Role of Glycated High Mobility Group Box-1 in Gastric Cancer.
Role of Glycated High Mobility Group Box-1 in Gastric Cancer.
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DOI：
10.3390/ijms22105185
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发表时间：
2021-05-13
影响因子：
5.6
通讯作者：
Kuniyasu H
中科院分区：
文献类型：
--
作者：
Kishi S;Nishiguchi Y;Honoki K;Mori S;Fujiwara-Tani R;Sasaki T;Fujii K;Kawahara I;Goto K;Nakashima C;Kido A;Tanaka Y;Luo Y;Kuniyasu H
糖基化终末产物（AGEs）是在高葡萄糖环境和氧化应激反应中产生的，并加剧各种疾病。Nε-（羧甲基）赖氨酸（CML）是由蛋白质的赖氨酸残基糖基化产生的AGE。有一些关于CML修饰导致蛋白质功能改变的报道;然而，其与癌症的关系尚不清楚。我们研究了CML高迁移率族蛋白1（HMGB 1）修饰的意义，HMGB 1是一种与癌症进展显著相关的细胞因子。与未处理的细胞相比，用乙二醛或葡萄糖处理胃癌细胞系TMK 1和MKN 74导致CML修饰增加。CML-HMGB 1通过氧化修饰，与原始HMGB 1和氧化HMGB 1相比，CML-HMGB 1更明显地激活AGE受体和下游AKT和NF-κB。CML-HMGB 1与DNA和组蛋白H3的结合亲和力降低，导致细胞核转位和细胞外分泌增强。与HMGB 1相比，CML-HMGB 1处理胃癌细胞可增强细胞增殖和侵袭，球体形成，并保护细胞免受毒胡萝卜素诱导的凋亡，并降低5-FU敏感性。此外，CML-HMGB 1在所有10个胃癌肿瘤标本中均以不同水平检测到。HMGB 1水平与原发肿瘤进展和远处转移相关，而CML-HMGB 1水平与原发肿瘤进展、淋巴结转移、远处转移和分期相关。此外，CML-HMGB 1水平与癌组织中的氧化应激和对新辅助治疗的抵抗相关。因此，CML对HMGB 1的修饰增强了HMGB 1的促癌作用。在这项研究中，CML-HMGB 1已被强调为一个新的治疗靶点，并希望在未来的CML-HMGB 1的分子结构分析。
Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. Nε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.
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影响因子：
7.3
作者：
Menini, Stefano;Iacobini, Carla;Pugliese, Giuseppe
通讯作者：
Pugliese, Giuseppe
影响因子：
5
作者：
Ohmori, Hitoshi;Luo, Yi;Kuniyasu, Hiroki
通讯作者：
Kuniyasu, Hiroki
影响因子：
7.4
作者：
通讯作者：
--
影响因子：
5.6
作者：
International Journal of Molecular Sciences Editorial Office
通讯作者：
International Journal of Molecular Sciences Editorial Office
影响因子：
5.6
作者：
Mori S;Kishi S;Honoki K;Fujiwara-Tani R;Moriguchi T;Sasaki T;Fujii K;Tsukamoto S;Fujii H;Kido A;Tanaka Y;Luo Y;Kuniyasu H
通讯作者：
Kuniyasu H