Authors' Affiliations: Institute of Molecular and Genomic Medicine, Division of Environmental Health and Occupational Medicine, National Health Research Institute, Miaoli; Department of Life Sciences, National Central University, Jhongli; Environment-Omics-Disease Research Center, China Medical University Hospital, Taichung; Departments of Medical Biotechnology, Chang Gung University; Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital; Head and Neck Oncology Group, Chang Gung Memorial Hospital, Taoyuan; Department of Oral and Maxillofacial Section, Chi-Mei Medical Center, Liouying; and Department of Oral Hygiene, Kaohsiung Medical University, Kaohsiung, Taiwan.
Cancer Res. 2014 Feb 1;74(3):751-64. doi: 10.1158/0008-5472.CAN-13-1297. Epub 2013 Dec 12.
MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein-coupled receptor kinase-interacting protein 1 (GIT1)-as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer.
微小 RNA 提供了识别和治疗侵袭性癌症的工具。我们使用高度侵袭性的同源口腔鳞状细胞癌 (OSCC) 细胞，这些细胞是通过体外和体内选择从侵袭性低的亲本细胞群建立的，使用微阵列表达分析来鉴定侵袭性细胞中 miR-491-5p 的相对和特异性降低。miR-491-5p 表达降低与 OSCC 患者的总体生存率差相关。在侵袭性 OSCC 细胞中过表达 miR-491-5p 可抑制其体外迁移行为和体内肺转移行为。我们将 G 蛋白偶联受体激酶相互作用蛋白 1 (GIT1)-定义为 miR-491-5p 调控的直接靶基因。GIT1 过表达足以挽救 miR-491-5p 介导的迁移/侵袭和肺转移抑制。相反，GIT1 沉默模拟了 miR-491-5p 抑制 OSCC 细胞迁移/侵袭和转移的能力。机制研究表明，miR-491-5p 过表达或 GIT1 衰减减少了焦点黏附，同时降低了静止状态下的桩蛋白、磷酸化桩蛋白、磷酸化 FAK、EGF/EGFR 介导的细胞外信号调节激酶 (ERK1/2) 激活以及 MMP2/9 水平和活性。在 OSCC 的临床标本中，GIT1 水平相对于配对的正常组织升高，与淋巴结转移相关，miR-491-5p 和 GIT1 的表达水平在 OSCC 中呈负相关，并且与肿瘤分级相关。综上所述，我们的研究结果确定了 OSCC 侵袭的功能轴，提示 miR-491-5p 和 GIT1 可作为该癌症预后的生物标志物。
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