Gastric Cancer Invasion Research Articles

Methodical approaches to annotation and labeling of histological images in order to automatically detect the layers of the stomach wall and the depth of invasion of gastric cancer

Development of original methodological approaches to annotation and labeling of histological images in relation to the problem of automatic segmentation of the layers of the stomach wall. Three image collections were used in the study: NCT-CRC-HE-100K, CRC-VAL-HE-7K, and part of the PATH-DT-MSU collection. The used part of the original PATH-DT-MSU collection contains 20 histological images obtained using a high performance digital scanning microscope. A labeling system is proposed that includes 5 classes (tissue types): areas of gastric adenocarcinoma (TUM), unchanged areas of the lamina propria (LP), unchanged areas of the muscular lamina of the mucosa (MM), a class of underlying tissues (AT), including areas of the submucosa, own muscular layer of the stomach and subserous sections, image background (BG). The advantage of this marking technique is to ensure high efficiency of recognition of the muscularis lamina (MM) - a natural «line» separating the lamina propria of the mucous membrane and all other underlying layers of the stomach wall. The disadvantages of the technique include a small number of classes, which leads to insufficient detailing of automatic segmentation. In the course of the study, an original technique for labeling and annotating images was developed, including 5 classes (types of tissues). This technique is effective at the initial stages of teaching mathematical algorithms for the classification and segmentation of histological images. Further stages in the development of a real diagnostic algorithm to automatically determine the depth of invasion of gastric cancer require the correction and development of the presented method of marking and annotation.

SATB1 enhances gastric cancer progression and metastasis via upregulation of CLIP4/DZIP1/ PRICKLE2 axis in gastric cancer patients

SATB1 (Special AT-rich sequence binding protein 1) plays key role in chromatin remodeling and geneexpression. SATB1 has been shown to promote invasion, migration and metastasis. However, the underlying molecular mechanisms, function and clinicopathological features of SATB1 in gastric cancer (GC) remains poorly understood. Here, we show that SATB1 plays critical role in GC progression. SATB1 upregulates in GC patients’ samples and shows co-apmlification with a subset of oncogenic proteins (PRICKLE2, ZEB1, CBWX7, WWTR1, ENAH, DZIP1, IGSF11, ZSCAN18, GFRA2, GFRA1, FGFR1, HDAC4, GHR, TIMP3, CLIP4, TAGLN and ILK) in different subtypes of GC. SATB1 shows positive correlation with GC promoting oncogenes and enhances the expression of metastasis associated genes in GC samples to potentiate GC progression. SATB1 enhances WNT/NOTCH signaling axis in GC samples. In contrast, STAB1 suppresses a network of tumor suppressor genes in GC samples. Moreover, SATB1 expression negatively correlates with GC patient’s survival. Importantly, we found that SATB1 co-amplified genes CLIP4, DZIP1 and PRICKLE2 independently involve in GC progression. Overexpression of CLIP4, DZIP1 and PRICKLE2 show poor survival rates in GC patients. DZIP1 empowers AKT3/FGF2/FGFR1 and CXCR3/CXCR6 in GC patients. PRICKLE2 enhances GC progression by targeting FGFR1/NOTCH3/WNT4 signaling. Taken together, these results identified novel roles of SATB1, CLIP4, DZIP1 and PRICKLE2 in the GC invasion, migration and metastasis using cancer bioinformatics approach. These results highlights clinical significance of SATB1, CLIP4, DZIP1 and PRICKLE2 in GC patients and furthermore, these proteins may serve as prognostic markers in GC. These results also provide SATB1, CLIP4, DZIP1 and PRICKLE2 as potential chemotherapeutic targets in treatment of gastric cancer patients.

LncRNA SNHG3 promotes gastric cancer cell proliferation and metastasis by regulating the miR-139-5p/MYB axis.

The long non-coding RNA (lncRNA) SNHG3 has been shown to play oncogenic roles in several cancer types, but the mechanisms underlying its activity are poorly understood. In this study, we aimed to explore the clinical relevance and mechanistic role of SNHG3 in gastric cancer (GC). We found that SNHG3 expression in GC cell lines and tissues was significantly increased, and the upregulation of this lncRNA was correlated with tumor clinical stage and decreased patient survival. Knocking down SNHG3 in GC cells impaired the proliferative, migratory, and invasive activity in vitro and constrained in vivo GC xenograft tumor growth. Mechanistically, SNHG3 was found to bind and sequester miR-139-5p, thereby indirectly promoting the upregulation of the miR-139-5p target gene MYB. These data demonstrated that SNHG3 functions in an oncogenic manner to drive GC proliferation, migration, and invasion by regulating the miR-139-5p/MYB axis.

