Malignant Tumor Of Digestive Tract Research Articles

Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2.

Pancreatic cancer remains an extremely malignant digestive tract tumor, posing a significant global public health burden. Patients with pancreatic cancer, once metastasis occurs, lose all hope of cure, and prognosis is extremely poor. It is important to investigate liver metastasis of Pancreatic cancer in depth, not just because it is the most common form of metastasis in pancreatic cancer, but also because it is crucial for treatment planning and prognosis assessment. This study aims to delve into the mechanisms of pancreatic cancer liver metastasis, with the goal of providing crucial scientific groundwork for the development of future treatment methods and drugs. We explored the mechanisms of pancreatic cancer liver metastasis using single-cell sequencing data (GSE155698 and GSE154778) and bulk data (GSE71729, GSE19279, TCGA-PAAD). Initially, Seurat package was employed for single-cell data processing to obtain expression matrices for primary pancreatic cancer lesions and liver metastatic lesions. Subsequently, high-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify genes associated with liver metastasis. Machine learning algorithms and COX regression models were employed to further screen genes related to patient prognosis. Informed by both biological understanding and the outcomes of algorithms, we meticulously identified the ultimate set of liver metastasis-related gene (LRG). In the study of LRG genes, various databases were utilized to validate their association with pancreatic cancer liver metastasis. In order to analyze the effects of these agents on tumor microenvironment, we conducted an in-depth analysis, including changes in signaling pathways (GSVA), cell differentiation (pseudo-temporal analysis), cell communication networks (cell communication analysis), and downstream transcription factors (transcription factor activity prediction). Additionally, drug sensitivity analysis and metabolic analysis were performed to reveal the effects of LRG on gemcitabine resistance and metabolic pathways. Finally, functional experiments were conducted by silencing the expression of LRG in PANC-1 and Bx-PC-3 cells to validate its influence to proliferation and invasiveness on PANC-1 and Bx-PC-3 cells. Through a series of algorithmic filters, we identified PAK2 as a key gene promoting pancreatic cancer liver metastasis. GSVA analysis elucidated the activation of the TGF-beta signaling pathway by PAK2 to promote the occurrence of liver metastasis. Pseudo-temporal analysis revealed a significant correlation between PAK2 expression and the lower differentiation status of pancreatic cancer cells. Cell communication analysis revealed that overexpression of PAK2 promotes communication between cancer cells and the tumor microenvironment. Transcription factor activity prediction displayed the transcription factor network regulated by PAK2. Drug sensitivity analysis and metabolic analysis revealed the impact of PAK2 on gemcitabine resistance and metabolic pathways. CCK8 experiments showed that silencing PAK2 led to a decrease in the proliferative capacity of pancreatic cancer cells and scratch experiments demonstrated that low expression of PAK2 decreased invasion capability in pancreatic cancer cells. Flow cytometry reveals that PAK2 significantly inhibited apoptosis in pancreatic cancer cell lines. Molecules related to the TGF-beta pathway decreased with the inhibition of PAK2, and there were corresponding significant changes in molecules associated with EMT. PAK2 facilitated the angiogenic potential of cancer cells and promotes the epithelial-mesenchymal transition process by activating the TGF-beta signaling pathway. Simultaneously, it decreased the differentiation level of cancer cells, consequently enhancing their malignancy. Additionally, PAK2 fostered communication between cancer cells and the tumor microenvironment, augments cancer cell chemoresistance, and modulates energy metabolism pathways. In summary, PAK2 emerged as a pivotal gene orchestrating pancreatic cancer liver metastasis. Intervening in the expression of PAK2 may offer a promising therapeutic strategy for preventing liver metastasis of pancreatic cancer and improving its prognosis.

Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.

The potential role of gut microbiota outer membrane vesicles in colorectal cancer.

Colorectal cancer (CRC) is a common malignant digestive tract tumor in colorectal regions. Considerable evidence now shows that the gut microbiota have essential roles in CRC occurrence and development. Most Gram-negative bacteria release outer membrane vesicles (OMVs) via outer membrane blistering, which contain specific cargoes which interact with host cells via intercellular communications, host immune regulation, and gut microbiota homeostasis. Studies have also shown that OMVs selectively cluster near tumor cells, thus cancer treatment strategies based on OMVs have attracted considerable research attention. However, little is known about the possible impact of gut microbiota OMVs in CRC pathophysiology. Therefore, in this review, we summarize the research progress on molecular composition and function of OMV, and review the microbial dysbiosis in CRC. We then focus on the potential role of gut microbiota OMVs in CRC. Finally, we examine the clinical potential of OMVs in CRC treatment, and their main advantages and challenges in tumor therapy.

