The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice.
The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice.
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DOI：
10.3390/ijms24119407
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发表时间：
2023-05-28
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
口腔癌主要是鳞状细胞癌，5年生存率约为50%。赖氨酰氧化酶（LOX）参与胶原和弹性蛋白的成熟。LOX的前肽在细胞外环境中由前胶原C蛋白酶释放为18 kDa蛋白质（LOX-PP），并具有肿瘤抑制特性。LOX前肽区的多态性（rs 1800449，G473 A）导致Gln对Arg的单个氨基酸取代。在这里，我们调查的频率rs 1800449在口腔鳞状细胞癌采用TCGA数据库资源，并确定了动力学和严重程度的癌前病变的发展，在野生型和相应的基因敲入小鼠暴露于4-硝基喹啉氧化物（4 NQO）的饮用水。数据显示，与野生型相比，OSCC在携带该变体的人类中更常见。敲入小鼠更易发生病变。LOX在小鼠组织中的免疫组织化学和体外研究指出野生型LOX-PP对LOX表达的负反馈途径在敲入小鼠中是缺乏的。数据进一步证明了敲入小鼠中T细胞表型向更允许肿瘤的条件的调节。数据提供了rs 1800449作为口腔癌易感性生物标志物的初步证据，并指出了更好地理解LOX-PP癌症抑制活性的功能机制的机会。
Oral cancer is primarily squamous-cell carcinoma with a 5-year survival rate of approximately 50%. Lysyl oxidase (LOX) participates in collagen and elastin maturation. The propeptide of LOX is released as an 18 kDa protein (LOX-PP) in the extracellular environment by procollagen C-proteinases and has tumor-inhibitory properties. A polymorphism in the propeptide region of LOX (rs1800449, G473A) results in a single amino acid substitution of Gln for Arg. Here we investigated the frequency of rs1800449 in OSCC employing TCGA database resources and determined the kinetics and severity of precancerous oral lesion development in wildtype and corresponding knockin mice after exposure to 4-nitroquinoline oxide (4 NQO) in drinking water. Data show that the OSCC is more common in humans carrying the variant compared to the wildtype. Knockin mice are more susceptible to lesion development. The immunohistochemistry of LOX in mouse tissues and in vitro studies point to a negative feedback pathway of wildtype LOX-PP on LOX expression that is deficient in knockin mice. Data further demonstrate modulations of T cell phenotype in knockin mice toward a more tumor-permissive condition. Data provide initial evidence for rs1800449 as an oral cancer susceptibility biomarker and point to opportunities to better understand the functional mechanism of LOX-PP cancer inhibitory activity.
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影响因子：
3.6
作者：
Vigneswaran, Nadarajah;Wu, Jean;Song, Anren;Annapragada, Ananth;Zacharias, Wolfgang
通讯作者：
Zacharias, Wolfgang
影响因子：
3.7
作者：
Bais MV;Nugent MA;Stephens DN;Sume SS;Kirsch KH;Sonenshein GE;Trackman PC
通讯作者：
Trackman PC
影响因子：
4
作者：
Min, Chengyin;Zhao, Yingshe;Romagnoli, Mathilde;Trackman, Philip C.;Sonenshein, Gail E.;Kirsch, Kathrin H.
通讯作者：
Kirsch, Kathrin H.
影响因子：
6.4
作者：
Albinger-Hegyi, Andrea;Stoeckli, Sandro J.;Hegyi, Ivan
通讯作者：
Hegyi, Ivan
影响因子：
3.1
作者：
Ren, Jinghua;Wu, Xiaoling;Huang, Tao
通讯作者：
Huang, Tao