Linc00467 promotion of gastric cancer development by directly regulating miR-7-5p expression and downstream epidermal growth factor receptor

ABSTRACT Linc00467 is a vital regulator in tumor progression. This study explores the molecular mechanisms of linc00467 in gastric cancer (GC). Linc00467 expression was obtained and analyzed in GC tissue through exploration in the cancer genome atlas database. Then, real-time quantitative polymerase chain reaction was used to detect linc000467 expression in GC cells. Cell functions were observed using cell counting Kit-8, Transwell assay, Western blotting to testify the proliferation, migration, invasion, and the relative expression of epidermal growth factor receptor (EGFR) in GC cells. Moreover, a dual-luciferase reporter gene assay was used to verify the relationship between linc00467 and miR-7-5p. Results showed that the expression of linc00467 was overexpressed in GC. Linc00467 silencing decreased the GC cell proliferation, migration, and invasion. With mRNA verification and combined previous research, linc00467 directly regulated the miR-7-5p expression and downstream EGFR expression. Inhibited miR-7-5p could restore cell function, EGFR expression of GC cells when linc00467 knockdown occurs. Altogether, linc00467 directly regulates the miR-7-5p and EGFR signaling pathway to promote GC proliferation, migration, and invasion.

MicroRNA-23a-3p influences the molecular mechanism of gastric cancer cells via CCL22/PI3K/Akt axis

ABSTRACT A great many microRNAs (miRNAs) have been reported to play different roles in human cancers, including gastric cancer (GC). However, the specific character of miR-23a-3p in GC has not been elucidated. This study was to explore the function of miR-23a-3p in GC. The results manifested that miR-23a-3p was down-regulated in GC and patients with reduced miR-23a-3p had poor prognosis. Functional experiments assured that elevated miR-23a-3p refrained GC proliferation, invasion, migration, PIK3/Akt phosphorylation and apoptosis, while knockdown miR-23a-3p accelerated the growth of GC. Double luciferase report experiments manifested that miR-23a-3p targeted CCL22 expression. Functional rescue experiments affirmed that the repression of elevated miR-23a-3p on GC was reversed by simultaneous augmented CCL22. In vivo, elevated miR-23a-3p restrained the volume and tumor of GC and reduced the expression of CCL22 and phosphorylated PIK3/Akt, while knockdown miR-23a-3p motivated tumor growth. In conclusion, the results of this study indicate that miR-23a-3p plays a repressive role in GC, and affects the progression of GC via down-regulating CCL22 and blocking PI3K/AKT signal transduction pathway, which may offer a new molecular target for clinical treatment of GC.

TRPV2 Promotes Cell Migration and Invasion in Gastric Cancer via the Transforming Growth Factor-β Signaling Pathway.

Transient receptor potential vanilloid 2 (TRPV2) is a highly Ca2+-permeable ion channel that is involved in a number of cellular processes. It is expressed in various human cancers; however, the role of TRPV2 in gastric cancer (GC) remains poorly understood. TRPV2 gene expression was knocked down in GC cell lines by small-interfering RNA (siRNA), and the biological roles of TRPV2 in the proliferation, migration, and invasion of GC cells were then investigated. The gene expression profile of GC was elucidated using a microarray analysis. TRPV2 expression in tumor tissue sections was analyzed by immunohistochemistry. The migration and invasion abilities of GC cells were inhibited by the knockdown of TRPV2. Moreover, the microarray assay revealed that TRPV2 was associated with the transforming growth factor (TGF)-β signaling pathway. Immunohistochemical staining showed that the strong expression of TRPV2 correlated with lymphatic invasion, venous invasion, pathological T (pT), pathological N (pN), and a poor prognosis in GC patients. TRPV2 appeared to promote tumor migration and invasion via the TGF-β signaling pathway, and the strong expression of TRPV2 was associated with a worse prognosis in GC patients.