β-elemene Suppresses Migration of Esophageal Squamous Cell Carcinoma by Modulating Expression of MMP9 through the PI3K/Akt/NF-κB Pathway.

β-elemene is a plant-derived drug with broad-spectrum anticancer activity. Studies have found that β-elemene can inhibit tumor cell proliferation, induce tumor cell apoptosis, and resist tumor cell migration and invasion. Esophageal cancer is a common digestive tract malignant tumor. Progress has been made in the treatment of esophageal cancer, including the use of β-elemene, but the mechanism of anti-migration is unclear. PI3K/Akt/NF- κB/MMP9 signaling pathway is involved in the regulation of tumor cell proliferation, migration, extracellular matrix(ECM), and basement membrane(BM) degradation. This study aims to investigate the effect of β-elemene on the migration of esophageal squamous cell carcinoma (ESCC) and its related mechanisms by bioinformatics, network pharmacology, and molecular docking methods. In this study, the differentially expressed genes (DEGs) of ESCC were screened through GeneCards and BATMAN-TCM databases combined with the Gene Expression Omnibus (GEO) database (GSE17351). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the functions and related pathways of the genes. The protein-protein interaction (PPI) network of these DEGs was constructed with the STRING database. Five hub genes were screened by CytoHubba plug-in Cytoscape according to the principle of degree value and the expressions of which were validated by the UALCAN database from the Cancer Genome Atlas (TCGA). The hub gene with the strongest binding energy was identified by molecular docking. A wound healing assay was subjected to assess the migration ability. RT-PCR was used to detect the content of migration-related mRNA. Western blotting was performed to examine the expression rates of Akt, NF-κB, and MMP9 in ESCC tissues by β-elemene and SC79. 71 target genes were obtained which were mainly involved in biological processes such as epidermal development and extracellular matrix decomposition. In addition, critical pathways, including PI3K/AKT signaling pathway and focal adhesion, were verified to be subject to β-elemene regulation. It exhibited marked binding affinity between β-elemene and MMP9 with an excellent docking score of -6.56 kcal/mol. The expression levels of Akt, NF-κB, and MMP9 in ESCC tissues were significantly upregulated compared to normal tissues. Western blot detection demonstrated that β-elemene specifically reduced the phosphorylation level of Akt, and its downstream target molecule NF-κB, thus resulting in reduced levels of their target proteins, including MMP9 in ESCC. A wound healing assay showed β-elemene inhibited the migration of ESCC cells. RT-PCR results found that the mRNA expression of Akt, NF-κB, and MMP9 in the β-elemene group was significantly lower than that in the control group. However, the application of SC79 partially reversed the effect of β-elemene. In summary, our study suggests that the anti-tumor migration effect of β-elemene on ESCC is associated with the inhibition of PI3K/Akt/NF-κB/MMP9 signalling pathway, and it provides a theoretical reference for further rational clinical application.

Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gβγ-VEGFR2 complex formation

Gastric cancer (GC) is a prevalent digestive tract malignant tumor characterized by an insidious onset, ease of metastasis, rapid growth, and poor prognosis. Here, we report that fibronectin type III domain containing 1 (FNDC1) has high expression in GC and indicates poor outcomes in patients with GC. FNDC1 over-expression or knockdown promotes or inhibits tumorigenesis and metastasis, respectively. The expression of FNDC1 is upregulated by TWIST1, strengthening its interaction with Gβγ and VEGFR2. The formation of the trimers, TWIST1 plus Gβγ and VEGFR2, increases VEGFR2 phosphorylation and Gβγ trafficking, which activates RAS-MAPK and PI3K-AKT signaling, benefiting GC progression. In this study, we demonstrated that arsenite can efficiently suppress FNDC1 expression, attenuating the formation of the trimers and downstream pathways. Altogether, our results indicate that FNDC1 might be a promising target for clinical treatment and prognostic judgment, while FNDC1 inhibition by arsenite provides a new opportunity for overcoming this fatal disease.

