KLF10/CBS increases the sensitivity of gastric carcinoma cells to methionine restriction by promoting sulfur transfer pathway.

Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met-) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine ß-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin-eosin staining was used to detect lung metastasis. Liquid chromatography-mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans-sulfur pathway lowered Met-'s inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans-sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR.

Ferroptosis and its current progress in gastric cancer.

Gastric Cancer (GC) is a prevalent malignancy within the digestive tract, ranking as the fifth most common malignant tumor worldwide. It is characterized by clinical features such as a tendency for metastasis and an unfavorable prognosis. Ferroptosis, a recently identified form of cell death, represents a novel mode of cellular demise that diverges from the traditional concepts of necrosis and apoptosis. Numerous studies have found that ferroptosis plays a significant role in the proliferation, metastasis, drug resistance, and microenvironment regulation within GC. This review summarizes the mechanism of ferroptosis and its role in the occurrence and development of GC cells. It provides examples demonstrating how various anti-tumor drugs can induce ferroptosis in GC cells. Additionally, it summarizes the potential application value of ferroptosis in the future treatment of GC.

The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity.

Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.

Methionine restriction attenuates the migration and invasion of gastric cancer cells by inhibiting nuclear p65 translocation through TRIM47.

The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells.

Upregulation of E-cadherin by the combination of methionine restriction and HDAC2 intervention for inhibiting gastric carcinoma metastasis.

Invasion and metastasis are the leading causes of death in individuals with malignant tumors, including gastric cancer. In this study, we aim to explore the effect and related mechanisms of methionine restriction (MR) on gastric carcinoma metastasis. In the MR cell model, gastric carcinoma cells are cultured in the MR medium, and in the animal model, BALB/c nude rodents are administered with a methionine-free diet after receiving injections of MKN45 cells into the caudal vein. Transwell assay is used to detect cell invasion and migration. Chromatin immunoprecipitation is performed to investigate the levels of H3K9me2, H3K27Ac, and H3K27me3 in the E-cadherin promoter. The results show that MR inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR increases E-cadherin while reducing the H3K27me3 level in the E-cadherin promoter. E-cadherin expression in gastric carcinoma cells is adversely regulated by HDAC2. Overexpressing HDAC2 reduces the H3K27Ac level in the E-cadherin promoter, while interfering with HDAC2 increases the H3K27Ac level. HDAC2 interference under MR conditions further upregulates E-cadherin expression and inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR combined with HDAC2 interference promotes E-cadherin expression by mediating the methylation and acetylation of E-cadherin, thus inhibiting the invasion, migration, and lung metastasis of gastric carcinoma cells. Our study provides a new theoretical basis for the inhibitory effect of MR on gastric cancer.

Breakthrough of chemiluminescence-based LAM urine test beyond HIV-positive individuals: Clinical diagnostic value of pulmonary tuberculosis in the general population.

To investigate the diagnostic value of a novel high-sensitivity urine lipoarabinomannan (LAM) test (chemiluminescence-based) for active tuberculosis in the general population. A retrospective study was conducted on 250 clinical suspected tuberculosis patients who were HIV-negative and visited the Fourth People's Hospital of Foshan from January 2022 to December 2022. Among them, there were 135 cases of pulmonary tuberculosis, 34 cases of extrapulmonary tuberculosis, and 81 cases of non-tuberculosis. Urine samples were collected for LAM antigen detection before treatment, and laboratory data of sputum smear acid-fast staining (smear method), sputum culture, and GeneXpert method were collected. Using clinical diagnosis as the reference standard, the diagnostic efficacy of 4 methods for detecting active tuberculosis was evaluated. For the 135 cases of pulmonary tuberculosis, the sensitivity of sputum smears, sputm culture, sputm GeneXpert method, and urine LAM were 29.6% (40/135), 45.9% (62/135), 59.3% (80/135), and 51.9% (70/135), respectively. The combination of LAM + GeneXpert and LAM + culture had the highest sensitivity for detecting active pulmonary tuberculosis, which were 71.0% and 78.2%, respectively. For the detection of sputum culture-negative pulmonary tuberculosis, the positive rates of smear, GeneXpert, and LAM were 0.0% (0/73), 53.4% (39/73), and 52.1% (38/73), respectively. LAM + smear and LAM + Genexpert could detect 52.1% and 68.5% of sputum culture-negative patients, respectively. The high-sensitivity urine LAM test holds promise for tuberculosis diagnosis in the general population. It demonstrates high-sensitivity, enabling the detection of sputum culture-negative pulmonary tuberculosis patients. Furthermore, when combined with existing methods, it can enhance the overall detection rate.

