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DUSP5P1 promotes gastric cancer metastasis and platinum drug resistance [RNA-seq]

ABSTRACT: We elucidated the functional significance and molecular mechanisms of DUSP5P1 lncRNA (dual specificity phosphatase 5 pseudogene 1) in gastric carcinogenesis. We demonstrated that gastric cancer (GC) patients with high DUSP5P1 expression had shortened survival in two independent cohorts. DUSP5P1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Mechanistically, DUSP5P1 activated ARHGAP5 transcription by directly binding to the promoter of ARHGAP5 with a binding motif of TATGTG. RNA-seq revealed that ARHGAP5 activated focal adhesion and MAPK signalling pathways to promote GC metastasis. DUSP5P1 also dysregulated platinum drug resistance pathway. Consistently, DUSP5P1 overexpression in GC cells antagonized cytotoxic effect of Oxaliplatin, and shDUSP5P1 plus Oxaliplatin exerted synergistic effect on inhibiting GC metastasis in vitro and in vivo. DUSP5P1 depletion also suppressed the growth of platinum drug-resistant PDO models. In conclusion, DUSP5P1 promoted GC metastasis by directly modulating ARHGAP5 expression to activate focal adhesion and MAPK pathways, serves as therapeutic target for platinum drug resistant GC, and is an independent prognostic factor in GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213560 | GEO | 2022/11/18

REPOSITORIES: GEO

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DUSP5P1 promotes gastric cancer metastasis and platinum drug resistance [ChIRP-seq]

Project description:We elucidated the functional significance and molecular mechanisms of DUSP5P1 lncRNA (dual specificity phosphatase 5 pseudogene 1) in gastric carcinogenesis. We demonstrated that gastric cancer (GC) patients with high DUSP5P1 expression had shortened survival in two independent cohorts. DUSP5P1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Mechanistically, DUSP5P1 activated ARHGAP5 transcription by directly binding to the promoter of ARHGAP5 with a binding motif of TATGTG. RNA-seq revealed that ARHGAP5 activated focal adhesion and MAPK signalling pathways to promote GC metastasis. DUSP5P1 also dysregulated platinum drug resistance pathway. Consistently, DUSP5P1 overexpression in GC cells antagonized cytotoxic effect of Oxaliplatin, and shDUSP5P1 plus Oxaliplatin exerted synergistic effect on inhibiting GC metastasis in vitro and in vivo. DUSP5P1 depletion also suppressed the growth of platinum drug-resistant PDO models. In conclusion, DUSP5P1 promoted GC metastasis by directly modulating ARHGAP5 expression to activate focal adhesion and MAPK pathways, serves as therapeutic target for platinum drug resistant GC, and is an independent prognostic factor in GC.

2022-11-18 | GSE213581 | GEO

MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer

Project description:Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identifified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classifification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal adhesion pathway and repressing the occurrence of EMT.

2021-07-16 | GSE180148 | GEO

Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice

Project description:Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we applied genome-edited gastric organoids to establish a series of primary GC models in mice, which elucidated the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC. Further, we found that the orthotopic GC, but not the subcutaneous GC even with the same genetic drivers, displayed remote metastasis, suggesting critical roles of the microenvironment in GC metastasis. Through single-cell RNA-seq analyses and functional studies, we revealed that the molecular interaction between fibronectin 1 on stomach-specific macrophages and integrin α6β4 on GC cells promoted liver metastasis. Taken together, our studies proposed a new strategy to model GC and dissected the genetic and microenvironmental factors driving the full-range gastric tumorigenesis.

2022-09-05 | GSE188761 | GEO

Small extracellular vesicles-delivered LSD1 promotes gastric cancer cell stemness

Project description:Although there are plenty of researches about nucleic acid in small extracellular vesicles (sEVs), properties of proteins identified as sEVs’ cargos and the mechanism of their action in recipient cell are poorly understood. Here, we show that lysine specific demethylase 1 (LSD1), the first identified histone demethylase in 2004, existed in the cell cultured medium of gastric cancer cells. Further investigation confirmed the presence of LSD1 in sEVs from gastric cancer cells and gastric cancer patient plasma, which is the first identified histone demethylase in sEVs. By shuttling from donor cells to recipient gastric cancer cells, sEVs-delivered LSD1 promoted the cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2 and CD44, and suppressed the oxaliplatin response of the recipient cells in vitro and in vivo, while LSD1 depleted sEVs failed to suppress the oxaliplatin response. Collectively, our findings give an evidence for LSD1 as a sEVs protein to promote stemness and suppress oxaliplatin response for the first time and constitute a future avenue to predict oxaliplatin response in gastric cancer clinically.