RGS16 regulates Hippo-YAP activity to promote esophageal cancer cell proliferation and migration

Esophageal Squamous Cell Carcinoma (ESCC) is a common malignant tumor of digestive tract, accounting for 90% of all pathological types of esophageal cancer. Despite the rapid development of multi-disciplinary treatment such as surgery, chemotherapy, radiotherapy and chemoradiotherapy, the prognosis of patients with ESCC is still poor. Regulators of G-protein signaling (RGSs) are involved in the processes of various cancers. The expression levels of its family member RGS16 are abnormally elevated in a variety of tumors, but its role in ESCC is still unclear. We found that RGS16 expression is aberrantly increased in ESCC tissues and correlated with poor prognosis of ESCC patients from The Cancer Genome Atlas (TCGA) database and our collected ESCC tissues. Moreover, knockdown of RGS16 in two ESCC cells could indeed inhibit their proliferation and migration. We further explored the molecular mechanism of RGS16 in ESCC, and the correlation analysis from TCGA database showed that the mRNA levels of RGS16 was positively correlated with that of CTGF and CYR61, two target genes of Hippo-YAP signaling. Consistently, RGS16- knockdown significantly inhibited the expression of CTGF and CYR61 in ESCC cells. We found that the phosphorylation levels of LATS1 and YAP were significantly increased and YAP translocated into the cytoplasm after depletion of RGS16 in ESCC cells. Also, RGS16-knockdown promoted the interaction between LATS1 and upstream kinase MST1. In addition, reintroduction of a constitutive active YAP5A mutant significantly rescued CTGF expression and cell proliferation in RGS16-knockdown cells. Together, our work revealed that RGS16 promoted YAP activity through disrupting the interaction between LATS1 and MST1, thus promoting the proliferation and migration of ESCC cells.

Analysis of load status and management strategies of main caregivers of patients with malignant tumors of digestive tract.

Caregiver load refers to the subjective and objective negative impact of caregivers in the care of patients, and excessive load will have a serious impact on patients and caregivers themselves and can reduce their quality of life. For the main caregivers, it not only needs to care for the patients in life and daily life, but also needs to pay the cost of treatment for the patients, coupled with the need to carry out their own original work, life, etc. excessive life pressure, economic pressure, work pressure, emotional pressure, etc. lead to heavy load of the main caregivers, which can easily cause caregivers to have different degrees of psychological problems, which will cause serious adverse effects on the caregivers themselves and cancer patients, not conducive to the construction of a harmonious family and society. This article analyzes the current situation of primary caregiver burden in patients with gastrointestinal malignant tumors, analyzes its influencing factors, and specifies specific treatment strategies. It is hoped to provide scientific guidance for later related research and application.

EZH2 regulates pancreatic cancer cells through E2F1, GLI1, CDK3, and Mcm4

Pancreatic cancer (PC) is one of the most common malignant tumors in digestive tract. To explore the role of epigenetic factor EZH2 in the malignant proliferation of PC, so as to provide effective medical help in PC. Sixty paraffin sections of PC were collected and the expression of EZH2 in PC tissues was detected by immunohistochemical assay. Three normal pancreas tissue samples were used as controls. The regulation of EZH2 gene on proliferation and migration of normal pancreatic cell and PC cell were determined by MTS, colony forming, Ki-67 antibody, scratch and Transwell assays. Through differential gene annotation and differential gene signaling pathway analysis, differentially expressed genes related to cell proliferation were selected and verified by RT-qPCR. EZH2 is mainly expressed in the nuclei of pancreatic tumor cells, but not in normal pancreatic cells. The results of cell function experiments showed that EZH2 overexpression could enhance the proliferation and migration ability of PC cell BXPC-3. Cell proliferation ability increased by 38% compared to the control group. EZH2 knockdown resulted in reduced proliferation and migration ability of cells. Compared with control, proliferation ability of cells reduced by 16%-40%. The results of bioinformatics analysis of transcriptome data and RT-qPCR demonstrated that EZH2 could regulate the expression of E2F1, GLI1, CDK3 and Mcm4 in normal and PC cells. The results revealed that EZH2 might regulate the proliferation of normal pancreatic cell and PC cell through E2F1, GLI1, CDK3 and Mcm4.

Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer

Colorectal cancer (CRC) is a common malignant tumor of the human digestive tract. Inorganic pyrophosphatase 1 (PPA1) plays an imperative role in the advancement of malignant tumors, but its function in CRC is ill-defined. In this study, we inspected the functions of PPA1 in CRC. The abundance of PPA1 in CRC tissues was analyzed by utilizing publicly available data from the The Cancer Genome Atlas and Human Protein Atlas project. Cell counting kit-8 assay and 5-ethynyl-2′-deoxyuridine assay were used to evaluate the viability and proliferation of CRC cells. Bioinformatics analysis was used to forecast the PPA1 related genes and signal pathways in CRC. The protein expression was examined by western blot. The xenograft model was implemented to determine the influence of PPA1 in CRC in vivo. Proliferating cell nuclear antigen, CD133, and CD44 contents in xenograft tumors were evaluated by immunohistochemistry. In the present study, we found that the PPA1 content was heightened in CRC, and the diagnostic value of PPA1 in CRC was enormous. Overexpression of PPA1 enhanced cell proliferation and stemness properties in CRC cells, while downregulation of PPA1 had the opposite effects. PPA1 promoted the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Activation of the PI3K/Akt signaling reversed the effect of PPA1 silencing on cell proliferation and stemness properties in CRC cells. Silencing of PPA1 reduced xenograft tumor growth via modulating the PI3K/Akt signaling pathway in vivo. In conclusion, PPA1 promoted cell proliferation and stemness properties in CRC by activating the PI3K/Akt signaling pathway.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

Spatial heterogeneity and Immune infiltration of cellular lysosomal pathways reveals a new blueprint for tumor heterogeneity in esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is a common Malignant tumor of digestive tract which have a potential association with lysosomal pathway. The purpose of this study was to explore the correlation between lysosome pathway and immune infiltration of ESCC. The cell type annotation of ESCC patients and the distribution of their gene markers were analyzed by single cell data. They were also grouped according to the expression of lysosomal pathways. Gene set variation analysis (GSVA) enriched pathway scoring, Cellchat cell communication was performed to demonstrate the tumour-associated pathway scores and interactions of different cell populations. Relevant differential genes were screened, prognostic risk markers were constructed and direct associations of lysosomal pathway-related gene risk scores with immune infiltration and tumour treatment drug sensitivity were assessed by algorithms. In cellular experiments, qPCR and flow cytometry were used to assess the role of the lysosomal pathway gene-MT1X on tumour cell development. ESCC single cell data were annotated into 7 Cluster clusters by t-sne downscaling analysis. Cellchat analysis revealed that the "MIF" cellular communication network is the main communication mode of the lysosomal pathway in ESCC cells. The lysosomal pathway genetic risk model was found to be significantly different from ESCC prognosis in both the training and validation groups. The lysosome pathway gene risk model was associated with treatment resistance in ESCC patients using oncopredict R package. The correlation between the expression of lysosomal-DEG and tumour immune infiltration and immune cell types by the MCPcounter method. Cellular assays showed that the lysosomal pathway gene MT1X was less expressed in oesophageal cancer cells than in normal oesophageal epithelial cells. Knockdown of MT1X significantly promoted the growth rate of oesophageal cancer cells. Based on the single cell sequencing technology and transcriptomic analysis, we confirmed that there is a close association between the lysosomal pathway and the immune infiltration and treatment sensitivity of ESCC, which may be a potential target for a new direction of ESCC therapy.

Ribosomal protein L31 (RPL31) inhibits the proliferation and migration of gastric cancer cells

Gastric cancer (GC) is a digestive tract malignant tumor and causes the third cancer-related mortality in the world. Aberrant expression of Ribosomal Protein L31 (RPL31) has been reported in several human cancers. The aim of this study was to explore the role and possible biological functions of RPL31 in GC. We firstly employed immunohistochemistry to examine RPL31 expression in tumor and para-cancerous tissues. By lentiviral transfection, we successfully constructed an RPL31-knockdown GC cell model and performed functional validation to reveal the effects of RPL31 on proliferation, apoptosis, cycle, migration, and tumor growth. Our data indicated that RPL31 was abundantly expressed in GC tissues and cell lines (AGS and MGC-803). In addition, RPL31 expression was positively correlated with the extent of tumor infiltrate of GC patients. Functionally, silencing RPL31 in AGS and MGC-803 cells significantly limited the ability of proliferation and migration, promoted cell apoptosis. Consistently, RPL31-knockdown GC cells inhibited the growth of xenografts in mice. Moreover, preliminary analysis on the downstream regulation mechanism revealed that RPL31 functioned as a tumor promoter through targeting JAK-STAT signaling pathway. In conclusion, inhibition of abnormally high expression of RPL31 in GC may be a potential therapeutic strategy for this disease.

Matrine restrains the development of colorectal cancer through regulating the AGRN/Wnt/β-catenin pathway.

