Elevation of TRIM44 potentiates propagation of gastric cancer stem cells.
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ABSTRACT:
SUBMITTER: Zhu H
PROVIDER: S-EPMC9293703 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGrowing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC.MethodsHIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed.ResultsHIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties.ConclusionOur study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.
| S-EPMC8406628 | biostudies-literature
Project description: Not available
| S-EPMC8016859 | biostudies-literature
Project description:Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which is characterized by a conserved RING finger, B-box, and coiled-coil domains, function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer. We analyzed seven gastric cancer cell lines and 112 primary tumors, which were curatively resected in our hospital between 2001 and 2003. Expression of the TRIM44 protein was detected in gastric cancer cell lines (2/7 cell lines; 29%) and primary tumor samples of gastric cancer (29/112 cases; 25%). Knockdown of TRIM44 expression using several specific siRNAs inhibited the proliferation, migration, and invasion of TRIM44-overexpressing cells. Overexpression of the TRIM44 protein was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.0038, log-rank test) in both intensity and proportion expression-dependent manner. TRIM44 positivity was independently associated with worse outcome in multivariate analysis (P = 0.0233, hazard ratio 3.37 [1.18-9.64]). These findings suggest that TRIM44 plays a crucial role in tumor cell proliferation through its overexpression, and highlight its usefulness as a predictor and potential therapeutic target in gastric cancer.
| S-EPMC7659272 | biostudies-literature
Project description:Cancer stem cells (CSCs) are responsible for cancer progression, metastasis, and recurrence. To date, the specific markers of CSCs remain undiscovered. The aim of this study was to identify novel biomarkers of gastric CSCs for clinical diagnosis using proteomics technology. CSC-like SP cells, OCUM-12/SP cells, OCUM-2MD3/SP cells, and their parent OCUM-12 cells and OCUM-2MD3 cells were used in this study. Protein lysates from each cell line were analyzed using QSTAR Elite Liquid Chromatography with Tandem Mass Spectrometry, coupled with isobaric tags for relative and absolute quantitation technology. Candidate proteins detected by proteomics technology were validated by immunohistochemical analysis of 300 gastric cancers. Based on the results of LC-MS/MS, eight proteins, including RBBP6, GLG1, VPS13A, DCTPP1, HSPA9, HSPA4, ALDOA, and KRT18, were up-regulated in both OCUM-12/SP cells and OCUM-2MD3/SP cells when compared to their corresponding parent cells. RT-PCR analysis indicated that the expression level of RBBP6, HSPA4, DCTPP1, HSPA9, VPS13A, ALDOA, GLG1, and CK18 was high in OCUM-12/SP and OCUM-2MD3/SP, in compared with the control of parent OCUM-12 and OCUM-2MD3. These proteins were significantly associated with advanced invasion depth, lymph node metastasis, distant metastasis, or advanced clinical stage. RBBP6, DCTPP1, HSPA4, and ALDOA expression in particular were significantly associated with a poor prognosis in the 300 gastric cancer patients. RBBP6 was determined to be an independent prognostic factor. The motility-stimulating ability of OCUM-12/SP cells and OCUM-2MD3/SP cells was inhibited by RBBP6 siRNA. These findings might suggest that the eight proteins, RBBP6, GLG1, VPS13A, DCTPP1, HSPA9, HSPA4, ALDOA, and KRT18, utilizing comparative proteomics analysis, were perceived to be potential CSC markers of gastric cancer. Of the eight candidate proteins, RBBP6 was suggested to be a promising prognostic biomarker and a therapeutic target for gastric cancer.