Nucleoporin 37 promotes the cell proliferation, migration, and invasion of gastric cancer through activating the PI3K/AKT/mTOR signaling pathway.

Gastric cancer is a kind of malignant tumor in the world. Emerging studies have proved the regulatory role of nucleoporin 37 in the development of several malignant tumors. However, the potential effect of NUP37 in gastric cancer is still unclear. In this study, we searched for the Cancer Genome Atlas analysis to explore the potential correlation between NUP37 and gastric cancer. Then, we analyzed NUP37 expression in gastric cancer tissues and cell lines. After constructing a NUP37-silenced model in NCI-N87 cells and a NUP37-overexpressed model in MKN45 cells, we evaluated the role of NUP37 in cell proliferation, migration, and invasion as well as its underlying mechanism. TCGA analysis showed that NUP37 expression was highly expressed in stomach adenocarcinoma, which showed a lower survival rate than normal samples. Moreover, NUP37 was found to be highly expressed in gastric cancer tissues and cell lines. Functionally, NUP37 deficiency promoted gastric cancer cell apoptosis and inhibited cell proliferation, migration, and invasion, whereas NUP37 overexpression exhibited the opposite results. Mechanically, upregulation of NUP37 activated the PI3K/AKT/mTOR signaling pathway. Furthermore, the rescue assay exhibited that the mTOR inhibitor rapamycin significantly reversed the promoting effect of NUP37 in cell proliferation, migration, and invasion. In conclusion, our study identified that NUP37 promoted malignant behavior of gastric cancer cells including invasion, proliferation, and migration through activating the PI3K and its downregulated signaling pathway, indicating that NUP37 might become a novel prognostic target for further gastric cancer therapy.

Prognostic Significance of Extracapsular Invasion in Gastric Cancer

Prognostic Significance of Extracapsular Invasion in Gastric Cancer

Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis

BackgroundFasting mimic diet is an effect approach for gastric cancer (GC) treatment. Exploring mechanisms of glucose deprivation-mediated GC suppression is required to develop novel therapeutic regimens. Farnesyltransferase 1 (FDFT1), as a novel target in basic research, has been reported to regulate malignant progression in some types of cancer. However, biological functions of FDFT1 in GC are still unclear. This study focused on biological functions of FDFT1 in GC and the association between glucose starvation (GS) and FDFT1.MethodsThe data derived from the Kaplan–Meier Plotter database were collected to identify the relationship between survival time and FDFT1 expression levels of GC patients. Bioinformatic analysis was performed to explore the biological functions of FDFT1. The expression levels of targeted genes and microRNAs (miRNAs) were detected with immunohistochemistry, quantitative real-time PCR and western blot. Malignant behaviors were measured using cell counting, cell counting kit-8, 5-ethynyl-2-deoxyuridine, wound healing, invasion transwell assays in vitro and constructions of subcutaneous and lung-metastatic tumors in vivo. The glycolysis of GC cells was determined by a series of metabolites, including lactate acid, pyruvic acid, ATP production, rates of glucose uptake, extracellular acidification rate and oxygen consumption rate.ResultsFDFT1 was downregulated in GC and negatively correlated with pathological T stage, pathological TNM stage and cancer differentiation. High expression of FDFT1 also indicated better prognosis of GC patients. FDFT1 upregulation attenuated proliferation, migration and invasion of GC. miR-216a-5p was identified as a critical suppressor of FDFT1 expression and miR-216a-5p/FDFT1 axis regulated malignant behaviors and glycolysis of GC cells. GS suppressed malignant behaviors of GC by targeting miR-216a-5p/FDFT1 axis both in vitro and in vivo.ConclusionThis study illustrated novel mechanisms by which GS effectively suppresses GC. FDFT1 may become a potential prognostic indicator and novel target of GC therapy.

