Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides

Abstract

Abstract.Apart from SERPINB2 and SERPINB5, the roles of the remaining 13 members of the human SERPINB family in cancer metastasis are still unknown. In the present study, we demonstrated that most of these genes are differentially expressed in tumor tissues compared to matched normal tissues from lung or breast cancer patients. Overexpression of each SERPINB gene effectively suppressed the invasiveness and motility of malignant cancer cells. Among all of the genes, the SERPINB1, SERPINB5 and SERPINB7 genes were more potent, and the inhibitory effect was further enhanced by co-expression of any two of them. In addition, single treatment of the synthetic peptides corresponding to the P5-P5' sequences of the reactive center loop (RCL) of SERPINB1, SERPINB5 or SERPINB7 markedly suppressed the invasive and migratory properties of the cancer cells in a dose-dependent manner. More significantly, combination treatment of these peptides in cancer cells further improved the suppressive effect by 20-40%. Here, we determined the expression of all SERPINB family members in lung and breast cancer patients, and identified those members with potent inhibitory ability toward invasion and migration, and designed RCL-derived peptides to suppress the malignancy of cancer cells. Forced re-expression of these anti-invasive SERPINB genes or application of the SERPINB RCL-peptides may provide a reasonable strategy against lethal cancer metastasis. IntroductionCancer metastasis is the leading cause of morbidity and mortality in cancer patients. It is a highly complex process, including cell detachment, migration, invasion, circulation in blood vessels, adhesion, colonization at other sites and formation of secondary tumors (1). Prior to tumor cell detachment from the primary site, which leads to cell migration and invasion in the metastasis process, the extracellular matrix (ECM) microenvironment must be degraded by proteases, such as urokinase plasminogen activator (uPA), uPA receptor (uPAR) and the plasmin network (2,3) and matrix metalloproteinases (MMPs) (4). On the other hand, protease inhibitors negatively regulate the proteolysis process in cancer metastasis, e.g. plasminogen activator inhibitors (PAIs), PAI-1 (SERPINE1) and PAI-2 (SERPINB2) against uPA/uPAR/plasmin network and the tissue inhibitor of matrix metalloproteinases (TIMPs), TIMP-1 to TIMP-4 against MMPs.Serine protease inhibitors (serpins) regulate many physiological processes, such as blood coagulation, fibrinolysis, inflammation, complement activation and cell migration (5). Based on their phylogenic relationships, the superfamily is divided into 16 different clades (A-P), in which human serpins are the first 9 clades (A-I) (6). The clade B serpins (SERPINB family) is the largest one within the human serpin superfamily. It contains 13 genes located on chromosome 6p25 (SERPINB1, SERPINB6 and SERPINB9) and 18q21 (the remaining members of the family). Unlike circulating serpins, the SERPINB family genes lack the N and C terminus extension regions common to other serpin...

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