| S-EPMC4224387 | biostudies-literature
Project description:Glioblastoma Multiforme (GBM) is characterized by high cancer cell heterogeneity and the presence of a complex tumor microenvironment. Those factors are a key obstacle for the treatment of this tumor type. To model the disease in mice, the current strategy is to grow GBM cells in serum-free non-adherent condition, which maintains their tumor-initiating potential. However, the so-generated tumors are histologically different from the one of origin. In this work, we performed high-throughput marker expression analysis and investigated the tumorigenicity of GBM cells enriched under different culture conditions. We identified a marker panel that distinguished tumorigenic sphere cultures from non-tumorigenic serum cultures (high CD56, SOX2, SOX9, and low CD105, CD248, ?SMA). Contrary to previous work, we found that 'mixed cell cultures' grown in serum conditions are tumorigenic and express cancer stem cell (CSC) markers. As well, 1% serum plus bFGF and TGF-? preserved the tumorigenicity of sphere cultures and induced epithelial-to-mesenchymal transition gene expression. Furthermore, we identified 12 genes that could replace the 840 genes of The Cancer Genome Atlas (TCGA) used for GBM-subtyping. Our data suggest that the tumorigenicity of GBM cultures depend on cell culture strategies that retain CSCs in culture rather than the presence of serum in the cell culture medium.
| S-EPMC5290038 | biostudies-literature
Project description:BackgroundBone marrow mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with tumor growth and progression. However, the roles of tumor-resident MSCs in cancer have not been thoroughly clarified. This study was to investigate the regulating effect of gastric cancer-derived MSCs (GC-MSCs) on gastric cancer and elucidate the underlying mechanism.MethodsGC-MSCs were isolated from primary human gastric cancer tissues and characterized. The effect of GC-MSCs on gastric cancer cell proliferation was analyzed by MTT assay and colony formation assay. Transwell migration assay was performed to evaluate the influence of GC-MSCs in gastric cancer cell migration. The regulating effects of interactions between gastric cancer cells and GC-MSCs on their pro-angiogenic abilities were analyzed in a co-culture system, with the expression, and secretion of pro-angiogenic factors detected by RT-PCR and Luminex assay. Tube formation assay was used to further validate the angiogenic capability of gastric cancer cells or GC-MSCs. Cytokine profiles in the supernatant of GC-MSCs were screened by Luminex assay and neutralizing antibody was used to identify the key effective cytokines. The activations of Akt and Erk1/2 in gastric caner cells were detected by Western blot.ResultsGC-MSC treatment enhanced the proliferation and migration of BGC-823 and MKN-28 cells, which was more potently than MSCs from adjacent non-cancerous tissues (GCN-MSCs) or bone marrow (BM-MSCs). Higher expression levels of pro-angiogenic factors were detected in GC-MSCs than GCN-MSCs or BM-MSCs. After 10 % GC-MSC-CM treatment, BGC-823, and MKN-28 cells expressed increased levels of pro-angiogenic factors and facilitated tube formation more potently than cancer cells alone. Furthermore, GC-MSCs produced an extremely higher level of interleukin-8 (IL-8) than GCN-MSCs or BM-MSCs. Blockade of IL-8 by neutralizing antibody significantly attenuated the tumor-promoting effect of GC-MSCs. In addition, 10 % CM of IL-8-secreted GC-MSCs induced the activations of Akt or Erk1/2 pathway in BGC-823 and MKN-28 cells.ConclusionTumor-resident GC-MSCs promote gastric cancer growth and progression more efficiently than GCN-MSCs or BM-MSCs through a considerable secretion of IL-8, which could be a possible target for gastric cancer therapy.
| S-EPMC4443537 | biostudies-literature
Project description:AIM:To investigate the genes regulated in mesenchymal stem cells (MSCs) and diffuse-type gastric cancer (GC), gene expression was analyzed. METHODS:Gene expression of MSCs and diffuse-type GC cells were analyzed by microarray. Genes related to stem cells, cancer and the epithelial-mesenchymal transition (EMT) were extracted from human gene lists using Gene Ontology and reference information. Gene panels were generated, and messenger RNA gene expression in MSCs and diffuse-type GC cells was analyzed. Cluster analysis was performed using the NCSS software. RESULTS:The gene expression of regulator of G-protein signaling 1 (RGS1) was up-regulated in diffuse-type GC cells compared with MSCs. A panel of stem-cell related genes and genes involved in cancer or the EMT were examined. Stem-cell related genes, such as growth arrest-specific 6, musashi RNA-binding protein 2 and hairy and enhancer of split 1 (Drosophila), NOTCH family genes and Notch ligands, such as delta-like 1 (Drosophila) and Jagged 2, were regulated. CONCLUSION:Expression of RGS1 is up-regulated, and genes related to stem cells and NOTCH signaling are altered in diffuse-type GC compared with MSCs.
