Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9

• Published in: PloS one 2013-06, Vol.8 (6), p.e67766-e67766
• Main Authors: Herr, Michael J, Kotha, Jayaprakash, Hagedorn, Nikolaus, Smith, Blake, Jennings, Lisa K
• Format: Article
• Language: English
• Subjects: Biochemistry; Biology; Cancer; CD9 antigen; Cell culture; Cell Line, Tumor; Cell surface; Fibrosarcoma; Fibrosarcoma - genetics; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Gelatinase B; Genotype & phenotype; Humans; Immunoglobulins; Immunology; Internal medicine; Invasiveness; Kinases; Laboratories; Liver cancer; Mathematics; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medicine; Metalloproteinase; Metastases; Metastasis; Morbidity; Motility; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Penicillin; Phenotype; Prostate; Regulators; Science; Signal transduction; Signal Transduction - genetics; Signaling; siRNA; Statistical analysis; Tetraspanin-29 - genetics; Tetraspanin-29 - metabolism; Tetraspanins - genetics; Tetraspanins - metabolism; Tumor cell lines; Up-regulation; Up-Regulation - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067766

Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080) to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression.