Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice
Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice
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抑制 Bcl6b 通过放大小鼠炎症促进胃癌
DOI：
10.1186/s12964-019-0387-6
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发表时间：
2019-07-09
影响因子：
8.4
通讯作者：
Luo，Qi-Cong
中科院分区：
文献类型：
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作者：
Cai，Wang-Yu;Lin，Ling-Yun;Luo，Qi-Cong
背景慢性胃炎是胃癌发生的重要原因，控制胃炎症被认为是临床预防胃癌发生的有效手段。然而，在体内确定胃癌发生相关炎症的主要调节因子仍然是一个未满足的需求。方法采用bcl6b - / -和C57BL/6背景下的野生型小鼠，采用苯并[a]芘（BaP）灌胃诱导炎症相关GC小鼠模型。腹腔注射去甲基化药物5-Aza-2′-脱氧胞苷（5-Aza）恢复Bcl6b的表达。采用人GC组织阵列检测BCL6B和CD3蛋白的表达，分析患者的生存情况。结果在bap诱导的小鼠胃癌发生过程中，bcl6b通过其自身启动子的高甲基化而逐渐下调，同时炎症反应增加。此外，在bap诱导的小鼠胃癌模型中，敲除Bcl6b显著加重了胃癌的严重程度，并加重了炎症反应。5-Aza对Bcl6b的再激活抑制了炎症扩增和bap诱导的GC发展，延长了野生型小鼠的生存时间，而5-Aza对Bcl6b - / -小鼠的治疗效果不显著。最后，在人胃癌组织中，BCL6B mRNA水平与炎症细胞因子呈显著负相关；bcl6b阴性和严重炎症的胃癌患者生存时间最短。结论Bcl6b基因失活在体内通过放大胃炎症反应促进胃癌发生，为胃癌治疗和再生医学提供了新的途径。
BackgroundChronic gastritis has been demonstrated to be a key cause of gastric cancer (GC), and control of gastric inflammation is regarded as an effective treatment for the clinical prevention of gastric carcinogenesis. However, there remains an unmet need to identify the dominant regulators of gastric oncogenesis-associated inflammation in vivo.MethodsThe mouse model for the study of inflammation-associated GC was induced by Benzo[a]pyrene (BaP) intragastric administration inBcl6b−/−and wildtype mice on a C57BL/6 background. 5-Aza-2′-deoxycytidine (5-Aza), the demethylation drug, was intraperitoneally injected to restore Bcl6b expression. Human GC tissue array was used to analyse patient survival based on BCL6B and CD3 protein expression.ResultsBcl6b was gradually downregulated by its own promoter hypermethylation in parallel to an increasing inflammatory response during the progression of BaP-induced gastric carcinogenesis in mice. Moreover, knockout of Bcl6b dramatically worsened the severity of gastric cancer and aggravated the inflammatory response in the BaP-induced mice GC model. Re-activation of Bcl6b by 5-Aza impeded inflammatory amplification and BaP-induced GC development, prolonging survival time in wildtype mice, whereas no notable curative effect occurred inBcl6b−/−mice with 5-Aza treatment. Finally, significant negative correlations were detected between the mRNA levels of BCL6B and inflammatory cytokines in human GC tissues; patients harbouring BCL6B-negetive and severe-inflammation GC tumours were found to exhibit the shortest survival time.ConclusionsEpigenetic inactivation of Bcl6b promotes gastric cancer through amplification of the gastric inflammatory response in vivo and offers a new approach for GC treatment and regenerative medicine.