Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Jinping, Shantou, Guangdong, 515041, P.R. China.
Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
Mol Cancer. 2024 Jun 7;23(1):124. doi: 10.1186/s12943-024-02016-9.
Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression.
In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM.
Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells.
OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.
肠上皮化生（IM）分为完全肠上皮化生（CIM）和不完全肠上皮化生（IIM）。IIM 患者发生胃癌的易感性增加，这凸显了早期筛查措施的重要性。除了诊断的复杂性外，IIM 患者胃癌进展的确切机制仍知之甚少。OLFM4 在多种肿瘤中过表达，包括结直肠癌、胃癌、胰腺癌和卵巢癌，其表达与肿瘤进展有关。
本研究使用来自两个临床中心的病理切片、IM 组织活检、胃癌前病变（PLGC）细胞模型、动物模型和类器官，探索 OLFM4 在 IIM 中的作用。
我们的研究结果表明，OLFM4 在 IIM 中表达高度增加，与 CDX2 和 MUC2 相比，对 IIM 的诊断准确性更高。OLFM4 与 MYH9 在 IM 类器官和 PLGC 动物模型中过表达。此外，OLFM4 与肌球蛋白重链 9（MYH9）一起，加速了 GSK3β 的泛素化，并通过 Wnt 信号通路导致β-连环蛋白水平升高，从而促进 PLGC 细胞的增殖和侵袭能力。
OLFM4 是 IIM 的一种新型生物标志物，可作为早期胃癌筛查的重要辅助手段，用于划定关键人群。最后，我们的研究确定了涉及 IM 进展的细胞信号通路。
