Abstract
BackgroundTumor susceptibility gene 101 (TSG101) was initially identified in fibroblasts as a tumor suppressor gene but subsequent studies show that TSG101 also functions as a tumor-enhancing gene in some epithelial tumor cells. Although previous studies have unraveled diverse biological functions of TSG101, the precise mechanism by which TSG101 is involved in carcinogenesis and tumor progression in a bidirectional and multifaceted manner remains unclear.MethodsTo reveal the mechanism underlying bidirectional modulation of cell invasion by TSG101, we used RNA interference to examine whether TSG101 depletion bidirectionally modulated matrix metalloproteinase (MMP)-9 expression in different cell types.ResultsTSG101 depletion promoted cell invasion of HT1080 cells but contrarily reduced cell invasion of HeLaS3 cells. In HT1080 cells, TSG101 depletion increased both baseline and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 secretion through enhancing MMP-9 mRNA expression, but did not affect the expression or activation of MMP-2. In contrast, TSG101 depletion decreased PMA-induced MMP-9 secretion through reducing MMP-9 mRNA expression in HeLaS3 cells. TSG101 depletion had little impact on the signaling pathways required for the activation of transcription of MMP-9 or MMP-9 mRNA stability in either cell line.ConclusionTSG101 bidirectionally modulates cell invasion through regulating MMP-9 mRNA expression in different cell types. Our results provide a mechanistic context for the role of TSG101 in cell invasion as a multifaceted gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1942-1) contains supplementary material, which is available to authorized users.
Highlights
Tumor susceptibility gene 101 (TSG101) was initially identified in fibroblasts as a tumor suppressor gene but subsequent studies show that TSG101 functions as a tumor-enhancing gene in some epithelial tumor cells
TSG101 depletion promotes cell invasion of HT1080 cells To explore the roles of TSG101 as a tumor susceptibility gene, we used RNA interference (RNAi) to examine whether TSG101 is involved in tumor cell biological behaviors such as migration and invasion in HT1080 fibrosarcoma cells
TSG101 depletion leads to increased levels of Matrix metalloproteinases (MMPs)-9 expression in HT1080 cells Gelatinases such as MMP-2 and MMP-9 play a crucial role in tumor cell aggressiveness such as invasion and metastasis [27,28,29,30]
Summary
Tumor susceptibility gene 101 (TSG101) was initially identified in fibroblasts as a tumor suppressor gene but subsequent studies show that TSG101 functions as a tumor-enhancing gene in some epithelial tumor cells. Several recent reports have demonstrated that TSG101 contrarily functions as a tumor-enhancing gene in some epithelial tumor cells [19, 20], suggesting that TSG101 may play divergent roles in carcinogenesis and tumor progression in different cell types. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that degrade the extracellular matrix (ECM) [21] This gene family consists of 23 members in human and is subdivided into two types: soluble MMPs and transmembrane-type MMPs. Most soluble MMPs are secreted from the cells as inactive zymogens that are activated on the cell membrane surface. Transmembrane-type MMPs are anchored to the cell membrane where they degrade the ECM and activate other MMPs. MMP activity is tightly regulated at the levels of transcription, activation of proenzymes by post-translational processes, and inhibition by endogenous proteins, i.e., tissue inhibitors of metalloproteinases (TIMP) [22]. A number of signaling pathways including the PKC, ERK, p38 kinase, JNK, PI3-K/Akt, and NF-κB signaling pathways are involved in the regulation of MMP-9 expression by various stimuli [38,39,40,41,42,43,44,45]
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