DMP-1 promoter-associated antisense strand non-coding RNA, panRNA-DMP-1, physically associates with EGFR to repress EGF-induced squamous cell carcinoma migration
DMP-1 promoter-associated antisense strand non-coding RNA, panRNA-DMP-1, physically associates with EGFR to repress EGF-induced squamous cell carcinoma migration
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DOI：
10.1007/s11010-020-04046-5
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发表时间：
2021-01-09
影响因子：
4.3
通讯作者：
Yamada, Satoru
中科院分区：
文献类型：
--
作者：
Suzuki, Shigeki;Yuan, Hang;Yamada, Satoru
越来越多的证据表明，特异性非编码RNA存在于多种恶性肿瘤组织中，并参与肿瘤的侵袭和转移。然而，关于非编码RNA在鳞状细胞癌（SQCC）侵袭和迁移中的确切作用知之甚少。最近，牙本质基质蛋白-1（dentinmatrixprotein-1，DNT-1）基因位点被鉴定为鳞状细胞癌（squamouscellcarcinoma，SQCC）组织和细胞中的转录活性位点。然而，目前还不清楚是否与细胞迁移相关的RNA存在于SQCC细胞中的EST-I基因位点。我们通过RACE方法在SQCC细胞和组织中鉴定了一种新的启动子相关非编码RNA（promoter-associated non-coding RNA，panRNA）-p53 -1，并对panRNA-p53 -1在EGF驱动的SQCC细胞迁移中的功能进行了研究。通过特异性siRNA抑制内源性panRNA-Ep-1表达和外源性panRNA-Ep-1过表达分别导致SQCC细胞中细胞向EGF迁移增加和抑制，并且panRNA-Ep-1的核表达由EGF刺激诱导。从机制上讲，抑制panRNA-Ep-1表达增加了EGF处理后EGFR的核定位，并且核panRNA-Ep-1与EGFR发生物理相互作用，这通过使用噬菌体递送的PP 7 RNA标记系统的RNA免疫沉淀测定得到证实。此外，免疫共沉淀分析显示，panRNA-STAT-1的抑制稳定了EGFR与STAT 3（EGFR的已知共转录因子）的相互作用，以诱导许多癌细胞中的迁移特性。基于这些发现，panRNA-STAT-1是一种EGFR相关RNA，可能通过调节EGFR核定位和EGFR与STAT 3的结合来抑制EGF诱导的SQCC迁移特性。
Accumulating evidence suggests that specific non-coding RNAs exist in many types of malignant tissues, and are involved in cancer invasion and metastasis. However, little is known about the precise roles of non-coding RNAs in squamous cell carcinoma (SQCC) invasion and migration. Recently, the dentin matrix protein-1 (DMP-1) gene locus was identified as a transcriptionally active site in squamous cell carcinoma (SQCC) tissue and cells. However, it is unclear whether RNA associated with cell migration exist at the DMP-1 gene locus in SQCC cells. We identified a novel promoter-associated non-coding RNA in the antisense strand of DMP-1 gene locus, promoter-associated non-coding RNA (panRNA)-DMP-1, by the RACE method in SQCC cells and tissues, and characterized the functions of panRNA-DMP-1 in EGF-driven SQCC cell migration. The inhibition of endogenous panRNA-DMP-1 expression by specific siRNAs and exogenous over-expression of panRNA-DMP-1 resulted in increased and suppressed cellular migration toward EGF in SQCC cells, respectively, and nuclear expression of panRNA-DMP-1 was induced by EGF stimulation. Mechanistically, suppression of panRNA-DMP-1 expression increased EGFR nuclear localization upon EGF treatment and nuclear panRNA-DMP-1 physically interacted with EGFR, which was confirmed by RNA immunoprecipitation assay using a bacteriophage-delivered PP7 RNA labeling system. Furthermore, co-immunoprecipitation assay revealed that suppression of panRNA-DMP-1 stabilized EGFR interaction with STAT3, a known co-transcription factors of EGFR, to induce migratory properties in many cancer cells. Based on these findings, panRNA-DMP-1 is an EGFR-associating RNA that inhibits the EGF-induced migratory properties of SQCC possibly by regulating EGFR nuclear localization and EGFR binding to STAT3.