Cancer functional states-based molecular subtypes of gastric cancer.

BACKGROUND: The treatment of gastric cancer remains a challenge. METHODS: We divided gastric cancer into three subtypes based on 14 cancer functional states. We investigated differences between subtypes through multi-omics data, especially at the single-cell level, which allowed us to analyze differences from the perspective of each type of cell rather than the whole. RESULTS: The cluster 1 is characterized by high levels of tumor progression-related cancer functional status, worst survival outcomes, low metabolic level, high infiltration of immunosuppressive cells, high copy number variations (CNV), and low tumor mutational burden (TMB). The cluster 2 is characterized by low levels of tumor progression-related cancer functional status, favorable prognosis, moderate metabolic level, low immune cell infiltration, high CNV, and moderate TMB. Then, the cluster 3 is characterized by the high level of all cancer functional status, high metabolic level, low CNV, high TMB, high infiltration of immune cells with high cytotoxicity, and better response to immunotherapy. We also established a prognostic model based on cancer functional status and validated its robustness. CONCLUSIONS: Collectively, our study identified gastric cancer subtypes and provided new insights into the clinical treatment of gastric cancer.

Methionine restriction enhances the chemotherapeutic sensitivity of colorectal cancer stem cells by miR-320d/c-Myc axis.

Chemotherapy resistance of colorectal cancer stem cells (CRC-SCs) has become a major challenge in clinical treatment of cancer. Methionine restriction (MR) enhances the therapeutic effect of chemotherapeutic agents. The aim of this study was to explore the molecular pathways that MR affects the chemotherapeutic sensitivity of CRC-SCs. CD133+ and CD133- SW480 or SW620 cells were isolated by magnetic-activated cell sorting (MACS). Mouse xenograft tumor model was established by subcutaneous inoculation of CD133+ SW480. MTT assay was used to detect cell viability. Phase distribution of cell cycle was detected by flow cytometry. Western blotting was used to detect drug-resistant related protein expression. miR-320d and transcription factor c-Myc expressions were detected by qRT-PCR. The interaction between miR-320d and c-Myc was verified by luciferase assay. CD133+ SW480 and SW620 cells were more resistant to 5-fluorouracil (5-FU) than CD133- cells. In vitro and in vivo experiments showed that 5-FU and MR combined therapy further inhibited CD133+ cell activity and ATP binding cassette subfamily G member 2 (ABCG2) expression, and reduced tumor volume compared with drug administration alone. Interference with miR-320d or overexpression of c-Myc reversed the increased chemotherapeutic sensitivity of CRC-SCs induced by synergistic therapy with 5-FU and MR. miR-320d can target and regulate c-Myc. Interference with c-Myc could reverse the increase in cell viability and ABCG2 expression caused by down-regulation of miR-320d. In conclusion, the combined chemotherapy with MR can enhance the chemotherapeutic sensitivity of CRC-SCs by up-regulation of miR-320d to inhibit c-Myc expression, which lays a molecular basis for MR regulation of chemotherapeutic sensitivity of CRC-SCs.

Exosome-mediated transfer of lncRNA HCG18 promotes M2 macrophage polarization in gastric cancer.

