The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner
The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner
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DOI：
10.1038/labinvest.2012.131
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发表时间：
2013-01-01
影响因子：
5
通讯作者：
Taupin, Doug
中科院分区：
文献类型：
--
作者：
Baird, Mhairi;Ang, Pei Woon;Taupin, Doug
粘液化生（MM）是一种分泌异常的表型，在螺杆菌诱导的胃癌发生过程中出现。HSPA 5是内质网应激激活的未折叠蛋白反应（UPR）的关键调节因子，在胃癌中过表达。我们研究了人类和小鼠MM和GC中UPR的激活。我们评估了人胃癌中ER应激标志物（HSPA 5、XBP 1和CHOP）的RNA和蛋白水平，并与幽门螺杆菌（H. pylori）状态，并检测正常胃粘膜及胃粘膜癌前病变（胃炎、肠上皮化生）组织中HSPA 5的表达。H.通过与AGS GC细胞共培养来评估UPR中的pylori感染。转基因K19-Wnt 1/C2mE小鼠和慢性猫螺杆菌感染的C57 Bl/6小鼠的化生和异型增生中的ER应激标志物（H.猫）感染进行比较。HSPA 5在24/73（33%）人胃癌中过表达。HSPA 5和XBP 1剪接的诱导与H.幽门螺杆菌相关性GC（对于XBP 1剪接，P = 0.007）。HSPA 5在MM组织中呈高表达，而在H.幽门感染CagA阳性H. pylori抑制HSPA 5表达和XBP 1剪接。在人和小鼠的正常胃粘膜中，HSPA 5组成型表达于MIST 1阳性的主细胞中。Hspa 5和Chop在慢性H.在K19-Wnt 1/C2mE小鼠自发性胃发育不良中，Mist 1表达缺失，与在H.幽门相关性人胃癌在幽门螺杆菌引起的慢性炎症和MM的环境中诱导UPR可能促进幽门螺杆菌感染的胃粘膜的肿瘤转化。实验室调查（2013）93，112-122; doi：10.1038/labinvest.2012.131;在线发表2012年10月29日
Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P = 0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa. Laboratory Investigation (2013) 93, 112-122; doi:10.1038/labinvest.2012.131; published online 29 October 2012