Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Free Radic Biol Med. 2021 Aug 20;172:312-329. doi: 10.1016/j.freeradbiomed.2021.06.012. Epub 2021 Jun 16.
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic recurrent and incurable gastrointestinal diseases with an unknown etiology that leads to a high risk of developing colitis-associated colorectal cancer (CRC).
In this study, we measured the expression characteristics of MELK in IBD and CRC tissues and explored the regulatory effect of OTSSP167 (a MELK-selective inhibitor) on the mice models of colitis and colitis-associated carcinogenesis and analyzed the specific molecular mechanisms.
DSS-induced colitis and colitis-associated carcinogenesis (CAC) model were treated with MELK inhibitor OTSSP167 then the fight against effect of OTSSP167 in the clinical symptoms of colitis and CAC was measured. In addition, underlying mechanism of OTSSP167 treatment in vitro and vivo including anti-ferroptosis and anti-inflammatory response effect was further explored.
We found that pharmacological inhibition of MELK was indicated to significantly alleviate the inflammatory response in mice with colitis, reduce intestinal damage, and effectively inhibit the occurrence and progression of colitis-propelled carcinogenesis, which was closely related to the regulation of gut microbial composition, and OTSSP167-mediated fecal microbiota transplantation effectively alleviated DSS-induced colitis. In addition, OTSSP167 treatment obviously inhibited ferroptosis in the intestinal tissue and suppressed macrophage infiltration and M1 polarization, which reduced the secretion of pro-inflammatory factors. Further exploration of the molecular mechanism revealed that OTSSP167 inhibited AKT/IKK/P65 and ERK/IKK/P65 signaling cascades both in vivo and in vitro, which may help alleviate intestinal inflammation and control the occurrence of cancer.
Our findings lay a theoretical foundation for the use of OTSSP167 as a treatment for IBD and its inhibition of the occurrence of colitis-associated carcinogenesis; additionally, MELK may be a potentially effective target molecule, thus providing more options for clinical treatment.
炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD），是一组病因不明的慢性复发性和不可治愈的胃肠道疾病，导致结肠炎相关结直肠癌（CRC）的风险很高。
本研究测量了 MELK 在 IBD 和 CRC 组织中的表达特征，并探讨了 OTSSP167（一种 MELK 选择性抑制剂）对结肠炎和结肠炎相关癌变小鼠模型的调节作用，并分析了具体的分子机制。
用 MELK 抑制剂 OTSSP167 处理 DSS 诱导的结肠炎和结肠炎相关癌变（CAC）模型，然后测量 OTSSP167 在结肠炎和 CAC 临床症状中的对抗作用。此外，还进一步探讨了 OTSSP167 在体内外的治疗机制，包括抗铁死亡和抗炎反应作用。
我们发现，药理抑制 MELK 明显减轻了结肠炎小鼠的炎症反应，减少了肠道损伤，并有效地抑制了结肠炎驱动的癌变的发生和进展，这与肠道微生物组成的调节密切相关，OTSSP167 介导的粪便微生物群移植有效地缓解了 DSS 诱导的结肠炎。此外，OTSSP167 治疗明显抑制了肠组织中的铁死亡，并抑制了巨噬细胞浸润和 M1 极化，减少了促炎因子的分泌。进一步的分子机制探索表明，OTSSP167 在体内和体外均抑制了 AKT/IKK/P65 和 ERK/IKK/P65 信号通路，这可能有助于缓解肠道炎症并控制癌症的发生。
我们的研究结果为使用 OTSSP167 治疗 IBD 及其抑制结肠炎相关癌变的发生奠定了理论基础；此外，MELK 可能是一个有潜力的有效靶分子，为临床治疗提供了更多选择。