BACKGROUND: Gastric cancer (GC) derived exosomes (Exos) aggravate GC development by facilitating M2 macrophage polarization and long non-coding RNA (lncRNA) HCG18 was highly expressed in GC. This study aimed to investigate whether the exosomal lncRNA HCG18 regulated the M2 macrophage polarization in GC and the possible mechanism. METHODS: The isolated GC cells (GCCs)-Exos were identified using transmission electron microscopy, Nanoparticle Tracking Analysis and Western blot. The GCCs-Exos function was verified by enzyme-linked immunosorbent assay and flow cytometry. Meanwhile, the exosomal lncRNA HCG18 function was determined using thein vitro assays. Furthermore, the underlying mechanism of the exosomal lncRNA HCG18 that regulated M2 macrophage polarization in GC was investigated using dual-luciferase reporter gene assay and RNA pull-down. RESULTS: After the validation of GCCs-Exos, the GCCs-Exos facilitated the M2 macrophage polarization. The in vitro assays confirmed that the exosomal lncRNA HCG18 positively regulated the M2 macrophage polarization. Mechanistically, lncRNA HCG18 bound to miR-875-3p, miR-875-3p bound to KLF4. Furthermore, GCCs-exosomal lncRNA HCG18 elevated the KLF4 expression by decreasing miR-875-3p in macrophages to facilitate M2 macrophage polarization, thus alleviating GC. The in vivo assays clarified that the GCCs-exosomal lncRNA HCG18 restrained the tumor growth of GC induced by M2 macrophages. CONCLUSION: GCCs-exosomal lncRNA HCG18 elevated KLF4 expression by decreasing miR-875-3p in macrophages to facilitate the M2 macrophage polarization.

Methionine deficiency promoted mitophagy via lncRNA PVT1-mediated promoter demethylation of BNIP3 in gastric cancer.

BACKGROUND: The occurrence of recurrence and metastasis after treatment is a major challenge in the treatment of gastric cancer. This study was based on the methionine (Met)-dependent characteristics of gastric cancer cells to explore the effect of Met deficiency on the occurrence and development of gastric cancer. METHODS: Human gastric cancer cell lines MKN45 and AGS and nude mice model were used to explore how Met affects gastric cancer by regulating lncRNA PVT1. RESULTS: The levels of lncRNA PVT1 in gastric cancer cells and human gastric cancer xenografts of nude mice were down-regulated under the condition of Met deficiency. The cell viability and cell proliferation were declined after MKN45 and SGC-790 cells were cultured in Met-deficient medium. LncRNA PVT1 could affect BNIP3 promoter DNA methylation level through its interaction with DNMT1. Moreover, the silence of lncRNA PVT1 and the up-regulation of BNIP3 level inhibited the gastric cancer cell proliferation. Met deficiency could up-regulate BNIP3 expression by inhibiting the binding of lncRNA PVT1 to DNMT1, and activate mitophagy, thus inhibiting gastric cancer cell proliferation. CONCLUSION: Our study suggested that Met deficiency could down-regulate the expression of lncRNA PVT1, further demethylated the promoter of BNIP3, thus inhibiting the proliferation of gastric cancer cells by activating mitophagy.

Transfer of LncRNA CRNDE in TAM-derived exosomes is linked with cisplatin resistance in gastric cancer.

This study explores the role of the long noncoding RNA (LncRNA) CRNDE in cisplatin (CDDP) resistance of gastric cancer (GC) cells. Here, we show that LncRNA CRNDE is upregulated in carcinoma tissues and tumor-associated macrophages (TAMs) of GC patients. In vitro experiments show that CRNDE is enriched in M2-polarized macrophage-derived exosomes (M2-exo) and is transferred from M2 macrophages to GC cells via exosomes. Silencing CRNDE in M2-exo reverses the promotional effect of M2-exo on cell proliferation in CDDP-treated GC cells and homograft tumor growth in CDDP-treated nude mice. Mechanistically, CRNDE facilitates neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1)-mediated phosphatase and tensin homolog (PTEN) ubiquitination. Silencing CRNDE in M2-exo enhances the CDDP sensitivity of GC cells treated with M2-exo, which is reduced by PTEN knockdown. Collectively, these data reveal a vital role for CRNDE in CDDP resistance of GC cells and suggest that the upregulation of CRNDE in GC cells may be attributed to the transfer of TAM-derived exosomes.