Colorectal cancer is a common malignant digestive tract tumor. This study aimed to explore the biological role and potential underlying mechanism of matrine in colorectal cancer. The mRNA expression of AGRN was measured using RT-qPCR. Cell proliferation, migration, invasion and apoptosis were determined using CCK-8, EdU, transwell assays and flow cytometry, respectively. Xenograft tumor experiment was performed to explore the action of matrine and AGRN on tumor growth in colorectal cancer in vivo. Immunohistochemistry (IHC) assay was applied for AGRN, β-catenin, and c-Myc expression in the tumor tissues from mice. Matrine dramatically repressed cell growth and reduced the level of AGRN in colorectal cancer cells. AGRN expression was boosted colorectal cancer tissues and cells. AGRN downregulation depressed cell proliferation, migration, invasion, and enhanced cell apoptosis in colorectal cancer cells. Moreover, matrine showed the anti-tumor effects on colorectal cancer cells via regulating AGRN expression. AGRN knockdown could inactivate the Wnt/β-catenin pathway in colorectal cancer cells. We found that AGRN downregulation exhibited the inhibition action in the progression of colorectal cancer by modulating the Wnt/β-catenin pathway. In addition, matrine could inhibit the activation of the Wnt/β-catenin pathway through regulating AGRN in colorectal cancer cells. Furthermore, xenograft tumor experiment revealed that matrine treatment or AGRN knockdown repressed the development of colorectal cancer via the Wnt/β-catenin pathway in vivo. Matrine retarded colorectal cancer development by modulating AGRN to inactivate the Wnt/β-catenin pathway.

The roles and mechanisms of the lncRNA-miRNA axis in the progression of esophageal cancer: a narrative review.

Esophageal cancer is one of the most common malignant digestive tract tumors. Despite various treatment methods, the prognosis of patients remains unsatisfactory, largely due to an insufficient understanding of the mechanisms involved in the pathogenesis and progression of esophageal cancer. More than 98% of the nucleotide sequences in the human genome do not encode proteins, and their transcription products are noncoding RNAs (ncRNAs), mainly long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). Experiments have shown that lncRNAs and miRNAs play crucial roles in the occurrence and progression of various human malignancies. These ncRNAs influence the progression of esophageal cancer through an intricate regulatory network. We herein summarized the roles and mechanisms of the lncRNA-miRNA axis in esophageal cancer cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), invasion and metastasis, drug resistance, radiotherapy resistance, and angiogenesis. This review provides a rationale for anticancer therapy that targets the lncRNA-miRNA axis in esophageal cancer. Related articles published in the PubMed database between 05/30/2008 to 09/10/2022 were identified using the following terms: "lncRNA AND miRNA AND esophageal cancer", "lncRNA AND miRNA AND cell proliferation", "lncRNA AND miRNA AND apoptosis", "lncRNA AND miRNA AND EMT", "lncRNA AND miRNA AND invasion and metastasis", "lncRNA AND miRNA AND drug resistance", and "lncRNA AND miRNA AND radiotherapy resistance". Published articles written in English available to readers were considered. We summarized the roles of the lncRNA-miRNA axis in the progression of esophageal cancer, including cell proliferation, apoptosis, EMT, invasion and metastasis, drug resistance, radio resistance, and other progressions, and determined that the lncRNA-miRNA axis may serve as a potential clinical treatment target for esophageal cancer. The lncRNA-miRNA axis is closely related to the progression of esophageal cancer and may act as a potential biological target for the clinical treatment of patients with esophageal cancer.

Roles of oncogenes in esophageal squamous cell carcinoma and their therapeutic potentials.

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer (EC) in Asia. It is a malignant digestive tract tumor with abundant gene mutations. Due to the lack of specific diagnostic markers and early cancer screening markers, most patients are diagnosed at an advanced stage. Genetic and epigenetic changes are closely related to the occurrence and development of ESCC. Here, We review the activation of proto-oncogenes into oncogenes through gene mutation and gene amplification in ESCC from a genetic and epigenetic genome perspective, We also discuss the specific regulatory mechanisms through which these oncogenes mainly affect the biological function and occurrence and development of ESCC through specific regulatory mechanisms. In addition, we summarize the clinical application value of these oncogenes is summarized, and it provides a feasible direction for clinical use as potential therapeutic and diagnostic markers.

Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

Screening and identification of CNIH4 gene associated with cell proliferation in gastric cancer based on a large-scale CRISPR-Cas9 screening database DepMap

BackgroundGastric cancer is a common malignant tumor of digestive tract. The study aimed to identify candidate genes associated with the proliferation and survival of gastric cancer cell through CRISPR-cas9 screening data, which may provide new therapeutic targets for gastric cancer patients. MethodsCandidate genes related to gastric cancer cell viability by CRISPR-cas9 screening from Depmap and genes differentially expressed between gastric cancer tissues and normal gastric tissues from TCGA were overlapped. WGCNA and KEGG analysis was conducted to performed to identify key pathways and genes. Using CMap, we identified small molecules that might reverse candidate gene expression of gastric cancer. LASSO regression was used to construct a signature to predict overall survival of gastric cancer patients. CCK8 assay was performed to assess the effects of candidate gene on gastric cancer cell proliferation. ResultsA total of 710 candidate genes related to gastric cancer cell viability in the DepMap were identified and overlapped with differentially expressed genes in TCGA database, which were enriched in the cell cycle pathway. CMap analysis suggested that molecule drug LY294002 might be a novel choice for gastric cancer treatment. Using Cox univariate analysis and Lasso analysis, we developed a prognostic model including 12 candidate genes, and conducted subgroup analysis and external validation. Moreover, knockdown of the key candidate gene CNIH4 inhibited the proliferation of gastric cancer cells. ConclusionCell cycle pathway and CNIH4, identified by CRISPR-cas9 screening, were a key pathway and gene that regulate cell viability in gastric cancer. CNIH4 has significant prognostic values and can serve as a new target for gastric cancer patient treatment.

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer

Colorectal cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure–activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 μM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 μM). Furthermore, compound 10 exhibited strong in vivo anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.

Knockdown of RAD51AP1 suppressed cell proliferation and invasion in esophageal squamous cell carcinoma

BackgroundEsophageal cancer is a common malignant tumor of digestive tract with esophageal squamous cell carcinoma (ESCC) being the main histological subtype. This study aimed to identify potential hub gene associated with the pathophysiology of ESCC through bioinformatics analysis and experiment validation.MethodsThree microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. The overlapping differentially expressed genes (DEGs) were analyzed by GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) pathway analyses were performed to predict the potential functions of DEGs. Nine hub genes were identified using protein–protein interaction (PPI) network and Cytoscape software. We selected RAD51-associated protein 1 (RAD51AP1) for further research because of its poor prognosis and it has not been sufficiently studied in ESCC. The effects of RAD51AP1 on proliferation, apoptosis, migration and invasion of ESCC cells were determined by in vitro functional assays.ResultsRAD51AP1 expression was significantly upregulated in ESCC tissues compared with normal tissues by using The Cancer Genome Atlas (TCGA) database. High expression of RAD51AP1 was associated with worse survival in ESCC patients. RAD51AP1 expression was positively associated with the enrichment of Th2 cells and T helper cells. Furthermore, CCK-8 and colony formation assays showed knockdown of RAD51AP1 inhibited the proliferation of ESCC cells. Flow cytometry analysis indicated knockdown of RAD51AP1 induced cell cycle arrest and apoptosis in ESCC cells. Transwell assay revealed knockdown of RAD51AP1 suppressed the migration and invasion of ESCC cells.ConclusionsFinally, our results demonstrated that RAD51AP1 silencing significantly inhibited cell proliferation and invasion in ESCC, thereby highlighting its potential as a novel target for ESCC treatment.

Pancreatic cancer associated micro-RNA

Pancreatic cancer, known as the king of cancer, is a common malignant tumor of digestive tract, with a high degree of malignancy, difficult diagnosis and treatment, and a 5-year survival rate1%, is one of the malignancies with the worst prognosis. Therefore, there is an urgent need for better methods to improve the diagnostic accuracy and better prognosis of pancreatic cancer. Targeted therapy and accurate monitoring of prognosis is one of the key topics of research. Since 2004, when the relationship between micro-RNA and cancer was first revealed, there has been a great deal of interest in the research of micro-RNA. Related categories have been identified as being associated with other cancers, such as lung cancer, and drugs that use micro-RNA to treat cancer have emerged, but only during clinical trials. In this review, we will discuss the relationship between micro-RNA and pancreatic cancer and specifically elaborate microRNA-125a-5p、microRNA-125b、 microRNa-423-3p、microRNa-let-7a. At the same time, we summarize the difficulties in using microRNA for targeted therapy and the current clinical situation.