Hsa_circ_0008434 regulates USP9X expression by sponging miR-6838-5p to promote gastric cancer growth, migration and invasion

BackgroundThe role of circular RNAs (circRNAs) in the occurrence and development of gastric cancer (GC) has recently attracted increasing interest. The following study investigates the role of a newly discovered hsa_circ_0008434, which has been confirmed to be highly expressed in GC tissues, in regulating GC biological behaviour.MethodsHigh-throughput RNA sequencing was used to identify differentially expressed genes between normal gastric tissues and GC tissues; actinomycin D and RNase R assays were used to determine the stability and loop structure of hsa_circ_0008434; and the miRanda database was used to predict the target genes of hsa_circ_0008434. The role of hsa_circ_0008434 in cell proliferation, migration, and invasion was examined using CCK-8, wound healing, Transwell and colony formation assays. The regulatory relationships among hsa_circ_0008434, microRNA-6838 (miR-6838), and ubiquitin-specific peptidase 9X (USP9X) were determined by dual-luciferase activity assays. The expression of hsa_circ_0008434 and miR-6838 was measured by qPCR; the expression of USP9X was detected by immunohistochemistry and Western blotting. The effects of hsa_circ_0008434 on in vivo tumour growth were assessed in xenograft models.ResultsWe found that hsa_circ_0008434 was one of the most upregulated circRNAs in GC tissue versus normal tissue. Further in vitro testing indicated that by acting as a miRNA sponge for miR-6838-5p, hsa_circ_0008434 promotes the expression of USP9X and further increases the proliferation, migration, and invasion of GC cells. In addition, animal studies indicated that hsa_circ_0008434 could promote tumour growth in vivo.ConclusionsHsa_circ_0008434 may promote GC proliferation, invasion and migration by regulating the expression of miR-6838 and USP9X.

Spatially Distinct Reprogramming of the Tumor Microenvironment Based On Tumor Invasion in Diffuse-Type Gastric Cancers.

Histologic features of diffuse-type gastric cancer indicate that the tumor microenvironment (TME) may substantially impact tumor invasiveness. However, cellular components and molecular features associated with cancer invasiveness in the TME of diffuse-type gastric cancers are poorly understood. We performed single-cell RNA-sequencing (scRNA-seq) using tissue samples from superficial and deep invasive layers of cancerous and paired normal tissues freshly harvested from five patients with diffuse-type gastric cancer. The scRNA-seq results were validated by immunohistochemistry (IHC) and duplex in situ hybridization (ISH) in formalin-fixed paraffin-embedded tissues. Seven major cell types were identified. Fibroblasts, endothelial cells, and myeloid cells were categorized as being enriched in the deep layers. Cell type-specific clustering further revealed that the superficial-to-deep layer transition is associated with enrichment in inflammatory endothelial cells and fibroblasts with upregulated CCL2 transcripts. IHC and duplex ISH revealed the distribution of the major cell types and CCL2-expressing endothelial cells and fibroblasts, indicating tumor invasion. Elevation of CCL2 levels along the superficial-to-deep layer axis revealed the immunosuppressive immune cell subtypes that may contribute to tumor cell aggressiveness in the deep invasive layers of diffuse-type gastric cancer. The analyses of public datasets revealed the high-level coexpression of stromal cell-specific genes and that CCL2 correlated with poor survival outcomes in patients with gastric cancer. This study reveals the spatial reprogramming of the TME that may underlie invasive tumor potential in diffuse-type gastric cancer. This TME profiling across tumor layers suggests new targets, such as CCL2, that can modify the TME to inhibit tumor progression in diffuse-type gastric cancer.See related commentary by Huang and Brekken, p. 6284.

Application of convolutional neural networks for evaluating the depth of invasion of early gastric cancer based on endoscopic images.

Recently, artificial intelligence (AI) has been used in endoscopic examination and is expected to help in endoscopic diagnosis. We evaluated the feasibility of AI using convolutional neural network (CNN) systems for evaluating the depth of invasion of early gastric cancer (EGC), based on endoscopic images. This study used a deep CNN model, ResNet152. From patients who underwent treatment for EGC at our hospital between January 2012 and December 2016, we selected 100 consecutive patients with mucosal (M) cancers and 100 consecutive patients with cancers invading the submucosa (SM cancers). A total of 3508 non-magnifying endoscopic images of EGCs, including white-light imaging, linked color imaging, blue laser imaging-bright, and indigo-carmine dye contrast imaging, were included in this study. A total of 2288 images from 132 patients served as the development dataset, and 1220 images from 68 patients served as the testing dataset. Invasion depth was evaluated for each image and lesion. The majority vote was applied to lesion-based evaluation. The sensitivity, specificity, and accuracy for diagnosing M cancer were 84.9% (95% confidence interval [CI] 82.3%-87.5%), 70.7% (95% CI 66.8%-74.6%), and 78.9% (95% CI 76.6%-81.2%), respectively, for image-based evaluation, and 85.3% (95% CI 73.4%-97.2%), 82.4% (95% CI 69.5%-95.2%), and 83.8% (95% CI 75.1%-92.6%), respectively, for lesion-based evaluation. The application of AI using CNN to evaluate the depth of invasion of EGCs based on endoscopic images is feasible, and it is worth investing more effort to put this new technology into practical use.

Prognostic aspects of lymphovascular invasion in localized gastric cancer: new insights into the radiomics and deep transfer learning from contrast-enhanced CT imaging.

Lymphovascular invasion (LVI) is a factor significantly impacting treatment and outcome of patients with gastric cancer (GC). We aimed to investigate prognostic aspects of a preoperative LVI prediction in GC using radiomics and deep transfer learning (DTL) from contrast-enhanced CT (CECT) imaging. A total of 1062 GC patients (728 training and 334 testing) between Jan 2014 and Dec 2018 undergoing gastrectomy were retrospectively included. Based on CECT imaging, we built two gastric imaging (GI) markers, GI-marker-1 from radiomics and GI-marker-2 from DTL features, to decode LVI status. We then integrated demographics, clinical data, GI markers, radiologic interpretation, and biopsies into a Gastric Cancer Risk (GRISK) model for predicting LVI. The performance of GRISK model was tested and applied to predict survival outcomes in GC patients. Furthermore, the prognosis between LVI (+) and LVI (-) patients was compared in chemotherapy and non-chemotherapy cohorts, respectively. GI-marker-1 and GI-marker-2 yield similar performance in predicting LVI in training and testing dataset. The GRISK model yields the diagnostic performance with AUC of 0.755 (95% CI 0.719-0.790) and 0.725 (95% CI 0.669-0.781) in training and testing dataset. Patients with LVI (+) trend toward lower progression-free survival (PFS) and overall survival (OS). The difference of prognosis between LVI (+) and LVI (-) was more noticeable in non-chemotherapy than that in chemotherapy group. Radiomics and deep transfer learning features on CECT demonstrate potential power for predicting LVI in GC patients. Prospective use of a GRISK model can help to optimize individualized treatment decisions and predict survival outcomes.

LncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis in gastric cancer by targeting miR-605-3p.

The article "LncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis in gastric cancer by targeting miR-605-3p", by Y.-Z. Su, M.-F. Cui, J. Du, B. Song, published in Eur Rev Med Pharmacol Sci 2020; 24 (3): 1158-1167-DOI: 10.26355/eurrev_202002_20167-PMID: 32096164, has been retracted by the authors since some experiment reagent in this article might be questionable (that may influence the accuracy of the final results). The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20167.

The long non-coding RNA HOXA11-AS activates ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p

BackgroundmiR-124-3p can inhibit integrin β3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge.MethodsLuciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models.ResultsWe found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo.ConclusionsWe demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC.

MiR-125a-5p promotes gastric cancer growth and invasion by regulating the Hippo pathway.

ObjectiveThis study was carried out to explore the potential involvement of miR‐125a‐5p in the oncogenic effects of EphA2, TAZ, and TEAD2 and the activity of the Hippo signaling pathway in gastric cancer progression.MethodsIn vitro transfection of miR‐125a‐5p mimics or inhibitors, qRT‐PCR, colony formation assays, and cell invasion assays were used to assess the effect of miR‐125a‐5p on the growth and invasion in gastric cancer (GC). Male nude mice bearing tumors derived from human GC cells were used for evaluating the effects of miR‐125a‐5p on tumor growth. Luciferase reporter assay, immunofluorescence, immunohistochemistry, qRT‐PCR, and immunoblotting were performed to explore the role of miR‐125a‐5p in the epithelial‐mesenchymal transition (EMT) and association among miR‐125a‐5p, EphA2, TAZ, and TEAD2 in GC cells.ResultsMiR‐125a‐5p enhanced GC cell viability and invasion in vitro, whereas inhibition of miR‐125a‐5p using a specific inhibitor and antagomir suppressed cancer cell invasion and tumor growth. Moreover, inhibition of miR‐125a‐5p reversed EMT in vitro. miR‐125a‐5p upregulated the expression of EphA2, TAZ, and TEAD2, promoted TAZ nuclear translocation, and induced changes in the activity of the Hippo pathway by enhancing the expression of TAZ target genes. Finally, miR‐125a‐5p was overexpressed in late‐stage GCs, and positive correlations were observed with its targets EphA2, TAZ, and TEAD2.ConclusionmiR‐125a‐5p can promote GC growth and invasion by upregulating the expression of EphA2, TAZ, and TEAD2.

