Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis.
Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis.
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BRAF/PA28γ/MEK1 信号轴的鉴定及其在口腔粘膜下纤维化上皮间质转化中的作用
DOI：
10.1038/s41419-022-05152-6
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发表时间：
2022-08-12
影响因子：
9
通讯作者：
Chen, Qianming
中科院分区：
文献类型：
--
作者：
Xie, Changqing;Li, Zaiye;Hua, Yufei;Sun, Silu;Zhong, Liang;Chen, Qian;Feng, Hui;Ji, Ning;Li, Taiwen;Zhou, Xikun;Zeng, Xin;Tang, Zhangui;Sun, Chongkui;Li, Jing;Chen, Qianming
口腔粘膜下纤维化 (OSF) 是一种慢性、隐匿的口腔潜在恶性疾病，与口腔鳞状细胞癌 (OSCC) 的风险相关 4-17%。我们之前的研究发现，蛋白酶体激活剂28γ（PA28γ）在口腔鳞状细胞癌中经常过度表达，并且与患者不良预后呈负相关。然而PA28γ在OSF发生发展中的作用尚不清楚。在这里，我们筛选了 PA28γ 相关基因并研究了它们在 OSF 中的功能。我们证明PA28γ的表达与MEK1呈正相关，并且从OSF组织的正常阶段到进展阶段逐渐升高。槟榔碱是 OSF 的致病成分，可以上调 PA28γ 和磷酸化 MEK1 的蛋白水平，并有助于上皮细胞的上皮间质转化 (EMT)。值得注意的是，PA28γ 可以与 MEK1 相互作用并上调其磷酸化水平。此外，槟榔碱上调 BRAF，而 BRAF 可以与 PA28γ 相互作用并上调其蛋白水平。此外，BRAF、PA28γ和MEK1可以形成蛋白质复合物，然后增强MEK1/ERK信号通路。 PA28γ蛋白稳定性的具体机制是BRAF通过抑制其泛素化来介导其降解。这些发现强调了 PA28γ 在 BRAF/MEK1 通路中的重要作用，并通过 OSF 中的 MEK1/ERK 激活增强 EMT。
Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4–17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.
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DOI：
10.1038/s41568-021-00365-x
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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