The ATF2/miR-3913-5p/CREB5 axis is involved in the cell proliferation and metastasis of colorectal cancer.

Various miRNAs have been shown to participate in the tumor progression and development of colorectal cancer (CRC). However, the role of miR-3913-5p in CRC are yet to be clearly defined. In the present study, we determine that miR-3913-5p is downregulated in CRC cell lines and CRC tissues. Exogenous miR-3913-5p expression weakens the CRC cells growth, migration and invasion. Mechanistically, miR-3913-5p directly targets the 3'UTR of CREB5. Overexpression of CREB5 reverses the suppression of CRC cells proliferation, migration and invasion induced by miR-3913-5p. Furthermore, ATF2 negatively regulates the transcription of miR-3913-5p by binding to its promoter. CREB5 can cooperate with ATF2. CREB5 is required for ATF2 in regulating miR-3913-5p. Finally, inverse correlations can be found between the expressions of miR-3913-5p and CREB5 or ATF2 in CRC tissues. Thus, a plausible mechanism of ATF2/miR-3913-5p/CREB5 axis regulating CRC progression is elucidated. Our findings suggest that miR-3913-5p functions as a tumor suppressor in CRC. ATF2/miR-3913-5p/CREB5 axis might be a potential therapeutic target against CRC progression.

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells.

Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/ß-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/ß-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.

Disruption of the CCDC43-FHL1 interaction triggers apoptosis in gastric cancer cells.

The coiled-coil domain-containing protein 43 (CCDC43) is essential to promote gastric cancer (GC) proliferation and invasion, while four and a half LIM domains 1 (FHL1) involves GC cells apoptosis. We attempted to address inter-relationship between CCDC43 and FHL1 in modulating GC cells growth and apoptosis. Levels of protein expression were assessed by western blot, immunofluorescence. Using EdU, plate colony formation, Matrigel invasion and animal models, we evaluated the function in vitro and in vivo. Apoptosis was evaluated by flow cytometry and Hoechst 33258 staining. Reciprocal co-immunoprecipitation (co-IP) analyses indicated that CCDC43 physically interacted with FHL1. The expression of CCDC43 was negatively correlated with FHL1. Moreover, up-regulation of CCDC43 resulted in FHL1 level decline, and the reverse is also true. CCDC43 expressed jointly with FHL1 group significantly decreases the ability of the growth, metastasis and invasion of GC cells compared with that of the CCDC43 group. Furthermore, siRNA-mediated repression of CCDC43 results in dissociation from FHL1 and causes suppression of GC cell proliferation and metastasis. CCDC43 repression mediates the stability of FHL1 protein. In addition, CCDC43 interacts with FHL1. Knockdown of CCDC43 plus FHL1 overexpression inhibits proliferation and migration and induces apoptosis of GC cells in vitro and vivo.

USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation.

As an important regulator of intracellular protein degradation, the mechanism of the deubiquitinating enzyme family in tumour metastasis has received increasing attention. Our previous study revealed that USP3 promotes tumour progression and is highly expressed in gastric cancer (GC). Herein, we report two critical targets, COL9A3 and COL6A5, downstream of USP3, via the isobaric tags for relative and absolute quantification technique. Mechanistically, we observed that USP3 interacted with and stabilised COL9A3 and COL6A5 via deubiquitination in GC. Importantly, we found that COL9A3 and COL6A5 were essential mediators of USP3-modulated oncogenic activity in vitro and in vivo. Examination of clinical samples confirmed that elevated expression of USP3, concomitant with increased COL9A3 and COL6A5 abundance, correlates with human GC progression. These data suggest that USP3 promotes GC progression and metastasis by deubiquitinating COL9A3 and COL6A5. These findings identify a mechanism of GC metastasis regarding USP3-mediated deubiquitinating enzyme activity and suggest potential therapeutic targets for GC management.

Vorinostat triggers miR-769-5p/3p-mediated suppression of proliferation and induces apoptosis via the STAT3-IGF1R-HDAC3 complex in human gastric cancer.

