Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium.

Bianca N Islam, Sarah K Sharman, Yali Hou, Rui Wang, Justin Ashby, Honglin Li, Kebin Liu, Kenneth J Vega, Darren D Browning

Carcinogenesis 2022 Jun 27

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A large body of evidence has demonstrated that cyclic-guanosine monophosphate (cGMP), signaling has anti-tumor effects that might be used for colon cancer prevention. The tumor-suppressive mechanism and the signaling components downstream of cGMP remain largely unknown. The present study has characterized the expression of cGMP-dependent protein kinases (PKG1, PKG2) in normal and cancerous tissue from human colon. PKG1 was detected in both normal and tumor tissue, where it localized exclusively to the lamina propria and stroma (respectively). In contrast, PKG2 localized specifically to the epithelium where its expression decreased markedly in tumors compared to matched normal tissue. Neither PKG isoform was detected at the RNA or protein level in established colon cancer cell lines. To test for a potential tumor-suppressor role of PKG2 in the colon epithelium, Prkg2 knockout (KO) mice were subjected to azoxymethane/dextran sulfate-sodium (AOM/DSS) treatment. PKG2 deficiency was associated with crypt hyperplasia (Ki67) and almost twice the number of polyps per mouse as wild-type (WT) siblings. In vitro culture of mouse colon epithelium as organoids confirmed that PKG2 was the only isoform expressed, and it was detected in both proliferating and differentiating epithelial compartments. Colon organoids derived from Prkg2 KO mice proliferated more rapidly and exhibited a reduced ability to differentiate compared to WT controls. Taken together our results highlight PKG2 as the central target of cGMP in the colon, where it suppresses carcinogenesis by controlling proliferation in an epithelial-cell intrinsic manner. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Bianca N Islam, Sarah K Sharman, Yali Hou, Rui Wang, Justin Ashby, Honglin Li, Kebin Liu, Kenneth J Vega, Darren D Browning. Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium. Carcinogenesis. 2022 Jun 27;43(6):584-593