NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5-Expressing Cells.
NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5-Expressing Cells.
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DOI：
10.1016/j.jcmgh.2018.08.005
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发表时间：
2019
影响因子：
7.2
通讯作者：
Ghishan FK
中科院分区：
文献类型：
--
作者：
Xu H;Li J;Chen H;Ghishan FK
Lgr5 过度表达已在结直肠癌 (CRC) 中检测到，包括一些结肠炎相关的 CRC 病例。在结肠炎相关的结直肠癌中，慢性炎症是致癌的一个促成因素。我们最近报道肠道 Na+/H+ 交换异构体 8 (NHE8) 在肠粘膜保护中发挥重要作用，NHE8 表达缺失会导致溃疡性结肠炎样病症。因此，我们推测NHE8可能参与肠道肿瘤的发生发展。我们通过免疫组织化学评估了人类 CRC 中的 NHE8 表达，并使用氧化偶氮甲烷/葡聚糖硫酸钠结肠癌模型研究了 NHE8 敲除 (KO) 小鼠的肿瘤负荷。我们还评估了 HT29NHE8KO 细胞的细胞增殖，并评估了异种移植 HT29NHE8KO 细胞的 NOD scid gamma (NSG) 小鼠的肿瘤生长。为了验证 Lgr5 和 NHE8 表达之间是否存在关系，我们通过聚合酶链反应和原位杂交分析了 NHE8KO 小鼠中 Lgr5 的表达。在结肠类器官培养物中证实了在缺乏 NHE8 的情况下 Lgr5 的表达和细胞增殖。还分析了 β-连环蛋白和 c-Myc 的表达以评估 Wnt/β-连环蛋白的激活。 NHE8 在人类 CRC 组织中检测不到。尽管只有 9% 的 NHE8 野生型小鼠在氧化偶氮甲烷/葡聚糖硫酸钠结肠癌模型中表现出肿瘤发生，但 NHE8KO 小鼠 (89%) 发生肿瘤的数量几乎增加了 10 倍。在缺乏 NHE8 的情况下，在 HT29NHE8KO 细胞中发现了更高的集落形成单位。在 NSG 小鼠中，与 HT29NHE8 野生型细胞相比，注射 HT29NHE8KO 细胞的部位出现了更大的肿瘤。此外，NHE8 缺陷导致结肠、HT29 衍生肿瘤和类结肠中 Lgr5 表达增加。 NHE8 的缺失也会增加 Wnt/β-catenin 的激活。 NHE8可能是调节肠道Wnt/β-catenin的内在因子。
Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+/H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis–like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors. We assessed NHE8 expression in human CRCs by immunohistochemistry and studied tumor burden in NHE8 knockout (KO) mice using an azoxymethane/dextran sodium sulfate colon cancer model. We also evaluated cell proliferation in HT29NHE8KO cells and assessed tumor growth in NOD scid gamma (NSG) mice xenografted with HT29NHE8KO cells. To verify if a relationship exists between Lgr5 and NHE8 expression, we analyzed Lgr5 expression in NHE8KO mice by polymerase chain reaction and in situ hybridization. Lgr5 expression and cell proliferation in the absence of NHE8 were confirmed in colonic organoid cultures. The expression of β-catenin and c-Myc also were analyzed to evaluate Wnt/β-catenin activation. NHE8 was undetectable in human CRC tissues. Although only 9% of NHE8 wild-type mice showed tumorigenesis in the azoxymethane/dextran sodium sulfate colon cancer model, almost 10 times more NHE8KO mice (89%) developed tumors. In the absence of NHE8, a higher colony formation unit was discovered in HT29NHE8KO cells. In NSG mice, larger tumors developed at the site where HT29NHE8KO cells were injected compared with HT29NHE8 wild type cells. Furthermore, NHE8 deficiency resulted in increased Lgr5 expression in the colon, in HT29-derived tumors, and in colonoids. The absence of NHE8 also increased Wnt/β-catenin activation. NHE8 might be an intrinsic factor that regulates Wnt/β-catenin in the intestine.
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影响因子：
8.8
作者：
Barker, Nick;Rookmaaker, Maarten B.;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
4.7
作者：
Hirsch, Daniela;Barker, Nick;Gaiser, Timo
通讯作者：
Gaiser, Timo
影响因子：
4.7
作者：
Cooper, HS;Murthy, S;Flanigan, A
通讯作者：
Flanigan, A
影响因子：
4.9
作者：
Clapper, Margie L.;Gary, Monique A.;Cooper, Harry S.
通讯作者：
Cooper, Harry S.
DOI：
10.1152/ajprenal.00492.2014
发表时间：
2015-01-01
影响因子：
4.2
作者：
Pirojsakul, Kwanchai;Gattineni, Jyothsna;Baum, Michel
通讯作者：
Baum, Michel