LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival
LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival
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LACTB 通过激活 ERBB3/EGFR-ERK 信号传导促进鼻咽癌转移，导致患者生存不利
DOI：
10.1016/j.canlet.2020.10.051
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发表时间：
2021-02-01
期刊：
影响因子：
9.7
通讯作者：
Qian, Chao-Nan
中科院分区：
文献类型：
--
作者：
Peng, Li-Xia;Wang, Ming-Dian;Qian, Chao-Nan
鼻咽癌（Nasopharyngeal carcinoma，NPC）起源于鼻咽上皮，是头颈部肿瘤中转移率最高的肿瘤。远处转移是治疗失败的主要原因，其机制尚不清楚。通过比较鼻咽癌组织和非癌鼻咽组织的表达谱，我们发现LACTB在肿瘤组织中高表达。我们发现LACTB蛋白在原发性NPC中的表达升高与患者生存率降低相关。LACTB是一种丝氨酸蛋白酶，是一种普遍存在于膜间隙的线粒体蛋白。它在肿瘤生物学中的作用仍然存在争议。我们发现LACTB启动子的不同甲基化模式导致其在鼻咽癌细胞中的差异表达。过表达LACTB可促进鼻咽癌细胞的体外运动和体内转移。而敲低LACTB则降低了NPC细胞的转移能力。然而，LACTB不影响细胞增殖。我们进一步发现LACTB促进NPC转移的作用依赖于ERBB 3/EGFR-ERK信号通路的激活，ERBB 3/EGFR-ERK信号通路反过来影响组蛋白H3的稳定性和随后的乙酰化。这些结果对揭示鼻咽癌转移的机制有一定的意义。
Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.