Kim Ji-Sun, Jeong Mi-Young, Yoon Ye Eun, Kim Yeonji, Lee InRyeong, Choi Jung-Won, Lee Ha Lim, Shin Min-Jeong, Hong SungHoi, Chi Sung-Gil, Lee Sung-Joon
Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea.
School of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, South Korea; Interdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea.
Biomed Pharmacother. 2025 Aug;189:118268. doi: 10.1016/j.biopha.2025.118268. Epub 2025 Jun 18.
Dietary fiber intake is associated with a reduced risk of colorectal cancer (CRC), partly through the microbial fermentation of fiber into short-chain fatty acids (SCFAs). Among these, propionate binds to olfactory receptor 51E2 (Or51e2), which is ectopically expressed in the colon, but its role in CRC remains unclear. In this study, we evaluated Or51e2 expression in murine CT26 CRC cells and mouse colon tissues. Intracellular cAMP levels and CRE-luciferase activity were measured in CT26 and Or51e2-transfected Hana3A cells. The effects of propionate on proliferation, apoptosis, and MEK/ERK signaling were examined in CT26 cells. In vivo, a colitis-associated CRC model was established in wild-type (WT) and Or51e2-knockout (Or51e2 KO) mice using azoxymethane and dextran sulfate sodium (AOM/DSS). Propionate was administered intraperitoneally, and tumor burden, colon length, polyp number, histological changes, and MEK/ERK phosphorylation were assessed. Or51e2 expression was higher than other SCFA receptors in both CT26 cells and mouse colon tissues. Propionate treatment increased intracellular cAMP, activated CRE-luciferase, inhibited cell proliferation, induced apoptosis, and suppressed MEK/ERK phosphorylation in an Or51e2-dependent manner. In vivo, propionate reduced tumor growth, polyp formation, and MEK/ERK activation in WT mice, but not in Or51e2 KO mice. These findings suggest that Or51e2 mediates the anti-tumor effects of propionate through modulation of cAMP and MEK/ERK signaling, supporting its potential as a therapeutic strategy for CRC treatment.
膳食纤维摄入量与结直肠癌（CRC）风险降低相关，部分原因是纤维经微生物发酵生成短链脂肪酸（SCFAs）。其中，丙酸酯与嗅觉受体51E2（Or51e2）结合，该受体在结肠中异位表达，但其在结直肠癌中的作用仍不清楚。在本研究中，我们评估了Or51e2在小鼠CT26结直肠癌细胞和小鼠结肠组织中的表达。在CT26细胞和转染了Or51e2的Hana3A细胞中测量细胞内cAMP水平和CRE荧光素酶活性。在CT26细胞中检测丙酸酯对细胞增殖、凋亡和MEK/ERK信号传导的影响。在体内，使用氧化偶氮甲烷和葡聚糖硫酸钠（AOM/DSS）在野生型（WT）和Or51e2基因敲除（Or51e2 KO）小鼠中建立结肠炎相关的结直肠癌模型。腹腔注射丙酸酯，评估肿瘤负荷、结肠长度、息肉数量、组织学变化和MEK/ERK磷酸化。在CT26细胞和小鼠结肠组织中，Or51e2的表达均高于其他SCFA受体。丙酸酯处理以Or51e2依赖的方式增加细胞内cAMP、激活CRE荧光素酶、抑制细胞增殖、诱导凋亡并抑制MEK/ERK磷酸化。在体内，丙酸酯可降低WT小鼠的肿瘤生长、息肉形成和MEK/ERK激活，但对Or51e2 KO小鼠无效。这些发现表明，Or51e2通过调节cAMP和MEK/ERK信号传导介导丙酸酯的抗肿瘤作用，支持其作为结直肠癌治疗策略的潜力。
