BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1.

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.

Artificial intelligence-based diagnosis of standard endoscopic ultrasonography scanning sites in the biliopancreatic system: a multicenter retrospective study.

BACKGROUND: There are challenges for beginners to identify standard biliopancreatic system anatomical sites on endoscopic ultrasonography (EUS) images. Therefore, the authors aimed to develop a convolutional neural network (CNN)-based model to identify standard biliopancreatic system anatomical sites on EUS images. METHODS: The standard anatomical structures of the gastric and duodenal regions observed by EUS was divided into 14 sites. The authors used 6230 EUS images with standard anatomical sites selected from 1812 patients to train the CNN model, and then tested its diagnostic performance both in internal and external validations. Internal validation set tests were performed on 1569 EUS images of 47 patients from two centers. Externally validated datasets were retrospectively collected from 16 centers, and finally 131 patients with 85 322 EUS images were included. In the external validation, all EUS images were read by CNN model, beginners, and experts, respectively. The final decision made by the experts was considered as the gold standard, and the diagnostic performance between CNN model and beginners were compared. RESULTS: In the internal test cohort, the accuracy of CNN model was 92.1-100.0% for 14 standard anatomical sites. In the external test cohort, the sensitivity and specificity of CNN model were 89.45-99.92% and 93.35-99.79%, respectively. Compared with beginners, CNN model had higher sensitivity and specificity for 11 sites, and was in good agreement with the experts (Kappa values 0.84-0.98). CONCLUSIONS: The authors developed a CNN-based model to automatically identify standard anatomical sites on EUS images with excellent diagnostic performance, which may serve as a potentially powerful auxiliary tool in future clinical practice.

The VAX2-LINC01189-hnRNPF signaling axis regulates cell invasion and migration in gastric cancer.

Transcription factors (TFs) and long noncoding RNAs (lncRNAs) contribute to gastric cancer (GC). However, the roles of TFs and lncRNAs in the invasion and metastasis of GC remain largely unknown. Here, we observed that the transcription factor VAX2 is significantly upregulated in GC cells and tissues and acts as an oncogene. Moreover, high VAX2 expression is associated with the advancement of tumors in GC. In terms of functionality, the enforced expression of VAX2 promotes the proliferation and metastasis of GC cells. Mechanistically, VAX2 specifically interacts with the LINC01189 promoter and represses LINC01189 transcription. Furthermore, LINC01189 exhibits significant downregulation in GC and functions as a suppressor gene. Functionally, it inhibits migratory and invasive abilities in GC cells. In the context of GC metastasis, VAX2 plays a role in modulating it by trans-repressing the expression of LINC01189. Additionally, LINC01189 binds to hnRNPF to enhance hnRNPF degradation through ubiquitination. The cooperation between LINC01189 and hnRNPF regulates GC cell invasion and migration. In addition, both VAX2 and hnRNPF are highly expressed, while LINC01189 is expressed in at low levels in GC tissues compared to normal gastric tissues. Our study suggests that VAX2 expression facilitates, while LINC01189 expression suppresses, metastasis and that the VAX2-LINC01189-hnRNPF axis plays a contributory role in GC development.

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.

Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling.

BACKGROUND: Altered miR-188-3p expression has been observed in various human cancers. AIM: To investigate the miR-188-3p expression, its roles, and underlying molecular events in gastric cancer. METHODS: Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression. Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays. The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay. A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival. A nude mouse tumor cell xenograft assay was used to confirm the in vitro data. RESULTS: MiR-188-3p was found to be lower in the plasma of gastric cancer patients, tissues, and cell lines compared to their healthy counterparts. It was associated with overall survival of gastric cancer patients (P < 0.001), tumor differentiation (P < 0.001), lymph node metastasis (P = 0.033), tumor node metastasis stage (I/II vs III/IV, P = 0.024), and American Joint Committee on Cancer stage (I/II vs III/IV, P = 0.03). Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy. CBL was identified as a direct target of miR-188-3p, with its expression antagonizing the effects of miR-188-3p on gastric cancer (GC) cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway. The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer. CONCLUSION: The current data provides ex vivo, in vitro, and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.

