could abolish the anti-tumor activity of curcumin. Our study confirms that curcumin is able to inhibit colon cancer by suppressing the Wnt/ß-catenin pathways via miR-130a. MiR-130a may serve as a new target of curcumin for CRC treatment.