Previous reports have shown that histone deacetylase inhibitors (HDACi) can alter miRNA expression in a range of cancers. Both the 5p-arm and 3p-arm of mature miRNAs can be expressed from the same precursor and involved in cancer progress. Nevertheless, the detailed mechanism by which vorinostat (SAHA), a HDACi, triggers miR-769-5p/miR-769-3p-mediated suppression of proliferation and induces apoptosis in gastric cancer (GC) cells remains elusive. Here, we showed that the miRNA-seq analysis of GC cells treated with SAHA identified seven differentially expressed miRNAs with both strands of the miRNA duplex. miR-769-5p/miR-769-3p expression was downregulated in GC tissues compared with normal tissues. Functionally, high expression of miR-769-5p/miR-769-3p blocked the malignant abilities of GC cells. Mechanistically, miR-769-5p/miR-769-3p targeted IGF1R and IGF1R overexpression rescued the effects of miR-769-5p/miR-769-3p on GC cells growth and metastasis. Moreover, STAT3 bound to the promoter of miR-769. Furthermore, miR-769-5p/miR-769-3p expression was negatively regulated by the STAT3-IGF1R-HDAC3 complex. Besides, miR-769-5p/miR-769-3p synergized with SAHA to promote GC cells apoptosis. Our studies suggest that miR-769-5p/miR-769-3p acts as a tumor suppressor by the STAT3-IGF1R-HDAC3 complex. Moreover, SAHA triggers miR-769-5p/miR-769-3p-mediated inhibition of proliferation and induces apoptosis in GC cells.

Identification of an EMT-Related Gene Signature for Predicting Overall Survival in Gastric Cancer.

BACKGROUND: It has been widely reported that epithelial-mesenchymal transition (EMT) is associated with malignant progression in gastric cancer (GC). Integration of the molecules related to EMT for predicting overall survival (OS) is meaningful for understanding the role of EMT in GC. Here, we aimed to establish an EMT-related gene signature in GC. METHODS: Transcriptional profiles and clinical data of GC were downloaded from The Cancer Genome Atlas (TCGA). We constructed EMT-related gene signature for predicting OS by using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Time-dependent receiver operating characteristic (ROC), Kaplan-Meier analysis were performed to assess its predictive value. A nomogram combining the prognostic signature with clinical characteristics for OS prediction was established. And its predictive power was estimated by concordance index (C-index), time-dependent ROC curve, calibration curve and decision curve analysis (DCA). GSE62254 dataset from Gene Expression Omnibus (GEO) was used for external validation. Quantitative real-time PCR (qRT-PCR) was used to detected the mRNA expression of the five EMT-related genes in human normal gastric mucosal and GC cell lines. To further understand the potential mechanisms of the signature, Gene Set Enrichment Analysis (GSEA), pathway enrichment analysis, predictions of transcription factors (TFs)/miRNAs were performed. RESULTS: A novel EMT-related gene signature (including ITGAV, DAB2, SERPINE1, MATN3, PLOD2) was constructed for OS prediction of GC. With external validation, ROC curves indicated the signature's good performance. Patients stratified into high- and low-risk groups based on the signature yielded significantly different prognosis. Univariate and multivariate Cox regression suggested that the signature was an independent prognostic variable. Nomogram for prognostication including the signature presented better predictive accuracy and clinical usefulness than the similar model without risk score to some extent with external validation. The qRT-PCR assays suggested that high expression of the five EMT-related genes could be found in human GC cell lines compared with normal gastric mucosal cell line. GSEA and pathway enrichment analysis revealed that focal adhesion and ECM-receptor interaction might be the two important pathways to the signature. CONCLUSION: Our EMT-related gene signature may have practical application as an independent prognostic factor in GC.

HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression.

HMGA1 protein is an architectural transcription factor that has been implicated in the progression of multiple malignant tumors. However, the role of HMGA1 in the growth and metastasis of gastric cancer (GC) has not yet been elucidated. Here, we show that HMGA1 is overexpressed in GC cells and the high expression of HMGA1 was correlated with worse survival in GC patients using a bioinformatics assay. Functionally, HMGA1 affected the EdU incorporation, colony formation, migration and invasion of GC cells by exogenously increasing or decreasing the expression of HMGA1. Mechanistically, HMGA1 directly bound to the SUZ12 and CCDC43 promoter and transactivated its expression in GC cells. Inhibition of SUZ12 and CCDC43 attenuated the proliferation, migration and invasiveness of HMGA1-overexpressing GC cells in vitro. Moreover, both HMGA1 and SUZ12/CCDC43 were highly expressed in cancer cells but not in normal gastric tissues, and their expressions were positively correlated. Finally, a tail vein metastatic assay showed that HMGA1 promoted SUZ12/CCDC43-mediated GC cell metastasis in vivo. Our findings suggest that HMGA1 promotes GC growth and metastasis by transactivating SUZ12 and CCDC43 expression, highlighting HMGA1 as a potential prognostic biomarker in the treatment of GC.