Constructing a new prognostic signature of gastric cancer based on multiple data sets.

In order to explore new prediction methods and key genes for gastric cancer. Firstly, we downloaded the 6 original sequencing data of gastric cancer on the Illumina HumanHT-12 platform from Array Expression and Gene Expression Omnibus, and used bioinformatics methods to identify 109 up-regulated genes and 271 down-regulated genes. Further, we performed univariate Cox regression analysis of prognostic-related genes, then used Lasso regression to remove collinearity, and finally used multivariate Cox regression to analyze independent prognostic genes (MT1M, AKR1C2, HEYL, KLK11, EEF1A2, MMP7, THBS1, KRT17, RPESP, CMTM4, UGT2B17, CGNL1, TNFRSF17, REG1A). Based on these, we constructed a prognostic risk proportion signature, and found that patients with high-risk gastric cancer have a high degree of malignancy. Subsequently, we used the GSE15459 data set to verify the signature. By calculating the area under the recipient operator characteristic curve of 5-year survival rate, the test set and verification set are 0.739 and 0.681, respectively, suggesting that the prognostic signature has a moderate prognostic ability. The nomogram is used to visualize the prognostic sig-nature, and the calibration curve verification showed that the prediction accuracy is higher. Finally, we verified the expression and prognosis of the hub gene, and suggested that HEYL, MMP7, THBS1, and KRT17 may be potential prognostic biomarkers.

Preparation of Internalizing RGD-Modified Recombinant Methioninase Exosome Active Targeting Vector and Antitumor Effect Evaluation.

BACKGROUND/AIMS: Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here, we prepare an active targeting drug carrier of low immunogenicity and toxicity for targeted therapy. METHODS: Immature dendritic cells (imDCs) from BALB/c mice were used as donor cells of exosomes (Exos) that were transfected with the plasmids expressing fusion proteins of a tumor-targeting peptide known as internalizing RGD (iRGD) to construct a type of tumor-targeting iRGD-Exos and observe the interaction between these iRGD-Exos. Also, recombinant methioninase (rMETase) was loaded into the iRGD-Exos by electroporation to construct iRGD-Exos-rMETase and to assess the tumor-targeting function of the iRGD-Exos-rMETase. Finally, 30 BALB/c were randomly divided into five groups (n = 6), to observe tumor growth in vivo. RESULTS: The iRGD-Exos-rMETase was 99.58 nm in diameter and presented a unique "goblet" structure under transmission electron microscopy (TEM), with the encapsulation efficiency (EE) of 19.05%. iRGD-Exos-rMETase group has the strongest tumor suppressive effect. Compared to the iRGD-Exos-rMETase group, rMETase group and the blank-Exos-rMETase group were less effective, while the PBS group and the iRGD-Exos group showed no inhibitory effect on tumor growth. After treatment, the iRGD-Exos-rMETase group had gastric tumors significantly smaller and lighter than the other groups (P < 0.05). CONCLUSION: The iRGD-Exos-rMETase is an effective antitumor therapy that delivers rMETase to tumor tissue using the iRGD-Exos. With its favorable inhibitory effect and tumor-targeting function, the iRGD-Exos-rMETase shows excellent potential value and exciting prospects in clinical applications.

Development of RNA binding proteins expression signature for prognosis prediction in gastric cancer patients.

It was reported that the expression of RNA binding proteins (RBPs) in malignant tumors is dysregulated and is closely related to tumorigenesis. However, some studies have confirmed the role of RBPs in gastric cancer (GC). We obtained data on gastric cancer in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and identified RBPs that are dysregulated between gastric normal and cancer tissues. Then, we systematically investigated the expression characteristics and clinical prognostic potential of these RBPs through bioinformatics methods. We found 278 dysregulated RBPs in the GC, 91 of which were up-regulated and 181 were down-regulated. We detected 4 hub RBPs (HNRNPL, PABPN1, PCF, SNRPN) are related to overall survival (OS), and 3 hub RBPs (EEF1A2, MRPS5, PCF1) are related to disease-specific survival (DSS), and furthermore, we constructed prognostic signatures. Analysis of the OS and DSS signature showed that the GC patients with high-risk groups have worse OS and DSS than the low-risk groups. The receiver operator characteristic (ROC) curves of the 5-year survival rate of OS and DSS prognosis signature were drawn, and the areas under the two curves were 0.62 and 0.64, respectively. We constructed nomograms to predict OS and DSS, and evaluated by the calibration curve, which showed the GC prediction ability of these two models. Furthermore, the expression of the above six genes was verified by PCR, which is consistent with our results.

Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37.

This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET+ homocysteine (HCY)- or MET-HCY+ medium. In MET+HCY-treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET+HCY--treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET+HCY-treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.

Identification of subtype-specific genes signature by WGCNA for prognostic prediction in diffuse type gastric cancer.

BACKGROUND: Gastric cancer is a common malignancy and had poor response to treatment due to its strong heterogeneity. This study aimed to identify essential genes associated with diffuse type gastric cancer and construct a powerful prognostic model. RESULTS: We conducted a weighted gene co-expression network analysis (WGCN) using transcripts per million (TPM) expression data from The Cancer Genome Atlas (TCGA) to find out the module related with diffuse type gastric cancer. Combining Least Absolute Shrinkage and Selection Operator (LASSO) with multi-cox regression, the 10 specific genes risk score model of diffuse type gastric cancer was established. The concordance index (0.97), the area under the respective ROC curves (AUCs) (1-years: 0.98; 3-years: 1; 5-years: 1) and survival difference of high- and low risk groups (p=2.84e-10) of this model in TCGA dataset were obtained. The moderate predicting performance was observed in the independent cohort of GSE15459 and GSE62254. The results of the gene set enrichment analysis (GSEA) using high-and low risk group as phenotype indicated differential expression of tumor-related pathways. CONCLUSION: Thus, we constructed a reliable prognostic model for diffuse type gastric cancer, which should be beneficial for clinical therapeutic decision-making.

[Recombinant methioninase regulates PI3K/Akt/Glut-1 pathway and inhibits aerobic glycolysis to promote apoptosis of gastric cancer cells].

OBJECTIVE: To investigate the molecular mechanism of recombinant methioninase (rMETase) in promoting apoptosis of gastric cancer cells. METHODS: Gastric cancer SGC-7901 cells were treated with rMETase (final concentration of 1.25 and 2.50 mmmol/L) for 72 h, and the changes in the cell viability were detected using CCK-8 method and the cell morphology changes were observed under an inverted microscope. Plate colony formation assay was used to evaluate colony formation ability of the cells, and flow cytometry was performed to analyze the changes in cell apoptosis and cell cycles. Glucose and lactate levels in the culture medium were determined using a colorimetric method and ATP concentration was detected using a fluorescence microplate reader; Western blotting was used to assess the effect of rMETase on PI3K/Akt pathway, glucose transporter-1 (GLUT-1), glycolysis- related proteins and apoptotic proteins in SGC-7901 cells. RESULTS: rMETase significantly inhibited the proliferation and clonal formation, promoted cell apoptosis, and induced cell cycle arrest in S phase in SGC-7901 cells (P < 0.05). With the increase of rMETase concentration, the cells showed obviously decreased glucose intake accompanied by decreased glycolysis and ATP concentration (P < 0.001). The results of Western blotting showed that the expressions of PI3K, p-Akt/t-Akt, GLUT-1, and the key glycolytic enzymes HK2, PFKM, LDHA, antiapoptosis protein Bcl-2 were all downregulated and the pro-apoptotic proteins Bax and caspase-3 were up-regulated in response to rMETase treatment in SGC-7901 cells (P < 0.01). CONCLUSIONS: rMETase can inhibit aerobic glycolysis, induce apoptosis and inhibit the proliferation of SGC-7901 cells by inhibiting the activity of PI3K/Akt/GLUT-1 pathway, suggesting its potential as a therapeutic agent for gastric cancer.

The renin-angiotensin system blockers and survival in digestive system malignancies: A systematic review and meta-analysis.

