MFAP2 is overexpressed in gastric cancer and promotes motility via the MFAP2/integrin α5β1/FAK/ERK pathway.
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ABSTRACT:
SUBMITTER: Yao LW
PROVIDER: S-EPMC7018958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThis study aimed to investigate the effect of NPTX1 on the prognosis of gastric cancer (GC), as well as the metastatic process in GC.Materials and methodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the association between NPTX1 expression and prognosis in GC. Quantitative real-time polymerase chain reaction and Western blots were applied to examine the expression of NPTX1 in GC cell lines and expression of genes in downstream pathways. The role of NPTX1 on the migration, invasion, adhesion, and proliferation of GC cell lines was investigated with the transwell assay, the adhesion assay, and the MTT assay. Immunofluorescence staining was used to observe the effect of NPTX1 knockdown on the morphology of cells.ResultsAccording to the review of TCGA and GEO databases of GC, we found that the expression of NPTX1 increased in cancer tissues and high NPTX1 expression was correlated with poor overall survival, which was associated with lymph node stage in clinicopathologic parameters. Knockdown of NPTX1 attenuated the migration, invasion, and adhesion abilities of GC cells. According to gene set enrichment analysis, NPTX1 was found to be positively related to integrin and focal adhesion (FA). Additionally, NPTX1 knockdown decreased the expression of integrin ?1 and integrin ?7, followed by deregulation of the expression of p-Src, p-Akt, p-Erk, MMP2, and MMP7, as well as inhibiting the formation of FA complexes and decreasing the length of pseudopods in GC cells.ConclusionOur study provides strong evidence that NPTX1 plays a crucial role in promoting metastasis and acts as a prognostic indicator in GC.
| S-EPMC6472287 | biostudies-literature
Project description:Increased Crabp2 levels have been found in various types of cancer, and are associated with poor patients' survival. Although Crabp2 is found to be overexpressed in lung cancer, its role in metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin ?1/FAK/ERK signaling. Inhibition of HuR or integrin ?1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis.
| S-EPMC6351595 | biostudies-literature
Project description:Alternative splicing is evolving as an eminent player of oncogenic signaling for tumor development and progression. Mucin 4 (MUC4), a type I membrane-bound mucin, is differentially expressed in pancreatic cancer (PC) and plays a critical role in its progression and metastasis. However, the molecular implications of MUC4 splice variants during disease pathogenesis remain obscure. The present study delineates the pathological and molecular significance of a unique splice variant of MUC4, MUC4/X, which lacks the largest exon 2, along with exon 3. Exon 2 encodes for the highly glycosylated tandem repeat (TR) domain of MUC4 and its absence creates MUC4/X, which is devoid of TR. Expression analysis from PC clinical samples revealed significant upregulation of MUC4/X in PC tissues with most differential expression in poorly differentiated tumors. In vitro studies suggest that overexpression of MUC4/X in wild-type-MUC4 (WT-MUC4) null PC cell lines markedly enhanced PC cell proliferation, invasion, and adhesion to extracellular matrix (ECM) proteins. Furthermore, MUC4/X overexpression leads to an increase in the tumorigenic potential of PC cells in orthotopic transplantation studies. In line with these findings, doxycycline-induced expression of MUC4/X in an endogenous WT-MUC4 expressing PC cell line (Capan-1) also displayed enhanced cell proliferation, invasion, and adhesion to ECM, compared to WT-MUC4 alone, emphasizing its direct involvement in the aggressive behavior of PC cells. Investigation into the molecular mechanism suggested that MUC4/X facilitated PC tumorigenesis via integrin-β1/FAK/ERK signaling pathway. Overall, these findings revealed the novel role of MUC4/X in promoting and sustaining the oncogenic features of PC.
| S-EPMC6047753 | biostudies-literature
Project description:IntroductionMicrofibril-associated protein 2 (MFAP2) is an extracellular matrix protein that interacts with fibrillin to modulate the function of microfibrils. MFAP2 has been reported to play a significant role in obesity, diabetes, and osteopenia, and has been shown to be upregulated in head and neck squamous cell carcinoma. However, the molecular function and prognostic value of MFAP2 have never been reported in gastric cancer (GC) or any other tumors.MethodsThe current study investigated the expression patterns, prognostic significance, functional role, and possible mechanisms of MFAP2 in GC.ResultsWe demonstrated that MFAP2 was overexpressed in GC tissues, and its overexpression was significantly correlated with poor overall and disease-free survival in patients with GC. Moreover, we found that MFAP2 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) phenotype in GC cells. MFAP2 might modulate EMT of GC cells by activating the TGF-β/SMAD2/3 signaling pathway.ConclusionThese findings provide novel evidence that MFAP2 plays a crucial role in the progression of GC. Therefore, MFAP2 may be a promising prognostic marker and a potent anticancer agent.