The TGF-ß/miR-31/CEACAM1-S axis inhibits CD4+ CD25+ Treg differentiation in systemic lupus erythematosus.

Defects causing concomitant loss of CD25 expression in regulatory T cells (Tregs) have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), an immune co-receptor, contributes to general T-cell function and activation. Our previous study revealed that CEACAM1 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with SLE. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1-S, was upregulated in PBMCs from patients with SLE. CEACAM1-S over-expression inhibits CD4+ CD25+ Treg differentiation, whereas knockdown of CEACAM1 had the opposite effect in vitro. CEACAM1-S is the target of miR-31. MiR-31 mimic inhibits CEACAM1 expression and enhances CD4+ CD25+ Treg differentiation, which was reversed by CEACAM1-S over-expression. Moreover, the circulating TGF-ß level was upregulated in SLE patients and TGF-ß reduced miR-31 expression via enhancing NF-κB activity. Importantly, CEACAM1 and TGF-ß mRNA levels were downregulated, while the miR-31 level and the abundance of CD4+ CD25+ Tregs were increased in inactive patients compared with that in patients with active SLE. In addition, CEACAM1-S expression was positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, while CD4+ CD25+ Treg abundance and miR-31 level were negatively correlated with the SLEDAI score. In conclusion, reduced activity of miR-31 by TGF-ß, via the inhibition of NF-ᴋB, acted to inhibit the differentiation of CD4+ CD25+ Tregs by directly targeting CEACAM1-S and to promote autoimmunity.

Coexpression of HOXA6 and PBX2 promotes metastasis in gastric cancer.

HOXA6 gene plays a role of the oncogene in various cancers. Nonetheless, its effect on gastric cancer (GC) occurrence and development is still unclear. We analysed whether HOXA6 interacts with the PBX2 protein using the STRING database. The molecular mechanism by which HOXA6 synergizes with PBX2 in GC metastasis is not fully understood. Here, we found that the expression of HOXA6 was increased in GC tissues and cell lines. The upregulation of HOXA6 was closely associated with differentiation, lymph node metastasis, AJCC stage, TNM stage, and poor survival outcome in GC patients based on tissue microarray (TMA) data. Moreover, the overexpression of HOXA6 promoted, whereas siRNA-mediated repression of HOXA6 inhibited, the cell proliferation, migration, and invasion of GC cells. Furthermore, HOXA6 could physically interact with and stabilize PBX2. In addition, HOXA6 and PBX2 expression was positively correlated in GC cells and tissue. HOXA6 and PBX2 suppression in GC cells also led to decreased migration and invasion potential in vitro. In vivo, HOXA6 was shown to cooperate with PBX2 to enhance cell metastasis via orthotopic implantation. These data indicate that HOXA6 promotes cell proliferation, migration, and invasion and that the HOXA6-PBX2 axis may be a useful biomarker for disease progression in GC.

Comprehensive Analysis of the Prognostic Values of the TRIM Family in Hepatocellular Carcinoma.

