ELK3 Controls Gastric Cancer Cell Migration and Invasion by Regulating ECM Remodeling-Related Genes

Lee, Min Wook; Cho, Hyeon-Ju; Park, Kyung-Soon; Jung, Hae-Yun

doi:10.3390/ijms23073709

Cited by 22 publications

(14 citation statements)

References 39 publications

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“…Yy1 is known to contribute to tumorigenesis, while Xbp1 supports MM cell growth and osteoclast formation 32,33 . On the other hand, Elk3 regulon was found to be active only in MSC from MM, suggesting a more invasive role as described in other cancers 34 ( Figure S9C ). Overall, our results suggest that MSC undergo a transcriptional shift at the stage of MGUS that persists throughout the course of the disease.…”

Section: Resultssupporting

confidence: 59%

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Cenzano,

Cócera,

Bantan

et al. 2024

Preprint

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Despite therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. To characterize the role that deregulation of the Bone Marrow (BM) microenvironment may have in the transition from healthy to Monoclonal Gammopathy of Undetermined Significance (MGUS), and from MGUS to MM, we performed single-cell RNA sequencing (scRNA-seq) of mesenchymal stromal cells (MSC) and endothelial cells (EC) from two mouse models, BIcgamma and MIcgamma, that recapitulate the principal clinical, genetic, and immunological characteristics of MGUS and MM patients. Our results identify distinct transcriptional dynamics between MSC and EC. While EC acquires a stress state during MGUS, a proliferating and angiogenic profile characterizes MM. On the other hand, MSC compromised their differentiation potential, exhibiting a more inflammatory profile that initiates from the MGUS stage. Interestingly, we identified interferon (IFN)-related myeloma signature in malignant EC of the BIcgamma model, which is also expressed in MSC but not observed in the most aggressive MIcgamma model and can be identified in a subgroup of MM patients. The analysis of the MSC and EC interactions with PC revealed stage-specific interactions of relevance for angiogenesis, immunomodulation, and MM extravasation. Finally, the translational relevance of our results in humans was confirmed on MSC from newly diagnosed patients at different stages of the disease. In summary, these results indicate a remodeling of the non-hematopoietic BM microenvironment in myeloma progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies.

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Section: Resultssupporting

confidence: 59%

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Cenzano,

Cócera,

Bantan

et al. 2024

Preprint

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“…COL1A1 ( 51 ) and COL3A1 ( 52 ) are structural proteins that surround the surrounding non-fibrous components that form the ECM skeleton. DCN ( 53 ), which is a polysaccharide-protein of the ECM, binds to cell surface receptors and mediates cancer suppression. FN1 ( 54 ) enhances the adhesion between tumor cells and the anchoring between tumor cells, the matrix, and the basement membrane without shedding and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Integrated pan-cancer analysis and experimental verification of the roles of tropomyosin 4 in gastric cancer

Guo

Zhao

et al. 2023

Front. Immunol.

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ObjectiveTo investigate the function of tropomyosin 4 (TPM4) using pan-cancer data, especially in gastric cancer (GC), using comprehensive bioinformatics analysis and molecular experiments.MethodsWe used UCSC Xena, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), TIMER2.0, GEPIA, cBioPortal, Xiantao tool, and UALCAN websites and databases for the extraction of pan-cancer data on TPM4. TPM4 expression was investigated with respect to prognosis, genetic alterations, epigenetic alterations, and immune infiltration. RNA22, miRWalk, miRDB, Starbase 2.0, and Cytoscape were used for identifying and constructing the regulatory networks of lncRNAs, miRNAs, and TPM4 in GC. Data from GSCALite, drug bank databases, and Connectivity Map (CMap) were used to analyze the sensitivity of drugs dependent on TPM4 expression. Gene Ontology (GO), enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG), wound healing assays, and (Matrigel) transwell experiments were used to investigate the biological functions of TPM4 in GC.ResultThe findings of the comprehensive pan-cancer analysis revealed that TPM4 has a certain diagnostic and prognosis value in most cancers. Alterations in the expression of TPM4, including duplications and deep mutations, and epigenetic alterations revealed that TPM4 expression is related to the expression of DNA methylation inhibitors and RNA methylation regulators at high concentrations. Besides, TPM4 expression was found to correlate with immune cell infiltration, immune checkpoint (ICP) gene expression, the tumor mutational burden (TMB), and microsatellite instability (MSI). Neoantigens (NEO) were also found to influence its response to immunotherapy. A lncRNA-miRNA -TPM4 network was found to regulate GC development and progression. TPM4 expression was related to docetaxel,5-fluorouracil, and eight small molecular targeted drugs sensitivity. Gene function enrichment analyses revealed that genes that were co-expressed with TPM4 were enriched within the extracellular matrix (ECM)-related pathways. Wound-healing and (Matrigel) transwell assays revealed that TPM4 promotes cell migration and invasion. TPM4, as an oncogene, plays a biological role, perhaps via ECM remodeling in GC.ConclusionsTPM4 is a prospective marker for the diagnosis, treatment outcome, immunology, chemotherapy, and small molecular drugs targeted for pan-cancer treatment, including GC treatment. The lncRNA-miRNA-TPM4network regulates the mechanism underlying GC progression. TPM4 may facilitate the invasion and migration of GC cells, possibly through ECM remodeling.

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“…ELK3 transcriptionally regulates cell migration-related genes in various cancer types including breast cancer. 25 , 28 , 29 , 52 , In addition, ELK3 controls immune response-related genes including chemokines to modulate the immune response. 32 , Combined with the role of CXCL16 in the response to NK92MI and primary NK cells, ELK3 might play a pleiotropic role in regulating multiple genes involved in different biological processes, including cancer progression and immune responses.…”

Section: Discussionmentioning

confidence: 99%

“… 23–27 ELK3 contributes to cancer metastasis by regulating cell migration-related genes. 28 , 29 ELK3 is involved in chemokine regulation that VEGF mediates lymphatic endothelial cell migration in lymphangiogenesis and also regulates macrophage recruitment in the immune response. 30–33 However, the role of ELK3 in anticancer immune responses is still not clear.…”

Section: Introductionmentioning

confidence: 99%

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer

Lee

Choi

et al. 2023

OncoImmunology

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Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) recruits immune cells including natural killer (NK) cells into tumors via the chemotactic activity of chemokine. ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Our findings demonstrate that the ELK3-CXCL16 axis modulates NK cell recruitment to increase NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.

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ELK3 Controls Gastric Cancer Cell Migration and Invasion by Regulating ECM Remodeling-Related Genes

Cited by 22 publications

References 39 publications

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Integrated pan-cancer analysis and experimental verification of the roles of tropomyosin 4 in gastric cancer

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer

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