Cancer-Specifically Re-Spliced TSG101 mRNA Promotes Invasion and Metastasis of Nasopharyngeal Carcinoma

Abstract

TSG101 (Tumor susceptibility 101) gene and its aberrantly spliced isoform, termed TSG101∆154-1054, are tightly linked to tumorigenesis in various cancers. The aberrant TSG101∆154-1054 mRNA is generated from cancer-specific re-splicing of mature TSG101 mRNA. The TSG101∆154-1054 protein protects the full-length TSG101 protein from ubiquitin-mediated degradation, implicating TSG101∆154-1054 protein in the progression of cancer. Here, we confirmed that the presence of TSG101∆154-1054 mRNA indeed caused an accumulation of the TSG101 protein in biopsies of human nasopharyngeal carcinoma (NPC), which was recapitulated by the overexpression of TSG101∆154-1054 in the NPC cell line TW01. We demonstrate the potential function of the TSG101∆154-1054 protein in the malignancy of human NPC with scratch-wound healing and transwell invasion assays. By increasing the stability of the TSG101 protein, TSG101∆154-1054 specifically enhanced TSG101-mediated TW01 cell migration and invasion, suggesting the involvement in NPC metastasis in vivo. This finding sheds light on the functional significance of TSG101∆154-1054 generation via re-splicing of TSG101 mRNA in NPC metastasis and hints at its potential importance as a therapeutic target.

Adding Some “Splice” to Stress Eating: Autophagy, ESCRT and Alternative Splicing Orchestrate the Cellular Stress Response

“…Alternative splicing also plays a role in the induction and maintenance of autophagy directly by altering splicing of autophagy-associated genes like Beclin1 [65] (Table 1) or indirectly via the splicing of genes such as Heh1 that modulate subcellular recruitment of the yeast homolog of CHMP7, Chmp7 [83] (Figure 2). Furthermore, alternative and/or mis-splicing of ESCRT genes that affect autophagy play roles in the pathogenesis of several diseases, including TSG101 in cancer and CHMP2B and VPS4B mis-splicing in the pathogenesis of FLTD and dental dysplasia I (respectively) [101,141] (Figure 4). These findings also have implications for therapy.…”

“…Tal negatively regulates the TSG101 levels by targeting the protein for ubiquitination. However, Chua et al [101] reported in 2019 that TSG101 accumulation results from TSG∆154-1054 by competitively binding to Tal and not MDM2, thus protecting TSG101 from polyubiquitination and proteasomal degradation, which in turn promotes malignancy. In addition, Tal cannot target TSG∆154-1054 for degradation either, regardless of Tal binding to TSG∆154-1054 [93].…”

The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing

“…The re-spliced TSG101 mRNA, TSG101Δ154-1054 mRNA ( Figure 1 a), produces an aberrant protein product that up-regulates the full-size TSG101 by interfering with the ubiquitin-dependent degradation of TSG101 protein [ 10 ]. Importantly, overexpression of the TSG101 protein enhances cell proliferation and promotes malignant tumor formation in nude mice [ 10 , 11 ]. TSG101 is essential for cell proliferation and survival, while its overexpression is closely associated with aggressive metastasis and progression in various cancers (reviewed in [ 12 ]).…”

Impact of Alternative Splicing Variants on Liver Cancer Biology

“…This process might result from the impairment during carcinogenesis of a not-yet well-understood mechanism existing in normal cells to prevent potentially harmful mRNA re-splicing events [ 12 ]. Cancer-specific re-splicing, such as that of TSG101 mRNA in nasopharyngeal carcinoma, has been proposed to be associated with enhanced invasiveness and metastasis [ 13 ].…”