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Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

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dc.contributor.authorLee, D-
dc.contributor.authorHam, IH-
dc.contributor.authorOh, HJ-
dc.contributor.authorLee, DM-
dc.contributor.authorYoon, JH-
dc.contributor.authorSon, SY-
dc.contributor.authorKim, TM-
dc.contributor.authorKim, JY-
dc.contributor.authorHan, SU-
dc.contributor.authorHur, H-
dc.date.accessioned2024-03-14T04:52:39Z-
dc.date.available2024-03-14T04:52:39Z-
dc.date.issued2024-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/32355-
dc.description.abstractBackground: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. Methods: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). Results: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. Conclusions: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.-
dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHCancer-Associated Fibroblasts-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Movement-
dc.subject.MESHFibroblasts-
dc.subject.MESHHumans-
dc.subject.MESHIntegrin beta1-
dc.subject.MESHNephritis, Interstitial-
dc.subject.MESHRNA, Small Interfering-
dc.subject.MESHStomach Neoplasms-
dc.subject.MESHTumor Microenvironment-
dc.titleTubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1-
dc.typeArticle-
dc.identifier.pmid38355577-
dc.identifier.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10868052-
dc.subject.keywordCancer-associated fibroblasts-
dc.subject.keywordDiffuse-type gastric cancer-
dc.subject.keywordIntegrin beta 1-
dc.subject.keywordTubulointerstitial nephritis antigen-like 1-
dc.subject.keywordTumor microenvironment-
dc.contributor.affiliatedAuthorHam, IH-
dc.contributor.affiliatedAuthorSon, SY-
dc.contributor.affiliatedAuthorHan, SU-
dc.contributor.affiliatedAuthorHur, H-
dc.type.localJournal Papers-
dc.identifier.doi10.1186/s12967-024-04963-9-
dc.citation.titleJournal of translational medicine-
dc.citation.volume22-
dc.citation.number1-
dc.citation.date2024-
dc.citation.startPage154-
dc.citation.endPage154-
dc.identifier.bibliographicCitationJournal of translational medicine, 22(1). : 154-154, 2024-
dc.identifier.eissn1479-5876-
dc.relation.journalidJ014795876-
Appears in Collections:
Journal Papers > Research Organization > Inflamm-aging Translational Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
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