Elevated Protein Kinase A Activity in Stomach Mesenchyme Disrupts Mesenchymal-epithelial Crosstalk and Induces Preneoplasia

Overview

Journal Cell Mol Gastroenterol Hepatol

Specialty Gastroenterology

Date 2022 Jun 11

PMID 35690337

Authors

Pawan Puri

Garfield Grimmett

Rawah Faraj

Laurielle Gibson

Ebony Gilbreath

Bradley K Yoder

Affiliations

Soon will be listed here.

Abstract

Background & Aims: 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.

Methods: We generated a novel Six2-CrePKAcαR (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.

Results: 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.

Conclusions: 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.

Citing Articles

Alternative splicing of CARM1 regulated by LincGET-guided paraspeckles biases the first cell fate in mammalian early embryos.

Wang J, Zhang Y, Gao J, Feng G, Liu C, Li X Nat Struct Mol Biol. 2024; 31(9):1341-1354.

PMID: 38658621 PMC: 11402786. DOI: 10.1038/s41594-024-01292-9.

Gastric intestinal metaplasia: progress and remaining challenges.

Tong Q, Pang M, Hu X, Huang X, Sun J, Wang X J Gastroenterol. 2024; 59(4):285-301.

PMID: 38242996 DOI: 10.1007/s00535-023-02073-9.

Stroma New Tune: Emerging Role of PKA in Maintaining Gastric Homeostasis.

Cho C, Mills J Cell Mol Gastroenterol Hepatol. 2022; 14(3):722-723.

PMID: 35793768 PMC: 9421578. DOI: 10.1016/j.jcmgh.2022.06.004.

References

Wang T, Dangler C, Chen D, Goldenring J, Koh T, Raychowdhury R . Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology. 1999; 118(1):36-47. DOI: 10.1016/s0016-5085(00)70412-4. View

Zavros Y, Eaton K, Kang W, Rathinavelu S, Katukuri V, Kao J . Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene. 2005; 24(14):2354-66. DOI: 10.1038/sj.onc.1208407. View

Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H . Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004; 64(21):7740-7. DOI: 10.1158/0008-5472.CAN-04-1617. View

Kirschner L, Yin Z, Jones G, Mahoney E . Mouse models of altered protein kinase A signaling. Endocr Relat Cancer. 2009; 16(3):773-93. DOI: 10.1677/ERC-09-0068. View

Liu W, Yang L, Liu Y, Yuan D, Zhao Z, Wang Q . Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice. Biosci Rep. 2020; 40(2). PMC: 7040465. DOI: 10.1042/BSR20181881. View

Zhang Y, Que J . BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract. Annu Rev Physiol. 2019; 82:251-273. DOI: 10.1146/annurev-physiol-021119-034500. View

Burkitt M, Varro A, Pritchard D . Importance of gastrin in the pathogenesis and treatment of gastric tumors. World J Gastroenterol. 2008; 15(1):1-16. PMC: 2653300. DOI: 10.3748/wjg.15.1. View

Koh T, Goldenring J, Ito S, Mashimo H, Kopin A, Varro A . Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology. 1997; 113(3):1015-25. DOI: 10.1016/s0016-5085(97)70199-9. View

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M . Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345(11):784-9. DOI: 10.1056/NEJMoa001999. View

10.

Busslinger G, Weusten B, Bogte A, Begthel H, Brosens L, Clevers H . Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution. Cell Rep. 2021; 34(10):108819. DOI: 10.1016/j.celrep.2021.108819. View

11.

Yokota S, Okabayashi T, Rehli M, Fujii N, Amano K . Helicobacter pylori lipopolysaccharides upregulate toll-like receptor 4 expression and proliferation of gastric epithelial cells via the MEK1/2-ERK1/2 mitogen-activated protein kinase pathway. Infect Immun. 2009; 78(1):468-76. PMC: 2798195. DOI: 10.1128/IAI.00903-09. View

12.

Takabayashi H, Shinohara M, Mao M, Phaosawasdi P, El-Zaatari M, Zhang M . Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice. Gastroenterology. 2014; 147(2):396-406.e7. PMC: 4197994. DOI: 10.1053/j.gastro.2014.04.015. View

13.

Farshidpour M, Ahmed M, Junna S, Merchant J . Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review. World J Gastrointest Oncol. 2021; 13(1):1-11. PMC: 7805271. DOI: 10.4251/wjgo.v13.i1.1. View

14.

Senger K, Pham V, Varfolomeev E, Hackney J, Corzo C, Collier J . The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci Signal. 2017; 10(475). DOI: 10.1126/scisignal.aah4273. View

15.

Le Guen L, Marchal S, Faure S, de Santa Barbara P . Mesenchymal-epithelial interactions during digestive tract development and epithelial stem cell regeneration. Cell Mol Life Sci. 2015; 72(20):3883-96. PMC: 5395663. DOI: 10.1007/s00018-015-1975-2. View

16.

Wang S, Gu Y, Wolff N, Stefanius K, Christie A, Dey A . Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl Acad Sci U S A. 2014; 111(46):16538-43. PMC: 4246264. DOI: 10.1073/pnas.1414789111. View

17.

Kapalczynska M, Lin M, Maertzdorf J, Heuberger J, Muellerke S, Zuo X . BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation. Nat Commun. 2022; 13(1):1577. PMC: 8948225. DOI: 10.1038/s41467-022-29176-w. View

18.

Todisco A, Mao M, Keeley T, Ye W, Samuelson L, Eaton K . Regulation of gastric epithelial cell homeostasis by gastrin and bone morphogenetic protein signaling. Physiol Rep. 2015; 3(8). PMC: 4562585. DOI: 10.14814/phy2.12501. View

19.

Sahoo N, Gu M, Zhang X, Raval N, Yang J, Bekier M . Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca Efflux Channel in the Tubulovesicle. Dev Cell. 2017; 41(3):262-273.e6. PMC: 5497767. DOI: 10.1016/j.devcel.2017.04.003. View

20.

Friis-Hansen L, Rieneck K, Nilsson H, Wadstrom T, Rehfeld J . Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice. Gastroenterology. 2006; 131(1):246-58. DOI: 10.1053/j.gastro.2006.04.031. View