吸烟导致的miR-30a/BiP轴失调会加速口腔癌进展。
Dysregulation of the miR-30a/BiP axis by cigarette smoking accelerates oral cancer progression.
作者信息
Chien Chu-Yen, Chen Ying-Chen, Lee Chien-Hsing, Wu Jia-Rong, Huang Tsai-Wang, Huang Ren-Yeong, Cheng Wan-Chien, Hsieh Alexander Cheng-Ting, Shieh Yi-Shing
机构信息
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City, Taiwan.
Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei City, Taiwan.
出版信息
Cancer Cell Int. 2021 Oct 30;21(1):578. doi: 10.1186/s12935-021-02276-1.
BACKGROUND
Cigarette smoking is the most significant cause of oral cancer progression. Cigarette smoke condensate (CSC) has been shown to induce endoplasmic reticulum (ER) stress. Binding immunoglobulin protein (BiP) being as an ER stress regulator, has been reported to be implicated in malignant behaviors. Therefore, the aim of this study was to investigate the role of the ER stress-responsive protein, BiP, in CSC-induced oral squamous cell carcinoma (OSCC) malignancy.
METHODS
The biological role of BiP in CSC-induced tumor progression was investigated in OSCC cells (YD38 and SCC25) and in a tumor xenograft mouse model. The expressions of related genes were investigated using quantitative RT-PCR and Western blot analysis. Cell migration and invasion were assessed using scratch wound healing and Transwell invasion assays. The effects of conditioned media from OSCC cells on the angiogenic activities of endothelial cells were analyzed using a tube formation assay. The interaction between miR-30a and BiP mRNA was detected using a luciferase reporter assay.
RESULTS
Our results demonstrated that CSC increased the expression of BiP in time- and dose-dependent manners in YD38 and SCC25 cells, and that silencing BiP abrogated CSC-induced cell invasion and tumor-associated angiogenesis. Notably, the putative miR-30a binding site was observed in the 3'untranslated region (UTR) of BiP mRNA, and miR-30a suppressed BiP expression by targeting 3'UTR of BiP transcript. In addition, CSC increased the expression of BiP in OSCC cells by downregulating miR-30a. We also showed that BiP promoted invasion and tumor-associated angiogenesis by increasing the production and secretion of vascular endothelial growth factor in CSC-exposed OSCC cells. Moreover, BiP inhibition suppressed OSCC growth and reduced tumor vessel density in tumor-bearing mice administered with CSC.
CONCLUSIONS
These observations suggest that epigenetic regulation of BiP via miR-30a downregulation is involved in CSC-induced OSCC progression.
背景
吸烟是口腔癌进展的最重要原因。香烟烟雾冷凝物（CSC）已被证明可诱导内质网（ER）应激。结合免疫球蛋白蛋白（BiP）作为一种内质网应激调节因子，据报道与恶性行为有关。因此，本研究的目的是探讨内质网应激反应蛋白BiP在CSC诱导的口腔鳞状细胞癌（OSCC）恶性进展中的作用。
方法
在OSCC细胞（YD38和SCC25）和肿瘤异种移植小鼠模型中研究BiP在CSC诱导的肿瘤进展中的生物学作用。使用定量RT-PCR和蛋白质印迹分析研究相关基因的表达。使用划痕伤口愈合和Transwell侵袭试验评估细胞迁移和侵袭。使用管形成试验分析OSCC细胞条件培养基对内皮细胞血管生成活性的影响。使用荧光素酶报告基因试验检测miR-30a与BiP mRNA之间的相互作用。
结果
我们的结果表明，CSC以时间和剂量依赖性方式增加YD38和SCC25细胞中BiP的表达，并且沉默BiP可消除CSC诱导的细胞侵袭和肿瘤相关血管生成。值得注意的是，在BiP mRNA的3'非翻译区（UTR）中观察到推定的miR-30a结合位点，并且miR-30a通过靶向BiP转录物的3'UTR抑制BiP表达。此外，CSC通过下调miR-30a增加OSCC细胞中BiP的表达。我们还表明，BiP通过增加暴露于CSC的OSCC细胞中血管内皮生长因子的产生和分泌来促进侵袭和肿瘤相关血管生成。此外，BiP抑制可抑制OSCC生长并降低给予CSC的荷瘤小鼠的肿瘤血管密度。
结论
这些观察结果表明，通过miR-30a下调对BiP进行表观遗传调控参与了CSC诱导的OSCC进展。
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