| S-EPMC6047603 | biostudies-literature
Project description:VPS35 is a key subunit of the retromer complex responsible for recognising cytosolic retrieval signals in cargo and is involved in neurodegenerative disease and tumour progression. However, the function and molecular mechanism of VPS35 in gastric cancer (GC) remains largely unknown. Here, we demonstrated that VPS35 was significantly upregulated in GC, which was associated with poor survival. VPS35 promoted GC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, VPS35 activated FAK-SRC kinases through integrin-mediated outside-in signalling, leading to the activation of YAP and subsequent IL-6 expression induction in tumour cells. What's more, combined mass spectrometry analysis of MGC-803 cell and bioinformatic analysis, we found that phosphorylation of VPS35 was enhanced in GC cells, and phosphorylated VPS35 has enhanced interaction with ITGB3. VPS35 interacted with ITGB3 and affected the recycling of ITGB3 in GC cells. Gain- and loss-of-function experiments revealed that VPS35 promoted tumour proliferation and metastasis via the IL-6/STAT3 pathway. Interestingly, we also found that STAT3 directly bound to the VPS35 promoter and increased VPS35 transcription, thereby establishing a positive regulatory feedback loop. In addition, we demonstrated that VPS35 knockdown sensitised GC cells to 5-FU and cisplatin. These findings provide evidence that VPS35 promotes tumour proliferation and metastasis, and highlight the potential of targeting VPS35- and IL-6/STAT3-mediated tumour interactions as promising therapeutic strategies for GC.
| S-EPMC10774127 | biostudies-literature
Project description:Gastric cancer is the fifth most common cancer worldwide with a poor survival rate. Therefore, it is important to identify predictive and prognostic biomarkers of gastric cancer. Laminin subunit beta 1 (LAMB1) is involved in attachment, migration, and organization during development, and its elevated expression has been associated with several cancers. However, the role and mechanism of LAMB1 in gastric cancer remains unknown. Here, we determined that LAMB1 is upregulated in gastric cancer tissues and contributes to cell growth and motility. Using a public database, we showed that LAMB1 expression was significantly upregulated in gastric cancer compared to normal tissues. LAMB1 was also found to be associated with poor prognosis in patients with gastric cancer. Overexpression of LAMB1 elevated cell proliferation, invasion, and migration; however, knockdown of LAMB1 decreased these effects in gastric cancer cells. U0126, an extracellular signal-regulated kinase (ERK) inhibitor, regulated the expression of LAMB1 in gastric cancer cells. Additionally, we showed that c-Jun directly binds to the LAMB1 promoter as a transcription factor and regulates its gene expression via the ERK pathway in gastric cancer cells. Therefore, our study indicates that LAMB1 promotes cell growth and motility via the ERK/c-Jun axis and is a potential biomarker and therapeutic target of gastric cancer.
| S-EPMC7826975 | biostudies-literature
Project description:Non-availability of an ideal alternative for autografts in treating critical-size bone defects is a major challenge in orthopedics. Phytocompounds have been proven to enhance osteogenesis via various osteogenic signaling pathways, but its decreased bioavailability and increased renal clearance limit its application. In this study, we designed a biocomposite scaffold comprising gelatin (Gel) and nanohydroxyapatite (nHAp) incorporated with diosmin (DM) and we investigated its bone forming potential in vitro and in vivo. Physiochemical characterization of the scaffold showed that DM had no effect on altering the material characteristics of the scaffold. The addition of DM enhanced the osteoblast differentiation potential of the scaffold in mouse mesenchymal stem cells at both cellular and molecular levels, possibly via the integrin-mediated activation of FAK and ERK signaling components. Using the rat tibial bone defective model, we identified the effect of DM in Gel/nHAp scaffold on enhancing bone formation in vivo. Based on our results, we suggest that Gel/nHAp/DM can be a potential therapeutic agent in scaffold-mediated bone regeneration.
