CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.
CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.
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DOI：
10.1136/gutjnl-2014-307190
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发表时间：
2015-04
期刊：
影响因子：
24.5
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Hayakawa Y;Jin G;Wang H;Chen X;Westphalen CB;Asfaha S;Renz BW;Ariyama H;Dubeykovskaya ZA;Takemoto Y;Lee Y;Muley A;Tailor Y;Chen D;Muthupalani S;Fox JG;Shulkes A;Worthley DL;Takaishi S;Wang TC
前胃泌素是胃泌素不完全裂解的前体，由胃窦 G 细胞分泌。胃泌素和前胃泌素均与胃上皮细胞亚群上表达的 CCK2 受体（Cckbr 或 CCK2R）结合。关于胃泌素肽和 CCK2R 如何调节胃干细胞和癌发生知之甚少。肠道祖细胞之间的相互转化已有记录，但其发生的机制尚不清楚。我们生成了 CCK2R-CreERT 小鼠并进行了诱导谱系追踪实验。 CCK2R+胃窦细胞和Lgr5+胃窦干细胞在三维体外系统中培养。我们将前胃泌素过表达小鼠与 Lgr5-GFP-CreERT 小鼠杂交，并检查了前胃泌素和 CCK2R 在 MNU 诱导的癌发生过程中 Lgr5+ 干细胞中的作用。通过谱系追踪实验，我们发现CCK2R在位置+4处定义了胃窦干细胞，其与Lgr5neg或低细胞群重叠，但与典型的胃窦Lgr5high干细胞不同。用前胃泌素治疗可将 Lgr5neg 或低 CCK2R+ 细胞转化为 Lgr5high 细胞，增加 CCK2R+ 细胞数量，并促进腺体裂变和对化学致癌物 MNU 的致癌作用。 CCK2R 的药理抑制或基因消除可减弱前胃泌素依赖性干细胞的扩增和致癌作用。 CCK2R 标记 +4 胃窦干细胞，可被前胃泌素激活和扩增，从而确定胃干细胞相互转化的一种激素触发因素以及胃癌化学预防和治疗的潜在靶点。
Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.