Elevated urokinase-specific surface receptor expression is maintained through its interaction with urokinase plasminogen activator.

Urokinase plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in various neoplasms, and play a key role in tumor progression and metastasis. In this study, we examined uPA and uPAR expression in a variety of human breast cancer cell lines and found that lines with elevated uPA expression also exhibited high uPAR expression, suggesting the possibility that uPA and uPAR are regulated in concert. To test this possibility, we introduced antisense uPA RNA and antisense uPAR RNA in MDA-MB-231 and BT-549 lines that express high levels of uPA and uPAR. Antisense uPA RNA not only downregulated uPA expression, but also greatly reduced uPAR expression in both lines. However, antisense uPAR RNA-reduced uPAR expression with no apparent inhibitory effect on the levels of uPA. These results indicate that expression of uPAR requires uPA but not vice versa. With a panel of uPA and uPAR monoclonal antibodies (mAbs), we observed that the mAbs disrupting uPA and uPAR interaction, rather than mAb inhibiting uPA protease activity, reduced uPAR expression. Moreover, adding soluble single chain uPA (scuPA) to MDA-MB-231 or BT-549 cells expressing antisense uPA mRNA-restored uPAR expression. These findings suggest that uPA dictates uPAR expression and that uPA binding to uPAR transmits signals for uPAR expression. Finally, we provided evidence that Fyn, a Src family kinase, is involved in uPA-induced uPAR expression.

Mahanivong C ，Yu J ，Huang S 《MOLECULAR CARCINOGENESIS》

Expressions of urokinase-type plasminogen activator, its receptor and plasminogen activator inhibitor-1 in gastric cancer cells and effects of Helicobacter pylori.

Iwamoto J ，Mizokami Y ，Takahashi K ，Nakajima K ，Ohtsubo T ，Miura S ，Narasaka T ，Takeyama H ，Omata T ，Shimokobe K ，Ito M ，Takehara H ，Matsuoka T ... -  《SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY》

The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion.

Hildenbrand R ，Schaaf A 《INTERNATIONAL JOURNAL OF ONCOLOGY》

Calcitonin inhibits invasion of breast cancer cells: involvement of urokinase-type plasminogen activator (uPA) and uPA receptor.

Han B ，Nakamura M ，Zhou G ，Ishii A ，Nakamura A ，Bai Y ，Mori I ，Kakudo K ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》

Role of urokinase plasminogen activator receptor in thrombospondin 1-mediated tumor cell invasion.

We previously showed that thrombospondin 1 (TSP-1) upregulates the plasminogen/plasmin system and promotes breast tumor cell invasion. Preliminary data from our laboratory using neutralizing antibodies suggested that the upregulation in breast tumor cell invasion seen in response to TSP-1 involved the urokinase plasminogen activator receptor (uPAR). To confirm these findings in MDA-MB-231 breast cancer cells, we developed three other strategies to study the role of uPAR in tumor cell adhesion and TSP-1-mediated tumor cell invasion: (a) enzymatic cleavage of uPAR with glycosylphosphatidylinositol-specific phospholipase C; (b) inhibition at the mRNA level with a uPAR antisense construct (cells named LKAS-MDA); (c) inhibition of plasminogen binding with the lysine analogue epsilon-aminocaproic acid. Adhesion to laminin and type I and type IV collagen with and without the addition of epsilon-aminocaproic acid was studied. Tumor cell invasion was studied in a modified Boyden chamber collagen invasion assay. Antisense uPAR inhibition decreased uPAR expression by 48-66% and cell-associated urokinase plasminogen activator (uPA) by 30-68%. Additionally, antisense uPAR inhibition induced a 68-70% reduction in uPA and plasmin activities. Antisense uPAR transfection increased tumor cell adhesion by 46-53%. A similar effect was observed in epsilon-aminocaproic acid-treated MDA-MB-231 cells. TSP-1-mediated tumor cell invasion was almost completely inhibited by either antisense uPAR inhibition or treatment with phospholipase C or epsilon-aminocaproic acid. We conclude that uPAR plays a crucial role in the regulation of tumor cell adhesion and TSP-1-mediated tumor cell invasion.

Albo D ，Berger DH ，Rothman VL ，Tuszynski GP ... -  《JOURNAL OF SURGICAL RESEARCH》