| S-EPMC6695412 | biostudies-literature
Project description:Reduced mechanical stimuli in many pathological cases, such as hemimastication and limited masticatory movements, can significantly affect the metabolic activity of mandibular condylar chondrocytes and the growth of mandibles. However, the molecular mechanisms for these phenomena remain unclear. In this study, we hypothesized that integrin-focal adhesion kinase (FAK)-ERK (extracellular signal-regulated kinase)/PI3K (phosphatidylinositol-3-kinase) signaling pathway mediated the cellular response of condylar chondrocytes to mechanical loading. Primary condylar chondrocytes were exposed to hydrostatic compressive forces (HCFs) of different magnitudes (0, 50, 100, 150, 200, and 250 kPa) for 2 h. We measured the viability, morphology, and apoptosis of the chondrocytes with different treatments as well as the gene, protein expression, and phosphorylation of mechanosensitivity-related molecules, such as integrin α2, integrin α5, integrin β1, FAK, ERK, and PI3K. HCFs could significantly increase the viability and surface area of condylar chondrocytes and decrease their apoptosis in a dose-dependent manner. HCF of 250 kPa resulted in a 1.51 ± 0.02-fold increase of cell viability and reduced the ratio of apoptotic cells from 18.10% ± 0.56% to 7.30% ± 1.43%. HCFs could significantly enhance the mRNA and protein expression of integrin α2, integrin α5, and integrin β1 in a dose-dependent manner, but not ERK1, ERK2, or PI3K. Instead, HCF could significantly increase phosphorylation levels of FAK, ERK1/2, and PI3K in a dose-dependent manner. Cilengitide, the potent integrin inhibitor, could dose-dependently block such effects of HCFs. HCFs enhances the viability and decreases the apoptosis of condylar chondrocytes through the integrin-FAK-ERK/PI3K pathway.
| S-EPMC5133847 | biostudies-literature
Project description:Aldo-keto reductase 1B10 (AKR1B10) is not expressed in normal breast, but upregulated in primary and metastatic breast cancers, being a negative prognostic factor. This study characterized the molecular mechanisms of AKR1B10-promoted breast cancer metastasis. Ectopic expression of AKR1B10 in breast cancer cells MCF-7 and MDA-MB-231 or siRNA-mediated silencing in BT-20 cells affected cell adhesion, migration and invasion in cell culture, and metastasis to the lung in the nude mice through upregulation of integrin α5 and δ-catenin. Silencing of integrin α5 or δ-catenin eradicated the cell adhesion and migration enhanced by AKR1B10, both of which acted synergistically. In these cells, the integrin α5 mediated focal adhesion kinase (FAK) signaling pathway was activated by AKR1B10, which, along with δ-catenin, stimulated Rac1-mediated cell migration and movement. In human primary and lymph node metastatic breast cancer, AKR1B10, integrin α5 and δ-catenin were correlatively upregulated with r=0.645 (p<0.0001) and r=0.796 (p<0.0001), respectively. These data suggest that AKR1B10 promotes breast cancer metastasis through activation of the integrin α5 and δ-catenin mediated FAK/Src/Rac1 signaling pathway.
| S-EPMC5190059 | biostudies-literature
Project description:Soluble VEGFR-1 (sVEGFR-1) acts both as a decoy receptor for VEGFs and as an extracellular matrix protein for α5β1 integrin. A sVEGFR-1-derived peptide that interacts with α5β1 integrin promotes angiogenesis. However, canonical signal downstream integrin activation is not induced, resulting into lack of focal adhesion maturation. We performed a gene expression profile of endothelial cells adhering on sVEGFR-1 compared to that of cells adhering on fibronectin, the principal α5β1 integrin ligand. Three protein kinase-C substrates, adducin, MARCKS, and radixin were differently modulated. Adducin and MARCKS were less phosphorylated whereas radixin was higher phosphorylated in sVEGFR-1 adhering cells, the latter leading to prolonged small GTPase Rac1 activation and induction of a pathway involving the heterotrimeric G protein α13. Altogether, our data indicated endothelial cell acquisition of an highly motile phenotype when adherent on sVEGFR-1. Finally, we indicated radixin as accountable for the angiogenic effect of α5β1 integrin interaction with sVEGFR-1 that in turn depends on an active VEGF-A/VEGFR-2 signaling.
2014-01-20 | GSE32560 | GEO