The HOXD9-mediated PAXIP1-AS1 regulates gastric cancer progression through PABPC1/PAK1 modulation.

Long non-coding RNAs (lncRNAs) have been functionally characterised in various diseases. LncRNA PAX-interacting protein 1-antisense RNA 1 (PAXIP1-AS1) has reportedly been associated with cancer development. However, its role in gastric cancer (GC) remains poorly understood. Here, we showed that PAXIP1-AS1 was transcriptionally repressed by homeobox D9 (HOXD9) and was significantly downregulated in GC tissues and cells. Decreased expression of PAXIP1-AS1 was positively correlated with tumour progression, while PAXIP1-AS1 overexpression inhibited cell growth and metastasis both in vitro and in vivo. PAXIP1-AS1 overexpression significantly attenuated HOXD9-enhanced epithelial-to-mesenchymal transition (EMT), invasion and metastasis in GC cells. Poly(A)-binding protein cytoplasmic 1 (PABPC1), an RNA-binding protein, was found to enhance the stability of PAK1 mRNA, leading to EMT progress and GC metastasis. PAXIP1-AS1 was found to directly bind to and destabilise PABPC1, thereby regulating EMT and metastasis of GC cells. In summary, PAXIP1-AS1 suppressed metastasis, and the HOXD9/PAXIP1-AS1/PABPC1/PAK1 signalling axis may be involved in the progression of GC.

The LINC00501-HSP90B1-STAT3 positive feedback loop promotes malignant behavior in gastric cancer cells.

Long non-coding RNAs (lncRNAs) have been implicated in gastric cancer (GC) carcinogenesis and progression. However, the role of LINC00501 in GC growth and metastasis remains unclear. In this study, we found that LINC00501 was frequently upregulated in GC cells and tissues and was closely related to adverse GC clinicopathological features. Aberrant overexpression of LINC00501 promoted GC cell proliferation, invasion, and metastasis both in vitro and in vivo. Mechanistically, LINC00501 stabilized client protein STAT3 from deubiquitylation by directly interacting with cancer chaperone protein HSP90B1. Furthermore, the LINC00501-STAT3 axis modulated GC cell proliferation and metastasis. In turn, STAT3 bound directly to the LINC00501 promoter and positively activated LINC00501 expression, thus forming a positive feedback loop, thereby accelerating tumor growth, invasiveness, and metastasis. In addition, LINC00501 expression was positively correlated with STAT3 and p-STAT3 protein expression levels in gastric clinical samples. Our results reveal that LINC00501 acts as an oncogenic lncRNA and that the LINC00501-HSP90B1-STAT3 positive feedback loop contributes to GC development and progression, suggesting that LINC00501 may be a novel potential biomarker and treatment target for GC.

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.

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.

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.

The CCDC43-ADRM1 axis regulated by YY1, promotes proliferation and metastasis of gastric cancer.

Previous studies have shown an association between coiled-coil domain-containing (CCDC) genes and different cancers. Our previous studies revealed that CCDC43 is highly expressed in colorectal cancer, but the expression and molecular mechanisms of CCDC43 in gastric cancer (GC) are yet to be determined. Here, we show that CCDC43 is overexpressed in gastric tissues. CCDC43 expression is closely related to tumor differentiation, lymph-node-metastasis, and prognosis of gastric cancer. Overexpression of CCDC43 promotes the proliferation, invasion, and metastasis of GC cells. CCDC43 may upregulate and stabilize ADRM1, resulting in the construction of the ubiquitin-mediated proteasome. In contrast, inhibition of ADRM1 could reverse the function of CCDC43 in GC both in vitro and in vivo. Our data demonstrate that transcription factor YY1 directly binds to CCDC43 and ADRM1 gene promoters, leading to over-expression of CCDC43 and ADRM1. Furthermore, in vitro experiments demonstrate that knock down of CCDC43 or ADRM1 attenuates the YY1-mediated malignant phenotypes. Finally, the association among YY1, CCDC43 and ADRM1 is validated in clinical samples. Our findings suggest that the CCDC43-ADRM1 axis regulated by YY1, promotes proliferation and metastasis of GC, and the axis may be a potential therapeutic target for GC.

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.