BACKGROUND: Accumulating pre-clinical and clinical studies suggested that the renin-angiotensin system blockers (RASBs) possess anti-carcinogenic properties, and their use is associated with favorable outcomes in many types of cancers. METHODS: A systematic literature search of relevant databases through January 2019 was conducted to identify studies assessing the RASBs on prognostic outcomes in digestive system malignancies patients on the basis of predetermined selection criteria for pooled hazard ratio (HR) with 95% confidence intervals (CIs). A total of 13 studies were included in the meta-analysis. RESULTS: The meta-analysis showed that the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) resulted in a significant improvement in overall survival (HR 0.79; 95%CI 0.70-0.89; P < .000), cancer-specific survival (HR 0.81; 95%CI 0.73-0.90; P < .000) and recurrence-free survival (HR 0.68; 95%CI 0.54-0.85; P = .001), but not progression-free survival (HR 0.88; 95%CI 0.73-1.07; P = .183) and disease-free survival (HR 0.50; 95%CI 0.11-2.39; P = .103). Subgroup analysis indicated that the use of RASBs has a significant improvement of overall survival (OS) in pancreatic cancer, liver cancer, and gastric cancer. Two studies evaluated the dose-response relationship between ACEIs/ARBs therapy and survival and showed higher doses and better survival [(1-364 defined daily doses: odds ratio (OR) 0.89, 95%CI 0.78-1.01, P = .076), (≥365 defined daily doses: OR 0.54, 95%CI: 0.24-1.24, P = .148]. CONCLUSIONS: Meta-analysis of studies supports a beneficial association between use of RASBs and survival of digestive system malignancies.

DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1.

Cancer stem cells are undifferentiated cancer cells that have self-renewal ability, a high tumorigenic activity, and a multilineage differentiation potential. MicroRNAs play a critical role in regulating gene expression during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer stem cells (GCSCs). The stem cell marker, CD44, was used to sort GCSCs by fluorescence-activated cell sorting. We found that CD44 (+) cells have higher invasiveness and form more number of sphere colonies than CD44 (-) cells. Quantitative real-time polymerase chain reaction (PCR) revealed that the miR-7-5p expression was remarkably downregulated in GCSCs but was significantly increased in the methionine-deprived medium. The downregulation of miR-7-5p results from the increased DNA methylation in the promoter region using the methylation-specific PCR. Overexpression of miR-7-5p reduced the formation of colony and decreased the invasion of GCSCs through targeting Smo and Hes1 and subsequent repressing Notch and Hedgehog signaling pathways in vitro. Notably, upregulating miR-7-5p inhibited the growth of tumor in the xenograft model. Hence, these data demonstrated that miR-7-5p represses GCSC invasion through inhibition of Smo and Hes1, which provides a potential therapeutic target of gastric cancer treatment.

METase/lncRNA HULC/FoxM1 reduced cisplatin resistance in gastric cancer by suppressing autophagy.

BACKGROUND: Autophagy plays an important role in regulating cisplatin (CDDP) resistance in gastric cancer cells. However, the underlying mechanism of methioninase (METase) in the regulation of autophagy and CDDP resistance of gastric cancer cells is still not clear. MATERIALS AND METHODS: Western blot was used to detect the levels of autophagy-related proteins, multidrug-resistant 1 (MDR-1), and FoxM1 protein. LncRNA HULC was detected by qRT-PCR. Cell viability was detected using CCK-8 assay. The interaction between lncRNA HULC and FoxM1 was confirmed by RNA pull-down and RIP assay. RESULTS: Lentiviral vector carrying METase (LV-METase) suppressed autophagy and CDDP resistance of drug-resistant gastric cancer cells. LncRNA HULC was significantly downregulated in drug-resistant gastric cancer cells transfected with LV-METase. Besides, we found that lncRNA HULC interacted with FoxM1. In addition, METase suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating HULC/FoxM1, and interfering HULC suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating FoxM1. Finally, interfering HULC inhibited tumor growth in vivo. CONCLUSION: METase suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating HULC/FoxM1 pathway.