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Project description:BACKGROUND:Recent evidence suggests that head and neck squamous cell carcinomas (HNSCCs) harbor a small subpopulation of highly tumorigenic cells, designated cancer stem cells. A limiting factor in cancer stem cell research is the intrinsic difficulty of expanding cells in an undifferentiated state in vitro. METHODS:Here, we describe the development of the orosphere assay, a method for the study of putative head and neck cancer stem cells. An orosphere is defined as a nonadherent colony of cells sorted from primary HNSCCs or from HNSCC cell lines and cultured in 3-dimensional soft agar or ultralow attachment plates. Aldehyde dehydrogenase activity and CD44 expression were used here as stem cell markers. RESULTS:This assay allowed for the propagation of head and neck cancer cells that retained stemness and self-renewal. CONCLUSION:The orosphere assay is well suited for studies designed to understand the pathobiology of head and neck cancer stem cells.
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Project description:Breast cancer stem cells (CSCs) are highly tumorigenic and possess the capacity to self-renew. Recent studies indicated that pluripotent gene NANOG involves in regulating self-renewal of breast CSCs, and expression of NANOG is correlated with aggressiveness of poorly differentiated breast cancer. We initially confirmed that breast cancer MCF-7 cells expressed NANOG, and overexpression of NANOG enhanced the tumorigenicity of MCF-7 cells and promoted the self-renewal expansion of CD24(-/low)CD44(+) CSC subpopulation. In contrast, knockdown of NANOG significantly affected the growth of breast CSCs. Utilizing flow cytometry, we identified five cyclohexylmethyl flavonoids that can inhibit propagation of NANOG-positive cells in both breast cancer MCF-7 and MDA-MB231 cells. Among these flavonoids, ugonins J and K were found to be able to induce apoptosis in non-CSC populations and to reduce self-renewal growth of CD24(-/low)CD44(+) CSC population. Treatment with ugonin J significantly reduced the tumorigenicity of MCF-7 cells and efficiently suppressed formation of mammospheres. This suppression was possibly due to p53 activation and NANOG reduction as either addition of p53 inhibitor or overexpression of NANOG can counteract the suppressive effect of ugonin J. We therefore conclude that cyclohexylmethyl flavonoids can possibly be utilized to suppress the propagation of breast CSCs via reduction of NANOG.
| S-EPMC3638599 | biostudies-literature
Project description:T cell infiltration into tumors is essential for successful immunotherapy against solid tumors. Herein, we found that the expression of hyaluronic acid synthases (HAS) was negatively correlated with patient survival in multiple types of solid tumors including gastric cancer. HA impeded in vitro anti-tumor activities of anti-mesothelin (MSLN) chimeric antigen receptor T cells (CAR-T cells) against gastric cancer cells by restricting CAR-T cell mobility in vitro. We then constructed a secreted form of the human hyaluronidase PH20 (termed sPH20-IgG2) by replacing the PH20 signal peptide with a tPA signal peptide and attached with IgG2 Fc fragments. We found that overexpression of sPH20-IgG2 promoted CAR-T cell transmigration through an HA-containing matrix but did not affect the cytotoxicity or cytokine secretion of the CAR-T cells. In BGC823 and MKN28 gastric cancer cell xenografts, sPH20-IgG2 promoted anti-mesothelin CAR-T cell infiltration into tumors. Furthermore, mice infused with sPH20-IgG2 overexpressing anti-MSLN CAR-T cells had smaller tumors than mice injected with anti-MSLN CAR-T cells. Thus, we demonstrated that sPH20-IgG2 can enhance the antitumor activity of CAR-T cells against solid tumors by promoting CAR-T cell infiltration.
| S-EPMC8313856 | biostudies-literature