Laboratory of Molecular Oncology, Translational Cancer Biology Program, Department of Oncology, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
J Cell Mol Med. 2018 Apr;22(4):2220-2230. doi: 10.1111/jcmm.13502. Epub 2018 Jan 29.
The molecular mechanisms for the dissemination and metastasis of gastrointestinal stromal tumours (GIST) are incompletely understood. The purpose of the study was to investigate the clinical relevance of integrin alpha 4 (ITGA4) expression in GIST. GIST transcriptomes were first compared with transcriptomes of other types of cancer and histologically normal gastrointestinal tract tissue in the MediSapiens in silico database. ITGA4 was identified as an unusually highly expressed gene in GIST. Therefore, the effects of ITGA4 knock-down and selective integrin alpha 4 beta 1 (VLA-4) inhibitors on tumour cell proliferation and invasion were investigated in three GIST cell lines. In addition, the prognostic role of ITGA4 expression in cancer cells was investigated in a series of 147 GIST patients with immunohistochemistry. Inhibition of ITGA4-related signalling decreased GIST cell invasion in all investigated GIST cell lines. ITGA4 protein was expressed in 62 (42.2%) of the 147 GISTs examined, and expression was significantly associated with distant metastases during the course of the disease and several adverse prognostic features. Patients whose GIST expressed strongly ITGA4 had unfavourable GIST-specific survival and overall survival compared to patients with low or no ITGA4 expression. Taken together, ITGA4 is an important integrin in the molecular pathogenesis of GIST and may influence their clinical behaviour.
胃肠道间质瘤（GIST）的传播和转移的分子机制尚不完全清楚。本研究旨在探讨整合素 alpha 4（ITGA4）在 GIST 中的表达与临床的相关性。首先在 MediSapiens 数据库中比较了 GIST 的转录组与其他类型癌症和组织学正常胃肠道组织的转录组。发现 ITGA4 在 GIST 中异常高表达。因此，在三种 GIST 细胞系中研究了 ITGA4 敲低和选择性整合素 alpha 4 beta 1（VLA-4）抑制剂对肿瘤细胞增殖和侵袭的影响。此外，还通过免疫组织化学方法在 147 例 GIST 患者中研究了 ITGA4 表达在癌细胞中的预后作用。抑制与 ITGA4 相关的信号通路可降低所有研究的 GIST 细胞系的侵袭。在检查的 147 例 GIST 中，有 62 例（42.2%）表达 ITGA4 蛋白，表达与疾病过程中的远处转移和几个不良预后特征显著相关。与低表达或不表达 ITGA4 的患者相比，ITGA4 表达较强的 GIST 患者的 GIST 特异性生存和总生存较差。综上所述，ITGA4 是 GIST 分子发病机制中的一个重要整合素，可能影响其临床行为。
