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ALG3 通过增加 α1,3-甘露糖化 uPAR 和 ADAM8 的相互作用促进卵巢癌细胞腹膜转移。

ALG3 Promotes Peritoneal Metastasis of Ovarian Cancer through Increasing Interaction of α1,3-mannosylated uPAR and ADAM8.

机构信息

Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.

Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian 116044, China.

出版信息

Cells. 2022 Oct 6;11(19):3141. doi: 10.3390/cells11193141.

DOI:10.3390/cells11193141
PMID:36231102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9563302/
Abstract

Peritoneal metastasis is the main cause of poor prognoses and high mortality in ovarian cancer patients. Abnormal protein glycosylation modification is associated with cancer malignancy. Elevated α1,3-mannosyltransferase 3 (ALG3), which catalyzes the α1,3-mannosylation of glycoproteins, has been found in some malignant tumors. However, the pathological significance of ALG3 and its regulatory mechanism in ovarian cancer metastasis is unclear. The results showed that the level of ALG3/α1,3-mannosylation was higher in human ovarian cancer tissues compared with normal ovarian tissues, as measured by Lectin chip, Western blot and Lectin blot analyses, as well as ovarian tissue microarray analysis. ALG3 was also correlated with the poor prognosis of ovarian cancer patients, according to survival analysis. The downregulation of ALG3 decreased the proliferation, stemness and peritoneal metastasis of ovarian cancer cells. The increase in urokinase plasminogen activator receptor (uPAR) α1,3-mannosylation catalyzed by ALG3 enhanced urokinase plasminogen activator (uPA)/uPAR activation and the interaction of uPAR with a disintegrin and metalloproteinase 8 (ADAM8), which promoted ovarian cancer peritoneal metastasis via the ADAM8/Ras/ERK pathway. Furthermore, decreased ALG3 suppressed ascites formation and the peritoneal metastasis of ovarian cancer cells in mice. This study highlights ALG3 as a potential diagnostic biomarker and prospective therapeutic target for ovarian cancer.

摘要

腹膜转移是卵巢癌患者预后不良和死亡率高的主要原因。异常的蛋白质糖基化修饰与癌症的恶性程度有关。在一些恶性肿瘤中发现了α1,3-甘露糖基转移酶 3（ALG3），它可以催化糖蛋白的α1,3-甘露糖化。然而，ALG3 的病理学意义及其在卵巢癌转移中的调控机制尚不清楚。研究结果表明，通过凝集素芯片、Western blot 和凝集素印迹分析以及卵巢组织微阵列分析，ALG3/α1,3-甘露糖化水平在人卵巢癌组织中高于正常卵巢组织。根据生存分析，ALG3 还与卵巢癌患者的不良预后相关。ALG3 的下调降低了卵巢癌细胞的增殖、干性和腹膜转移能力。ALG3 催化的尿激酶型纤溶酶原激活物受体（uPAR）α1,3-甘露糖化增加了尿激酶型纤溶酶原激活物（uPA）/uPAR 的激活以及 uPAR 与解整合素金属蛋白酶 8（ADAM8）的相互作用，通过 ADAM8/Ras/ERK 通路促进卵巢癌腹膜转移。此外，ALG3 的下调抑制了小鼠腹水的形成和卵巢癌细胞的腹膜转移。这项研究强调了 ALG3 作为卵巢癌潜在的诊断生物标志物和有前途的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/45ffa591bbb8/cells-11-03141-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/067162f8e74e/cells-11-03141-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/3d11416ab3f7/cells-11-03141-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/8ec3e683a26e/cells-11-03141-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/ba03c4c1caef/cells-11-03141-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/9fb85a213514/cells-11-03141-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/2c97dc544b0b/cells-11-03141-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/5b6bb19e6c9a/cells-11-03141-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/45ffa591bbb8/cells-11-03141-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/067162f8e74e/cells-11-03141-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/3d11416ab3f7/cells-11-03141-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/8ec3e683a26e/cells-11-03141-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/ba03c4c1caef/cells-11-03141-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/9fb85a213514/cells-11-03141-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/2c97dc544b0b/cells-11-03141-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/5b6bb19e6c9a/cells-11-03141-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9074/9563302/45ffa591bbb8/cells-11-03141-g008.jpg

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