Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium
Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium
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DOI：
10.1093/carcin/bgac022
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发表时间：
2022-03-31
期刊：
影响因子：
4.7
通讯作者：
Browning, Darren D.
中科院分区：
文献类型：
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作者：
Islam, Bianca N.;Sharman, Sarah K.;Browning, Darren D.
环-GMP 在结肠中具有肿瘤抑制作用，但下游信号传导尚不清楚。在这里，我们证明 2 型 cGMP 依赖性蛋白激酶是结肠上皮中的中央 cGMP 效应器，可抑制增殖和癌变。大量证据表明，环鸟苷单磷酸 (cGMP) 信号传导具有抗肿瘤作用，可用于预防结肠癌。 cGMP 的肿瘤抑制机制和下游信号传导成分仍然很大程度上未知。本研究表征了人类结肠正常组织和癌组织中 cGMP 依赖性蛋白激酶（PKG1、PKG2）的表达。 PKG1 在正常组织和肿瘤组织中均被检测到，其仅定位于固有层和间质（分别）。相比之下，PKG2 特异性定位于上皮细胞，与匹配的正常组织相比，其在肿瘤中的表达显着降低。在已建立的结肠癌细胞系中，在 RNA 或蛋白质水平上均未检测到 PKG 同种型。为了测试 PKG2 在结肠上皮细胞中潜在的肿瘤抑制作用，对 Prkg2 敲除 (KO) 小鼠进行氧化偶氮甲烷/葡聚糖硫酸钠 (AOM/DSS) 治疗。 PKG2 缺陷与隐窝增生 (Ki67) 相关，并且每只小鼠的息肉数量几乎是野生型 (WT) 同胞的两倍。小鼠结肠上皮作为类器官的体外培养证实 PKG2 是唯一表达的亚型，并且在增殖和分化的上皮区室中均检测到它。与 WT 对照相比，来自 Prkg2 KO 小鼠的结肠类器官增殖更快，并且分化能力降低。总而言之，我们的结果强调 PKG2 是结肠中 cGMP 的中心靶标，它通过以上皮细胞内在方式控制增殖来抑制癌发生。
Cyclic-GMP is tumor suppressive in the colon but the downstream signaling is unknown. Here, we demonstrate that type 2 cGMP-dependent protein kinase is the central cGMP effector in the colon epithelium where it inhibits proliferation and carcinogenesis.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.