Elevated Protein Kinase A Activity in Stomach Mesenchyme Disrupts Mesenchymal-epithelial Crosstalk and Induces Preneoplasia.
Elevated Protein Kinase A Activity in Stomach Mesenchyme Disrupts Mesenchymal-epithelial Crosstalk and Induces Preneoplasia.
复制标题
DOI：
10.1016/j.jcmgh.2022.06.001
复制
发表时间：
2022
影响因子：
7.2
通讯作者：
Yoder, Bradley K.
中科院分区：
文献类型：
--
作者：
Puri, Pawan;Grimmett, Garfield;Faraj, Rawah;Gibson, Laurielle;Gilbreath, Ebony;Yoder, Bradley K.
胃中的间质-上皮串扰（MEC）通过诸如骨形态发生蛋白（BMP）和细胞外信号调节激酶（ERK）的途径来执行。MEC的错误调节破坏胃内稳态并导致肿瘤发生。蛋白激酶A（PKA）与BMP和ERK信号传导交叉;然而，PKA在胃发育和体内平衡中的功能仍不清楚。我们产生了一种新的Six 2-Cre+/-PKAcαRfl/wt（CA-PKA）小鼠，其中在胃间充质祖细胞中诱导了组成型活性PKAcαR的表达。谱系追踪确定胃中Six 2-Cre的时空活性。为了对CA-PKA小鼠进行表型分型，进行了组织学、共免疫荧光、免疫印迹、mRNA测序和生物信息学分析。谱系追踪表明，Six 2-Cre在胃中的活性仅限于间充质隔室。CA-PKA小鼠表现出胃稳态破坏，其特征为异常粘膜发育和上皮过度增殖;最终出现胃体癌前病变的多种特征，包括壁细胞减少、粘液细胞增生、具有肠特征的痉挛肽表达化生以及异型增生和侵袭性囊性腺。此外，突变体体显示出显著的慢性炎症，其特征在于淋巴细胞和髓源性抑制细胞沿着先天性和适应性免疫系统组分的上调的浸润。观察到炎性介质和STAT 3活化的显著上调。从机制上讲，我们确定存在ERK 1/2的激活和BMP/SMAD信号转导的下调，其特征在于BMP抑制剂gremlin 1的显著上调。我们报告了PKA信号在胃MEC执行中的新作用，并表明胃间质中的PKA激活通过创建与BMP/SMAD信号下调和ERK 1/2激活相关的促炎和促增殖微环境来驱动癌前病变。
Mesenchymal-epithelial crosstalk (MEC) in the stomach is executed by pathways such as bone morphogenetic protein (BMP) and extracellular signal-regulated kinase (ERK). Mis-regulation of MEC disrupts gastric homeostasis and causes tumorigenesis. Protein Kinase A (PKA) crosstalks with BMP and ERK signaling; however, PKA function(s) in stomach development and homeostasis remains undefined. We generated a novel Six2-Cre+/-PKAcαRfl/wt (CA-PKA) mouse in which expression of constitutive-active PKAcαR was induced in gastric mesenchyme progenitors. Lineage tracing determined spatiotemporal activity of Six2-Cre in the stomach. For phenotyping CA-PKA mice histological, co-immunofluorescence, immunoblotting, mRNA sequencing, and bioinformatics analyses were performed. Lineage tracing showed that Six2-Cre activity in the stomach is restricted to the mesenchymal compartment. CA-PKA mice showed disruption of gastric homeostasis characterized by aberrant mucosal development and epithelial hyperproliferation; ultimately developing multiple features of gastric corpus preneoplasia including decreased parietal cells, mucous cell hyperplasia, spasmolytic peptide expressing metaplasia with intestinal characteristics, and dysplastic and invasive cystic glands. Furthermore, mutant corpus showed marked chronic inflammation characterized by infiltration of lymphocytes and myeloid-derived suppressor cells along with the upregulation of innate and adaptive immune system components. Striking upregulation of inflammatory mediators and STAT3 activation was observed. Mechanistically, we determined there is an activation of ERK1/2 and downregulation of BMP/SMAD signaling characterized by marked upregulation of BMP inhibitor gremlin 1. We report a novel role of PKA signaling in gastric MEC execution and show that PKA activation in the gastric mesenchyme drives preneoplasia by creating a proinflammatory and proproliferative microenvironment associated with the downregulation of BMP/SMAD signaling and activation of ERK1/2.
登录
查看更多内容
构成蛋白激酶A在骨细胞和晚成骨细胞中的活性会对骨骼产生合成代谢作用。
影响因子：
4.1
作者：
Kao, Richard S.;Abbott, Marcia J.;Louie, Alyssa;O'Carroll, Dylan;Lu, Weidar;Nissenson, Robert
通讯作者：
Nissenson, Robert
DOI：
10.1016/j.jcmgh.2017.01.013
发表时间：
2017-05
影响因子：
7.2
作者：
Hayakawa Y;Fox JG;Wang TC
通讯作者：
Wang TC
影响因子：
29.4
作者：
Friis-Hansen, Lennart;Rieneck, Klaus;Rehfeld, Jens F.
通讯作者：
Rehfeld, Jens F.
影响因子：
29.4
作者：
Hagen SJ;Ang LH;Zheng Y;Karahan SN;Wu J;Wang YE;Caron TJ;Gad AP;Muthupalani S;Fox JG
通讯作者：
Fox JG
影响因子：
30.8
作者：
Kirschner, LS;Carney, JA;Stratakis, CA
通讯作者：
Stratakis, CA