Abstract
Urokinase plasminogen activator receptor (uPAR), a member of the lymphocyte antigen 6 protein superfamily, is overexpressed in different types of cancers and plays an important role in tumorigenesis and development. In this study, we successfully targeted uPAR by CRISPR/Cas9 system in two human cancer cell lines with two individual sgRNAs. Knockout of uPAR inhibited cell proliferation, migration and invasion. Furthermore, knockout of uPAR decreases resistance to 5-FU, cisplatin, docetaxel, and doxorubicin in these cells. Although there are several limitations in the application of CRISPR/Cas9 system for cancer patients, our study offers valuable evidences for the role of uPAR in cancer malignancy and drug resistance.
Highlights
Urokinase plasminogen activator receptor, known as CD87 and encoded by PLAUR gene, is a member of the lymphocyte antigen 6 protein superfamily [1]. uPAR is a glycoprotein consisting of 313 amino acid residues with only the extracellular domain, no transmembrane and intracellular structures, and is attached to the cell membrane via glycosylphosphatidylinositol anchors [1]. uPAR binds to and activates uPA to cleaving plasminogen to plasmin, triggering the remodeling of extracellular matrix and playing a key role in cell adhesion, migration, proliferation, and survival [2]
To establish cell lines stably expressed sgRNA to target uPAR, HCT8/T, and KBV200 cells were selected with puromycin after transduction with LentiCRISPRv2 viral supernatant
The sequencing results of PCR productions showed that 1 base was inserted into the target position of HCT8/T uPAR-sg1 cells and 3 base mismatches and a large deletion in the target position of HCT8/T uPAR-sg2 cells (Figure 1D)
Summary
Urokinase plasminogen activator (uPA) receptor (uPAR), known as CD87 and encoded by PLAUR gene, is a member of the lymphocyte antigen 6 protein superfamily [1]. uPAR is a glycoprotein consisting of 313 amino acid residues with only the extracellular domain, no transmembrane and intracellular structures, and is attached to the cell membrane via glycosylphosphatidylinositol anchors [1]. uPAR binds to and activates uPA to cleaving plasminogen to plasmin, triggering the remodeling of extracellular matrix and playing a key role in cell adhesion, migration, proliferation, and survival [2]. UPAR binds to and activates uPA to cleaving plasminogen to plasmin, triggering the remodeling of extracellular matrix and playing a key role in cell adhesion, migration, proliferation, and survival [2]. Besides uPA, uPAR can interact with other proteins, including vitronectin, integrins, and EGFR, etc to regulate multiple signal pathways [2]. The inhibitors blocks the interaction of uPAR with uPA, including: small molecules UK1 [4], WX-UK1 [5], WX-671 [6], etc; peptides Mupain-1 [7], AE105 [8], ATF [9], etc; and monoclonal antibody ATN-291 [10]. There are inhibitors that inhibit the interaction of uPAR with integrins, including: peptides P25 [11], a325 [12], H245A [13], etc; and monoclonal antibody ATN-658 [14]. It is necessary to develop new approaches to target uPAR for treatment cancer and other diseases
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