BACKGROUND: Accumulating studies have demonstrated the abnormal expressions and prognostic values of certain members of the tripartite motif (TRIM) family in diverse cancers. However, comprehensive prognostic values of the TRIM family in hepatocellular carcinoma (HCC) are yet to be clearly defined. METHODS: The prognostic values of the TRIM family were evaluated by survival analysis and univariate Cox regression analysis based on gene expression data and clinical data of HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The expression profiles, protein-protein interaction among the TRIM family, prediction of transcription factors (TFs) or miRNAs, genetic alterations, correlations with the hallmarks of cancer and immune infiltrates, and pathway enrichment analysis were explored by multiple public databases. Further, a TRIM family gene-based signature for predicting overall survival (OS) in HCC was built by using the least absolute shrinkage and selection operator (LASSO) regression. TCGA-Liver Hepatocellular Carcinoma (LIHC) cohort was used as the training set, and GSE76427 was used for external validation. Time-dependent receiver operating characteristic (ROC) and survival analysis were used to estimate the signature. Finally, a nomogram combining the TRIM family risk score and clinical parameters was established. RESULTS: High expressions of TRIM family members including TRIM3, TRIM5, MID1, TRIM21, TRIM27, TRIM32, TRIM44, TRIM47, and TRIM72 were significantly associated with HCC patients' poor OS. A novel TRIM family gene-based signature (including TRIM5, MID1, TRIM21, TRIM32, TRIM44, and TRIM47) was built for OS prediction in HCC. ROC curves suggested the signature's good performance in OS prediction. HCC patients in the high-risk group had poorer OS than the low-risk patients based on the signature. A nomogram integrating the TRIM family risk score, age, and TNM stage was established. The ROC curves suggested that the signature presented better discrimination than the similar model without the TRIM family risk score. CONCLUSION: Our study identified the potential application values of the TRIM family for outcome prediction in HCC.

The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer.

PURPOSE: Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. METHODS: To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. RESULTS: We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman's correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. CONCLUSION: Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells.

MicroRNA­500a­5p inhibits colorectal cancer cell invasion and epithelial­mesenchymal transition.

The development of malignant tumors is a series of complex processes, the majority of which have not been elucidated. The aim of the present study was to investigate the microRNAs (miRNAs/miR) that affect the migration and invasion abilities of CRC cells. Our previous reports have revealed that miR­500a­5p suppressed CRC cell growth and malignant transformation. The present study demonstrated that overexpression of miR­500a­5p reduced the expression of vimentin, while increasing the expression of E­cadherin. Inhibition of miR­500a­5p resulted in spindle­like morphological changes and reorganization of F­actin in CRC cells. Furthermore, miR­500a­5p attenuated the transforming growth factor­ß signaling pathway in EMT. Additionally, emodin inhibited the miR­500a­5p inhibitor and suppressed the EMT process. In animal models of metastasis using nude mice, EMT and LoVo cell metastasis was modulated by miR­500a­5p. Therefore, the findings of the present study demonstrated that miR­500a­5p is associated with a positive therapeutic outcome in terms of invasion/migration of CRC cells and mesenchymal­like cell changes.

HOXD9 promote epithelial-mesenchymal transition and metastasis in colorectal carcinoma.

BACKGROUND: HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colorectal cancer (CRC), is mostly unknown. METHODS: The HOXD9 protein expression levels were analyzed using immunofluorescence, immunohistochemistry (IHC) assays, and western blot. The in vivo and in vitro roles of HOXD9 in CRC were determined using colony formation and EdU incorporation, CCK-8, wound scratch and transwell invasion assay, and animal models. RESULTS: Expression of HOXD9 was higher in CRC than in matched healthy tissues. High expression of HOXD9 has significantly associated with the American Joint Committee on Cancer (AJCC) stages, tumor differentiation, lymph node metastasis, and other serious invasions, and it had a poor prognosis. In vitro, HOXD9 encouraged proliferation, movement and EMT processes in cells of CRC. Also, TGF-ß1 promoted the expression of HOXD9 and this effect was dependent on the dose and downregulation of HOXD9 repressed TGF-ß1 -induced EMT. In vivo, HOXD9 promoted the invasive and metastasis of CRC cells via orthotopic implantation. CONCLUSIONS: The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo.

Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia.

Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.

HOXD9 promotes the growth, invasion and metastasis of gastric cancer cells by transcriptional activation of RUFY3.

BACKGROUND: The transcription factor HOXD9 is one of the members of the HOX family, which plays an important role in neoplastic processes. However, the role of HOXD9 in the growth and metastasis of gastric cancer (GC) remains to be elucidated. METHODS: In vitro functional role of HOXD9 and RURY3 in GC cells was determined using the TMA-based immunohistochemistry, western blot, EdU incorporation, gelatin zymography, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. In vivo tumor growth and metastasis were conducted in nude mice. RESULTS: HOXD9 is overexpressed in GC cells and tissues. The high expression of HOXD9 was correlated with poor survival in GC patients. Functionally, HOXD9 expression significantly promoted the proliferation, invasion and migration of GC cells. Mechanically, HOXD9 directly associated with the RUFY3 promoter to increase the transcriptional activity of RUFY3. Inhibition of RUFY3 attenuated the proliferation, migration and invasiveness of HOXD9-overexpressing GC cells in vitro and in vivo. Moreover, both HOXD9 and RUFY3 were highly expressed in cancer cells but not in normal gastric tissues, with their expressions being positively correlated. CONCLUSIONS: The evidence presented here suggests that the HOXD9-RUFY3 axis promotes the development and progression of human GC.

Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer.

BACKGROUND: The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown. METHODS: Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models. RESULTS: USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-ß1 induced USP3 expression, and USP3 knockdown inhibited TGF-ß1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein. CONCLUSIONS: These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC.

Coexpression of FOXK1 and vimentin promotes EMT, migration, and invasion in gastric cancer cells.

In human gastric cancer (GC), the upregulation of FOXK1 and vimentin is frequently observed in cancer cells and correlates with increased malignancy. We report that FOXK1 synergizes with vimentin to promote GC invasion and metastasis via the induction of epithelial-mesenchymal transition (EMT). We showed that higher expression levels of FOXK1 were significantly associated with GC development. FOXK1 can physically interact with and stabilize vimentin. Moreover, a positive correlation between the expression of FOXK1 and vimentin was found in GC cells. Higher expression levels of these two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage, and poorer prognosis. Furthermore, the coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of EMT in GC cells. However, the siRNA-mediated repression of vimentin in FOXK1-overexpressing cells reversed the EMT-like phenotype and reduced GC cell migration and invasion in vitro and in vivo. Altogether, our findings suggest that the vimentin-FOXK1 axis provides new insights into the molecular mechanisms underlying EMT regulation during GC progression and metastasis.

Integrated comparison of the miRNAome and mRNAome in muscles of dermatomyositis and polymyositis reveals common and specific miRNA-mRNAs.

AIM: Dermatomyositis (DM) and polymyositis (PM) are refractory systemic autoimmune diseases with unknown pathogenesis. miRNAs is an important epigenetic mechanism to regulate gene expression. METHODS: We performed whole miRNAs analysis, transcription analysis and the association between miRNAome and mRNAome. RESULTS: For transcription and miRNAs analysis, there were common and specific mRNAs and miRNAs in the muscles of DM and PM. Among them, the expression levels of miR-196a-5p and CPM were negatively correlated in PM, miR-193b-3p and NECAP2 were negatively correlated in DM and PM. Protein carboxypeptidase M (CPM) plays roles in the degradation of extracellular proteins and in the migration and invasion of cancer cells, and protein NECAP2 plays roles in adaptor protein AP-1-mediated fast recycling from early endosomes. The functions of them in the pathogenesis of DM/PM need further studies. CONCLUSION: Our study identified and confirmed differentially miRNAs and mRNAs in DM and PM. Our observations have laid the groundwork for further diagnostic and mechanistic studies of DM and PM.

The FOXK1-CCDC43 Axis Promotes the Invasion and Metastasis of Colorectal Cancer Cells.

BACKGROUND/AIMS: The CCDC43 gene is conserved in human, rhesus monkey, mouse and zebrafish. Bioinformatics studies have demonstrated the abnormal expression of CCDC43 gene in colorectal cancer (CRC). However, the role and molecular mechanism of CCDC43 in CRC remain unknown. METHODS: The functional role of CCDC43 and FOXK1 in epithelial-mesenchymal transition (EMT) was determined using immunohistochemistry, flow cytometry, western blot, EdU incorporation, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. RESULTS: The CCDC43 gene was overexpressed in human CRC. High expression of CCDC43 protein was associated with tumor progression and poor prognosis in patients with CRC. Moreover, the induction of EMT by CCDC43 occurred through TGF-ß signaling. Furthermore, a positive correlation between the expression patterns of CCDC43 and FOXK1 was observed in CRC cells. Promoter assays demonstrated that FOXK1 directly bound and activated the human CCDC43 gene promoter. In addition, CCDC43 was necessary for FOXK1- mediated EMT and metastasis in vitro and vivo. Taken together, this work identified that CCDC43 promoted EMT and was a direct transcriptional target of FOXK1 in CRC cells. CONCLUSION: FOXK1-CCDC43 axis might be helpful to develop the drugs for the treatment of CRC.