Mao Xiaqiong, Liu Tongtai, Yu Shunying, Wei Yuqi, Zhou Chunli, Kuai Xiaoyi
Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
Cancer Gene Ther. 2025 Jan;32(1):51-60. doi: 10.1038/s41417-024-00846-9. Epub 2024 Nov 19.
Gastric cancer (GC) is one of the most lethal cancers. However, the underlying mechanisms are not yet fully understood. Here, we investigated the role of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in tumor initiation and progression in GC and proposed therapeutic strategies for CEACAM6-positive patients. In this article, we found that CEACAM6 overexpression promoted GC initiation and progression by overactivating FAO. CEACAM6 promotes SLC27A2 expression, contributing to enhanced fatty acid incorporation. CEACAM6 interacts with both SLC27A2 and USP29, facilitating the deubiquitination of USP29 on SLC27A2. Pharmacological inhibition of SLC27A2 attenuates the tumor-initiating ability of GC. Taken together, CEACAM6 overexpression facilitates GC progression by upregulating fatty acid uptake through SLC27A2, thereby contributing to FAO. Genetic ablation of SLC27A2 is a promising therapeutic strategy for patients with CEACAM6-positive GC.
胃癌（GC）是最致命的癌症之一。然而，其潜在机制尚未完全明确。在此，我们研究了癌胚抗原相关细胞黏附分子6（CEACAM6）在胃癌发生和进展中的作用，并为CEACAM6阳性患者提出了治疗策略。在本文中，我们发现CEACAM6的过表达通过过度激活脂肪酸氧化（FAO）促进胃癌的发生和进展。CEACAM6促进溶质载体家族27成员2（SLC27A2）的表达，有助于增强脂肪酸掺入。CEACAM6与SLC27A2和泛素特异性蛋白酶29（USP29）相互作用，促进USP29对SLC27A2的去泛素化。对SLC27A2的药理抑制减弱了胃癌的肿瘤起始能力。综上所述，CEACAM6的过表达通过上调SLC27A2介导的脂肪酸摄取促进胃癌进展，从而促进脂肪酸氧化。对SLC27A2进行基因敲除是治疗CEACAM6阳性胃癌患者的一种有前景的治疗策略。
