Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Korea.
Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea.
Mol Cells. 2021 Nov 30;44(11):784-794. doi: 10.14348/molcells.2021.0130.
Leiomyosarcoma (LMS) is a mesenchymal malignancy with a complex karyotype. Despite accumulated evidence, the factors contributing to the development of LMS are unclear. Here, we investigated the role of tight-junction protein 1 (TJP1), a membrane-associated intercellular barrier protein during the development of LMS and the tumor microenvironment. We orthotopically transplanted SK-LMS-1 cells and their derivatives in terms of TJP1 expression by intramuscular injection, such as SK-LMS-1 Sh-Control cells and SK-LMS-1 Sh-TJP1. We observed robust tumor growth in mice transplanted with LMS cell lines expressing TJP1 while no tumor mass was found in mice transplanted with SK-LMS-1 Sh-TJP1 cells with silenced TJP1 expression. Tissues from mice were stained and further analyzed to clarify the effects of TJP1 expression on tumor development and the tumor microenvironment. To identify the TJP1-dependent factors important in the development of LMS, genes with altered expression were selected in SK-LMS-1 cells such as cyclinD1, CSF1 and so on. The top 10% of highly expressed genes in LMS tissues were obtained from public databases. Further analysis revealed two clusters related to cell proliferation and the tumor microenvironment. Furthermore, integrated analyses of the gene expression networks revealed correlations among TJP1, CSF1 and CTLA4 at the mRNA level, suggesting a possible role for TJP1 in the immune environment. Taken together, these results imply that TJP1 contributes to the development of sarcoma by proliferation through modulating cell-cell aggregation and communication through cytokines in the tumor microenvironment and might be a beneficial therapeutic target.
平滑肌肉瘤（LMS）是一种具有复杂核型的间充质恶性肿瘤。尽管有大量证据，但导致 LMS 发展的因素仍不清楚。在这里，我们研究了紧密连接蛋白 1（TJP1）在 LMS 发展和肿瘤微环境中的作用。我们通过肌肉内注射，将 TJP1 表达不同的 SK-LMS-1 细胞及其衍生物进行了原位移植，例如 SK-LMS-1 Sh-Control 细胞和 SK-LMS-1 Sh-TJP1 细胞。我们观察到表达 TJP1 的 LMS 细胞系移植的小鼠中出现了强大的肿瘤生长，而在沉默 TJP1 表达的 SK-LMS-1 Sh-TJP1 细胞移植的小鼠中则没有发现肿瘤块。对小鼠组织进行染色并进一步分析，以阐明 TJP1 表达对肿瘤发展和肿瘤微环境的影响。为了确定 TJP1 表达对 LMS 发展重要的依赖因子，我们选择了在 SK-LMS-1 细胞中表达发生改变的基因，如 cyclinD1、CSF1 等。从公共数据库中获得了 LMS 组织中高表达基因的前 10%。进一步分析揭示了与细胞增殖和肿瘤微环境相关的两个聚类。此外，基因表达网络的综合分析表明 TJP1、CSF1 和 CTLA4 在 mRNA 水平上存在相关性，提示 TJP1 在免疫环境中可能发挥作用。综上所述，这些结果表明，TJP1 通过调节细胞-细胞聚集和细胞间通讯来促进肉瘤的发展，这可能是一个有益的治疗靶点。
