Differential Notch1 and Notch2 Expression and Frequent Activation of Notch Signaling in Gastric Cancers
Differential Notch1 and Notch2 Expression and Frequent Activation of Notch Signaling in Gastric Cancers
复制标题
胃癌中 Notch1 和 Notch2 的差异表达以及 Notch 信号传导的频繁激活
DOI：
10.1043/2009-0665-oa.1
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发表时间：
2011-04-01
影响因子：
4.6
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Sun, Yuan;Gao, Xue;Li, Hong
上下文。- Notch1和Notch2的生物学效应随癌症类型的不同而不同，它们在胃癌（GCs）中的潜在作用在很大程度上仍然未知。本研究旨在通过检测Notch1、Notch2和Notch靶基因Hes1在胃癌、癌前胃病变和非癌性内镜胃粘膜中的表达，并通过抑制胃癌细胞中的Notch信号转导来解决上述问题。通过组织芯片免疫组化染色、Western blotting和逆转录聚合酶链反应，研究了74例胃癌手术标本、10例内镜标本和4例人胃癌细胞株中Notch1、Notch2和Hes1的表达状况，并通过2种γ -分泌酶抑制剂处理2例胃癌细胞株，阐明了Notch信号通路的重要性。-Notch1在非癌性胃粘膜中未检出，但在慢性胃炎的16.7%（24例中有4例）、肠化生的50.0%（18例中有9例）、肠GC的54.2%（48例中有26例）、弥漫性GC的23.1%（26例中有6例）中有核易位表达，可见Notch1在肠化生与慢性胃炎、肠GC与弥漫性GC的检出率差异有统计学意义（P = 0.03; P = 0.005）。Notch2核易位频率在非癌性内镜黏膜中为10.0%(1 / 10)，在癌前病变中为71.4%(30 / 42)，在GC组织中为97.3%(72 / 74)，表明Notch2表达与肠道GC和弥漫性GC形成均有相关性（P < 0.001）。在非癌组织、42.9%的癌前组织和81.1%的癌组织中，核- hes1标记率为1 / 10，与Notch2核易位密切相关（P < 0.001），而与Notch1核易位密切相关（P = 0.42）。在4例弥漫性胃癌细胞系中，只有Notch2表达并伴有Hes1核标记。γ -分泌酶抑制剂L-685,458和DAPT抑制Notch信号传导可阻止Hes1核易位，但既不抑制生长也不诱导细胞死亡。-本研究表明Notch2表达与GC形成密切相关，Notch1上调与胃病变肠样表型的潜在联系。虽然抑制Notch活性不能达到抗GC的效果，但激活的Notch信号可能反映了潜在的GC风险。（Arch Pathol Lab Med. 2011;135:451-458）
Context.-The biologic effects of Notch1 and Notch2 vary with cancer types and their potential role(s) in gastric cancers (GCs) remains largely unknown.Objectives.-This study aimed to address the previously mentioned issue by checking the expression of Notch1, Notch2, and Notch target gene Hes1 in GCs, premalignant gastric lesions, and noncancerous endoscopic gastric mucosa and by inhibiting Notch signal transduction in GC cells.Design.-The status of Notch1, Notch2, and Hes1 expression in 74 GC surgical specimens, 10 endoscopic samples, and 4 human GC cell lines was evaluated by tissue microarray-based immunohistochemical staining, Western blotting, and reverse transcription-polymerase chain reaction, and the importance of Notch signaling was elucidated by treating 2 GC cell lines with 2 gamma-secretase inhibitors.Results.-Notch1 was undetectable in noncancerous gastric mucosa but was expressed with nuclear translocation in 16.7% (4 of 24) of chronic gastritis, 50.0% (9 of 18) of intestinal metaplasia, 54.2% (26 of 48) of intestinal GC, and 23.1% (6 of 26) of diffuse GC, showing distinct differences of Notch1 detection rates between either intestinal metaplasia and chronic gastritis or intestinal GCs and diffuse GCs (P = .03; P = .005, respectively). Notch2 nuclear translocation frequencies were 10.0% (1 of 10) in noncancerous endoscopic mucosa, 71.4% (30 of 42) in premalignant lesions, and 97.3% (72 of 74) in GC tissues, demonstrating a correlation of Notch2 expression with both intestinal GC and diffuse GC formation (P < .001). The rates of nuclear-Hes1 labeling were 1 of 10 among noncancerous, 42.9% premalignant, and 81.1% cancer tissues, which were closely correlated with Notch2 (P < .001) rather than Notch1 (P = .42) nuclear translocation. Only Notch2 was expressed accompanied with Hes1 nuclear labeling in the 4 GC cell lines established from diffuse GC cases. Inhibition of Notch signaling with gamma-secretase inhibitors, L-685,458 and DAPT, prevented Hes1 nuclear translocation but neither suppressed growth nor induced cell death.Conclusions.-This study demonstrated a close correlation of Notch2 expression with GC formation and the potential link of Notch1 upregulation with intestinal-like phenotypes of gastric lesions. Although inhibition of Notch activity failed to achieve anti-GC effects, the activated Notch signaling may reflect a potential GC risk. (Arch Pathol Lab Med. 2011;135:451-458)