Transcription Factor CTCFL Promotes Cell Proliferation, Migration, and Invasion in Gastric Cancer via Activating DPPA2.

Objective To explore the relationship between CTCFL and DPPA2 and validate the positive role of CTCFL/DPPA2 in cell malignant behaviors in gastric cancer. Methods We predicted gastric cancer-related transcription factors and corresponding target mRNAs through bioinformatics. Levels of CTCFL and DPPA2 were assessed via qRT-PCR and western blot. In vitro experiments were utilized to assay the cell biological behaviors. CHIP was utilized for the assessment of the targeted relationship between CTCFL and DPPA2. Results CTCFL and DPPA2 were both highly expressed in gastric cancer cells, and high CTCFLL and DPPA2 could promote cell malignant behaviors. CHIP validated that DPPA2 was a target of CTCFL. In addition, high DPPA2 rescued the repressive impact of CTCFL silencing on the cell proliferation, migration, and invasion in gastric cancer. Conclusion The transcription factor CTCFL fosters cell proliferative, migratory, and invasive properties via activating DPPA2 in gastric cancer.

Retrospective analysis of surgically treated pT4b gastric cancer with pancreatic head invasion.

BACKGROUNDFor advanced gastric cancer patients with pancreatic head invasion, some studies have suggested that extended multiorgan resections (EMR) improves survival. However, other reports have shown high rates of morbidity and mortality after EMR. EMR for T4b gastric cancer remains controversial.AIMTo evaluate the surgical approach for pT4b gastric cancer with pancreatic head invasion.METHODSA total of 144 consecutive patients with gastric cancer with pancreatic head invasion were surgically treated between 2006 and 2016 at the China National Cancer Center. Gastric cancer was confirmed in 76 patients by postoperative pathology and retrospectively analyzed. The patients were divided into the gastrectomy plus en bloc pancreaticoduodenectomy group (GP group) and gastrectomy alone group (GA group) by comparing the clinicopathological features, surgical outcomes, and prognostic factors of these patients.RESULTSThere were 24 patients (16.8%) in the GP group who had significantly larger lesions (P < 0.001), a higher incidence of advanced N stage (P = 0.030), and less neoadjuvant chemotherapy (P < 0.001) than the GA group had. Postoperative morbidity (33.3% vs 15.3%, P = 0.128) and mortality (4.2% vs 4.8%, P = 1.000) were not significantly different in the GP and GA groups. The overall 3-year survival rate of the patients in the GP group was significantly longer than that in the GA group (47.6%, median 30.3 mo vs 20.4%, median 22.8 mo, P = 0.010). Multivariate analysis identified neoadjuvant chemotherapy [hazard ratio (HR) 0.290, 95% confidence interval (CI): 0.103–0.821, P = 0.020], linitis plastic (HR 2.614, 95% CI: 1.024–6.675, P = 0.033), surgical margin (HR 0.274, 95% CI: 0.102–0.738, P = 0.010), N stage (HR 3.489, 95% CI: 1.334–9.120, P = 0.011), and postoperative chemoradiotherapy (HR 0.369, 95% CI: 0.163–0.836, P = 0.017) as independent predictors of survival in patients with pT4b gastric cancer and pancreatic head invasion. CONCLUSIONCurative resection of the invaded pancreas should be performed to improve survival in selected patients. Invasion of the pancreatic head is not a contraindication for surgery.

LncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus.

Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

LncRNA PTCSC3 and lncRNA HULC Negatively Affect Each Other to Regulate Cancer Cell Invasion and Migration in Gastric Cancer [Retraction

[This retracts the article DOI: 10.2147/CMAR.S254944.].