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Background Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. Methods CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. Results CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. Conclusions CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.

Metastasis is the major cause of death in colorectal cancer (CRC). Although multiple genes have been identified to be responsible for the development of CRC, the molecular changes that enable CRC cells to undergo early local invasion and to form distant metastatic colonies still remain largely unknown. Herein, we investigated the role of Forkhead box protein C2 (FOXC2) and explored the underlying mechanisms in invasion and metastasis of CRC. We show that both high FOXC2 expression and nuclear localization of FOXC2 are significantly correlated with advanced TNM (T=primary tumor; N=regional lymph nodes; M=distant metastasis) stages. FOXC2 enhanced the invasive abilities of CRC cells in vitro and promoted local invasion and distant metastasis in an orthotopic mouse metastatic model of CRC. Microarray analysis revealed that overexpression of FOXC2 increased the proto-oncogene MET tyrosine kinase expression and activated the hepatocyte growth factor (HGF)-MET signaling pathway. Furthermore, luciferase reporter assays and chromatin immunoprecipitation assays revealed that FOXC2 directly associated with MET promoter to increase the transcriptional activity of MET. Inhibition of MET attenuates the invasive phenotype and metastatic potential of FOXC2-overexpressing CRC cells, indicating that MET is a major mediator of FOXC2-promoted metastasis. In addition, FOXC2 expression was positively correlated with MET expression in CRC tissue samples. Our findings suggest that FOXC2 has a crucial role in CRC metastasis by regulating HGF-MET signaling via inducing MET expression, highlighting FOXC2 as a potential therapeutic target for preventing or reducing metastasis in CRC.

Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase patients’ response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.

Background Gastric cancer (GC) is one of the most common malignancies in China. B-cell translocation gene 3 (BTG3) has been identified as a tumor suppressor in several tumors, but its role in GC remains unknown. This study aimed to detect the expression of BTG3 and its prognostic value in GC tissues and determine its function in the progression of GC. Methodology The expression of BTG3 was detected in GC cell lines and tissues by real-time RT-PCR, Western blot or immunohistochemistry. A series of in vitro and in vivo assays were performed to evaluate the effect of BTG3 on proliferation, migration and invasion of GC cells. Results B-cell translocation gene 3 was obviously down-regulated in GC tissues. Its expression was positively correlated with distant metastasis ( P  < 0.05). Patients with lower BTG3 expression had shorter overall survival time ( P  = 0.015). BTG3 suppressed the proliferation of GC cells in vitro and in vivo. It also inhibited migration and invasion of GC cells in vitro. Conclusion Down-regulation of BTG3 is closely associated with proliferation, migration and invasion in GC. It may be a novel prognostic biomarker for GC patients.

Building a reliable prediction model can mitigate the need for actual experiments, hence saving time and cost. To this end, this study presents a methodology to predict weld quality for a particular friction stir weld configuration using machine learning and metaheuristic algorithms including K-nearest neighbor (KNN), fuzzy KNN (FKNN), and the artificial bee colony (ABC). The ABC algorithm was utilized to determine the best (F)KNN model with optimal K value and feature subset. First, models were built based on only experimental conditions including spindle rotational speed, plunge force, and feed rate, as well as derived values including a speed ratio and an empirical force index (EFI). The best model was identified to be 1-NN comprised of three features, i.e., rotational speed, feed rate, and EFI, with 93.16% classification accuracy based on leave-one-out cross-validation. The majority of data points leading to error were found to lie mostly on the boundaries between classes. It was shown that classification error could be reduced by removing those points, which is cheating and not recommended. Instead, it is recommended to improve classification accuracy without omitting dissenting data by introducing additional information to better distinguish misclassified data points. To this end, wavelet energy features extracted from weld signals of X-Force, Y-Force, spindle rotational speed, feed rate, and plunge force were added to the original feature pool. In order to determine the impact of each weld signal feature set, each signal feature set was individually tested. After applying ABC to the expanded feature pool to build the best model, perfect classification accuracy was achieved in several cases. The results suggest that adding signal features can greatly improve the effectiveness of model predictability of friction stir weld quality.

Background: MiR-214 is aberrantly regulated in several tumours, but its underlying mechanisms in colorectal cancer (CRC) metastasis remain largely unknown. This study aimed to demonstrate the function and potential mechanism of miR-214 in regulating invasion and metastasis of CRC. Methods: The transcription factor and targets of miR-214 were predicted by bioinformatics and validated using ChIP and dual-luciferase reporter assay. DNA methylation status was explored using bisulphite sequencing PCR. The in vitro and in vivo function of miR-214 in CRC was evaluated using MTT, plate colony formation, Matrigel invasion and animal models. Real-time PCR or western blotting was performed to detect FOXD3 , miR-214 and MED19 expressions in CRC cells and clinical specimens. Results: MiR-214 was downregulated in CRC and was significantly correlated with lymphatic metastasis. Downregulation of miR-214 might due to promoter hypermethylation in CRC. FOXD3 was validated as a transcription factor of miR-214 by ChIP assay. Dual-luciferase assay identified MED19 as a target of miR-214 in CRC. In vitro and in vivo experiments showed that miR-214 mediated the inhibiting effect of FOXD3 on proliferation, invasion and metastasis by targeting MED19 . Spearman’s correlation analysis showed a positive correlation between FOXD3 and miR-214 , and negative correlations between FOXD3 and MED19 , miR-214 and MED19 in CRC cells and clinical specimens. Conclusions: FOXD3 / miR-214 / MED19 axis is important for the regulation of growth, invasion and metastasis of CRC. Targeting the miR-214 -mediated axis might be helpful for the treatment of CRC.