2021-12-22 | PXD020223 | Pride

Small extracellular vesicles-delivered LSD1 promotes gastric cancer cell stemness

2021-07-30 | PXD021511 | Pride

CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Most patients are at an advanced stage at diagnosis, and are not eligible for curative therapy. Chemotherapy is an alternative treatment for advanced HCCs, but resistance is found in many patients. Understanding the underlying mechanisms in chemo-resistance is critical to further improve the efficacy of HCC treatment. In this study, we found that increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2, and Id-1 could upregulate CCN2 in a positive feedback manner. Moreover, CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK signaling pathway and upregulating Id-1 expression. Meanwhile, MAPK/Id-1 signaling was demonstrated as one of the most important autocrine signaling pathways regulated by CCN2 in oxaliplatin-resistant models, and combination with sorafenib could improve the efficacy of oxaliplatin in HCC. Conclusions: These findings suggest that CCN2-MAPK-Id-1 loop feedback amplification is involved in oxaliplatin-resistant HCC, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating HCC progression and oxaliplatin resistance.

2019-01-02 | GSE124529 | GEO

Genome-wide analysis of long noncoding RNA expression profile in gastric cancer

Project description:Gastric cancer (GC) remains one of the most prevalent tumor worldwide, and ranks third in cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have been reported to play significant role in the progression and metastasis in gastric cancer (GC), however, the molecular mechanism are largely elusive. We aim to identify up-regulated lncRNA in GC and study their function in promoting tumor progression and metastasis.

2023-11-13 | GSE193109 | GEO

Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response.Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response

Project description:Oxaliplatin is a widely used anti-cancer drug. It is part of treatment regimens for colorectal and pancreatic cancers, but it is tested in esophageal, biliary tract, gastric or hepatocellular cancers as well. Contrary to this wide application, there is only limited amount of information about oxaliplatin mechanism and response to treatment. We have performed whole-cell proteomic study to obtain cellular response induced by oxaliplatin. For this purpose we have treated CCRF-CEM cell line by 5xIC50 (29.3 μM) for half-time to caspase activation (240 min). The complex proteomic comparison was done on the treated vs. un-treated cells by high-resolution mass spectrometry. We have identified 4049 proteins in average from three biological replicates. From such pool just 76 proteins were significantly downregulated and 31 proteins upregulated in at least of two replicates. Both upregulated and dowregulated proteins are involved in DNA damage response, which is the most significant effect of platinum drugs. Downregulated proteins are split into three fractions. One fraction was centrosomal proteins or proteins involved in G2/M regulation. Second fraction was RNA processing proteins or proteins of processome of both ribosomal subunits. Downregulation of those proteins shows to ongoing nucleolar stress. Third fraction consisted of several ribosomal proteins. This should be sign of ribosomal stress. Nucleolar and ribosomal stress are stress responses manifesting by nucleolar shrinkage or and by inhibition of ribosomal biogenesis. Cellular response to oxaliplatin is thus DNA damage response, which triggers nucleolar and subsequent ribosomal stress.

2017-05-11 | PXD003543 | Pride

Quantitative proteomic Analysis Reveals up-regulation of caveolin-1 in FOXP3-overexpressed human gastric cancer cells

Project description:Forkhead box protein 3 (FOXP3) is implicated in tumor progression and prognosis in various types of tumor cells. We have recently reported that FOXP3 inhibited proliferation of gastric cancer (GC) cells through activating the apoptotic signaling pathway. In this study, we found that over-expression of FOXP3 inhibited GC cell migration, invasion and proliferation. Then, the label-free quantitative proteomic approach was employed to further investigating the down-stream proteins regulated by FOXP3, resulting in a total of 3,978 proteins quantified, including 186 significantly changed proteins. Caveolin-1 (CAV1), as a main constituent protein of caveolae, was one of those changed proteins up-regulated in FOXP3-overexpressed GC cells, moreover, it was assigned as one of the node proteins in the protein-protein interaction network and the key protein involved in focal adhesion pathway by bioinformatics analysis. Further biological experiments confirmed that FOXP3 directly bound to the promoter regions of CAV1 to positively regulate CAV1 transcription in GC cells. In summary, our study suggested that FOXP3 can be considered as a tumor suppressor in GC via positively regulating CAV1 through transcriptional activation, and this FOXP3-CAV1 transcriptional regulation axis may play an important role in inhibiting invasion and metastasis of GC cells.

2017-11-03 | PXD007725 | Pride

Gastric Cancer Cell Lines

Project description:Regions of recurrent genomic amplification and deletion are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes lying within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms besides gene amplification for up-regulating RAB23. siRNA silencing of RAB23 reduced the invasive potential of both amplified and nonamplified GC cell lines. RAB23 gene amplifications were observed in 13% of primary gastric carcinomas. In two independent patient cohorts, RAB23 transcript and protein expression was significantly associated with diffuse-type gastric cancer (dGC) compared to intestinal-type gastric cancer (iGC), providing further evidence that dGC and iGC likely represent two molecularly distinct tumor types. Our study demonstrates that investigating focal chromosomal amplifications by combining highresolution aCGH with expression profiling is a powerful general strategy for identifying novel cancer genes in recurrent regions of chromosomal aberration. Keywords: gastric cancer cell lines, comparative genomic hybridization, gene expression profiling Affy 100K SNP profiling and 32K BAC Array profiling for 7 Gastric Cancer Cell Lines

2010-05-14 | E-GEOD-10611 | biostudies-arrayexpress

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