Receptor tyrosine kinase, RON, promotes tumor progression by regulating EMT and the MAPK signaling pathway in human oral squamous cell carcinoma
Receptor tyrosine kinase, RON, promotes tumor progression by regulating EMT and the MAPK signaling pathway in human oral squamous cell carcinoma
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DOI：
10.3892/ijo.2019.4836
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发表时间：
2019-08-01
影响因子：
5.2
通讯作者：
Yoon, Tae Mi
中科院分区：
文献类型：
--
作者：
Kim, Sun-Ae;Lee, Kyung-Hwa;Yoon, Tae Mi
已知受体酪氨酸激酶，受体D 'origine nantais（罗恩）与各种类型癌症的进展、转移和预后相关。然而，罗恩在人类口腔鳞状细胞癌（OSCC）中的作用尚不清楚。本研究评价了罗恩是否影响人口腔鳞癌的致癌行为、致癌信号通路和临床结局，包括生存率。采用逆转录聚合酶链反应（RT-PCR）、定量聚合酶链反应（PCR）、免疫组化和Western blotting检测罗恩mRNA和蛋白表达水平。使用细胞侵袭、迁移和凋亡测定来评估小干扰RNA介导的罗恩或snail家族转录阻遏物2（SLUG）敲低的功能效应。罗恩敲低抑制肿瘤细胞的侵袭和迁移，并增强人OSCC细胞的凋亡。罗恩敲低还降低MAPK信号蛋白如ERK 1/2、JNK和p38的磷酸化。此外，罗恩敲低抑制了上皮间质转化（EMT）相关转录因子SLUG的表达。SLUG基因敲低可阻断巨噬细胞刺激蛋白（MSP）介导的罗恩激活对OSCC细胞侵袭和迁移的增强作用。在MSP介导的罗恩激活作用下，OSCC细胞形态改变为梭形。罗恩在新鲜和石蜡包埋的人口腔鳞癌组织中均过表达。综上所述，这些结果表明，罗恩通过调节EMT相关因子SLUG和MAPK通路在OSCC中促进肿瘤进展。本研究为RON靶向药物在口腔鳞癌治疗中的应用提供了理论依据。
The receptor tyrosine kinase, recepteur d'origine nantais (RON), is known to be associated with the progression, metastasis, and prognosis of various types of cancers. Nevertheless, the role of RON in human oral squamous cell carcinoma (OSCC) is unclear. This study evaluated whether RON affects oncogenic behavior, oncogenic signaling pathways, and clinical outcomes, including survival, in human OSCC. Reverse transcription-PCR, quantitative PCR, western blotting and immunohistochemical staining were used to determine mRNA and protein expression levels of RON. Cell invasion, migration and apoptosis assays were used to assess the functional effects of small interfering RNA-mediated knockdown of RON or snail family transcriptional repressor 2 (SLUG). RON knockdown suppressed tumor cell invasion and migration and enhanced apoptosis in human OSCC cells. RON knockdown also decreased the phosphorylation of MAPK signaling proteins, such as ERK1/2, JNK and p38. In addition, RON knockdown suppressed the expression of the epithelial mesenchymal transition (EMT)-related transcription factor, SLUG. SLUG knockdown blocked the enhancement of cell invasion and migration induced by macrophage-stimulation protein (MSP)-mediated RON activation in OSCC cells. The cell morphology was changed to spindle-like shape under MSP-mediated RON activation in OSCC cells. RON was overexpressed in both fresh and paraffin-embedded human OSCC tissues. Taken together, these results indicate that RON contributed to tumor progression by regulating the EMT-related factor, SLUG, and the MAPK pathway in OSCC. This study may provide a theoretical basis for the application of RON-targeting agents, currently being studied in various cancer fields, for the treatment of OSCC.