Background: Diaphanous-related formins (DRFs), actin necleator, have been known to participate in the progression of cancer cells. We previously reported that FMNL2 (Formin-like2), a member of DRFs, was a positive regulator in colorectal cancer (CRC) metastasis, yet proteins and pathways required for the function of this pro-invasive DRFs remain to be identified. Methods: The relationship between FMNL2 and COMMD10 was examined using Co-IP, GST pull-down, immunofluorescence and in vitro ubiquitination assay. The in vitro and in vivo function of COMMD10 in CRC was evaluated using CCK-8 proliferation assay, plate colony formation, cell cycle, apoptosis and animal models. The inhibition of NF- κ B signalling by COMMD10 was detected using dual-luciferase reporter assay and western blotting. Co-IP, GST pull-down and nuclear protein extraction assay were performed to evaluate the effect on p65 by COMMD10. Real-time PCR and western blotting were performed to detect expressions of FMNL2, COMMD10 and p65 in paired tissues. Results: FMNL2 targets COMMD10 for ubiquitin-mediated proteasome degradation in CRC cells. COMMD10 targets p65 NF- κ B (nuclear factor- κ B) subunit and reduces its nuclear translocation, thereby leading to the inactivation of NF- κ B pathway and suppression of CRC invasion and metastasis. Inhibition of NF- κ B signalling by COMMD10 is necessary for FMNL2-mediated CRC cell behaviours. Downregulation of COMMD10 predicts poor prognosis of CRC patients. The expressions of FMNL2, COMMD10 and p65 are highly linked in CRC tissues. Conclusions: These data demonstrate that the FMNL2/COMMD10/p65 axis acts as a critical regulator in the maintenance of metastatic phenotypes and is strongly associated with negative clinical outcomes.

With the advance of information technology, many fields have begun using data clustering to reveal data structures and obtain useful information. Most of the existing clustering algorithms are susceptible to outliers and noises as well as the initial solution. The fuzzy c-ordered-means (FCOM) method can handle outlier and noise problems by using Huber’s M-estimators and Yager’s OWA operator to enhance its robustness. However, the result of the FCOM algorithm is still unstable because its initial centroids are randomly generated. Besides, the attributes’ weight also affect the clustering performance. Thus, this study first proposed an intuitionistic fuzzy weighted c-ordered-means (IFWCOM) algorithm that combines intuitionistic fuzzy sets (IFSs), the feature-weighted and FCOM together to improve the clustering result. Moreover, this study proposed a real-coded genetic algorithm-based IFWCOM (GA-IFWCOM) that employs the genetic algorithm to exploit the global optimal solution of the IFWCOM algorithm. Twelve benchmark datasets were used for verification in the experiment. According to the experimental results, the GA-IFWCOM algorithm achieved better clustering accuracy than the other clustering algorithms for most of the datasets.

Background Colorectal cancer (CRC) is one of the most common cancers in the world. MicroRNAs play important roles in the progression of CRC. This study aimed to investigate the role of miR-206 and its novel mechanism in the invasion and metastasis of CRC. Methodology Real-time RT-PCR or Western blotting was used to detect the expressions of miR-206, FMNL2 and c-MET in CRC cell lines and tissues. Luciferase reporter assays were conducted to detect the associations between miR-206 and 3′UTRs of FMNL2 and c-MET. A series of loss-of-function and gain-of-function assays were performed to evaluate the effect of miR-206 on the proliferation, invasion and metastasis of CRC cells. Results miR-206 was significantly down-regulated in CRC tissues and correlated closely with differentiation, lymphatic metastasis and serosal invasion. miR-206 suppressed CRC cell proliferation by arresting CRC cells in the G1/G0 phase and accelerating apoptosis. miR-206 also inhibited cell invasion and lung metastasis in CRC cells. Mechanically, FMNL2 and c-MET were identified as direct targets of miR-206. And FMNL2 rescued the suppression of miR-206 in the proliferation and invasion of CRC cells. Conclusions This study revealed functional and mechanistic links between miR-206 and oncogene FMNL2 and c-MET in the progression of CRC. miR-206 functioned as a tumor suppressor in the progression of CRC by targeting FMNL2 and c-MET. Restoration of miR-206 expression may represent a promising therapeutic approach for targeting malignant CRC.