ABSTRACT
Tight junction protein 1 (TJP1) is a membrane-associated cytosolic protein important for cell-cell communication in intercellular barriers in epithelial and non-epithelial cells. Here, we explored the functional involvement of TJP1 in non-epithelial tumors such as soft tissue sarcoma, especially in leiomyosarcoma (LMS). TJP1 expression in soft tissue sarcoma was analyzed in normal and tumor tissues as well as from public datasets such as the TCGA provisional dataset, in which TJP1 expression was compared with other subtypes such as undifferentiated sarcomas, and myxofibrosarcomas. SK-LMS-1 cell lines with reduced TJP1 expression showed attenuated anchorage-independent colony formation as well as reduced intercellular aggregation on non-coated culture plates compared with control as well as parental SK-LMS-1 cells. Transcriptome profiling following TJP1 knockdown in SK-LMS-1 cells suggested the involvement of several signaling pathways, including NF-κB pathway and growth factor receptor signaling. In addition, TJP1 downregulation induced enhanced response against anti-cancer agents, doxorubicin and gefitinib. Taken together, these results suggest that TJP1 contributes to sarcoma genesis and might be useful therapeutic target. KEY MESSAGES: ⢠TJP1 expression at RNA level higher in tumor than in normal tissues of sarcoma. ⢠Targeting TJP1 attenuates cell-cell aggregation and anchorage-independent growth. ⢠Targeting TJP1 is beneficial in anti-cancer therapy in LMS.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cell Communication/drug effects , Cell Communication/genetics , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Leiomyosarcoma/genetics , Zonula Occludens-1 Protein/genetics , CRISPR-Cas Systems , Cell Line, Tumor , Cell Proliferation , Gene Editing , Gene Expression Profiling , Gene Silencing , Humans , Janus Kinases/metabolism , Leiomyosarcoma/drug therapy , Leiomyosarcoma/metabolism , Leiomyosarcoma/pathology , NF-kappa B/metabolism , RNA, Small Interfering/genetics , STAT Transcription Factors/metabolism , Signal Transduction , Transcriptome , Zonula Occludens-1 Protein/antagonists & inhibitorsABSTRACT
BACKGROUND: Several studies have investigated the molecular drivers and therapeutic targets in adult soft tissue sarcomas. However, such studies are limited by the genomic heterogeneity and rarity of sarcomas, particularly in those with complex and unbalanced karyotypes. Additional biomarkers are needed across sarcoma types to improve therapeutic strategies. To investigate the molecular characteristics of complex karyotype sarcomas (CKSs) for therapeutic targets, we performed genomic profiling. RESULTS: The mutational landscape showed that TP53, ATRX, and PTEN genes were highly mutated. CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures. Integrated analysis of genomic and transcriptomic data revealed several pathways related to PDGFR, which could be a strategic target for anti-sarcoma therapy. CONCLUSIONS: This study provides a detailed molecular classification of CKSs and proposes several therapeutic targets. Targeted or combinational therapies for treating CKS should be considered before chemotherapy.
