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

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 alpha 1,3-mannosyltransferase 3 (ALG3), which catalyzes the alpha 1,3-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/alpha 1,3-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) alpha 1,3-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.

Automated summary

Peritoneal metastasis is a major factor contributing to poor prognosis and high mortality in ovarian cancer patients. This study demonstrates that elevated levels of ALG3 and alpha 1,3-mannosylation are associated with ovarian cancer malignancy and poor patient prognosis. The downregulation of ALG3 inhibits proliferation and peritoneal metastasis of ovarian cancer cells. Additionally, ALG3 enhances uPAR activation and promotes ovarian cancer peritoneal metastasis through the ADAM8/Ras/ERK pathway. Overall, ALG3 could serve as a potential diagnostic biomarker and therapeutic target for ovarian cancer.