Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China.
Department of Oncology, Department of Gastroenterology, Haian Hospital of Traditional Chinese Medicine, Haian, Jiangsu 226600, China.
J Proteome Res. 2022 Sep 2;21(9):2160-2172. doi: 10.1021/acs.jproteome.2c00221. Epub 2022 Aug 4.
Gastric cancer is one of the cancers with the highest morbidity and mortality. Although several therapeutic approaches have been developed to treat this disease, the overall survival rate is still very low due to metastasis, drug resistance, and so forth. Therefore, it is necessary to discover new regulatory molecules and signaling pathways that modulate the metastasis of gastric cancer cells. A Disintegrin And Metalloprotease 12 (ADAM12) was highly expressed in gastric cancer tissues and presented in the patient urine. However, it is unclear whether and how ADAM12 regulates the migration of gastric cancer cells. In this work, we used the secretome protein enrichment with click sugars (SPECS) method to purify the secreted glycosylated proteins and performed quantitative proteomics to identify the secreted proteins that were differentially regulated by ADAM12S, the short and secreted form of ADAM12. Our proteomic and biochemical analyses revealed that ADAM12S upregulated the cell surface glycoprotein CD146, a cell adhesion molecule and melanoma marker, which was dependent on the catalytic residue of ADAM12S. Furthermore, we discovered that the ADAM12S-enhanced migration of gastric cancer cells was, at least partially, mediated by CD146. This work may help to evaluate whether ADAM12 could be a potential therapeutic target for the treatment of gastric cancer patients.
胃癌是发病率和死亡率最高的癌症之一。尽管已经开发了几种治疗方法来治疗这种疾病，但由于转移、耐药性等原因，总体生存率仍然很低。因此，有必要发现新的调节分子和信号通路来调节胃癌细胞的转移。一种解整合素和金属蛋白酶 12（ADAM12）在胃癌组织中高度表达，并存在于患者尿液中。然而，ADAM12 是否以及如何调节胃癌细胞的迁移尚不清楚。在这项工作中，我们使用了带有点击糖的外泌体蛋白富集（SPECS）方法来纯化分泌的糖基化蛋白，并进行了定量蛋白质组学分析，以鉴定 ADAM12S（ADAM12 的短分泌形式）差异调节的分泌蛋白。我们的蛋白质组学和生化分析表明，ADAM12S 上调了细胞表面糖蛋白 CD146，一种细胞黏附分子和黑色素瘤标志物，这依赖于 ADAM12S 的催化残基。此外，我们发现 ADAM12S 增强的胃癌细胞迁移至少部分是由 CD146 介导的。这项工作可能有助于评估 ADAM12 是否可以成为治疗胃癌患者的潜在治疗靶点。
