TSPAN1 inhibits metastasis of nasopharyngeal carcinoma via suppressing NF-kB signaling.

Nasopharyngeal carcinoma (NPC) originates in the epithelial cells of the nasopharynx and is a common malignant tumor in southern China and Southeast Asia. Metastasis of NPC remains the main cause of death for NPC patients even though the tumor is sensitive to radiotherapy and chemotherapy. Here, we found that the transmembrane protein tetraspanin1 (TSPAN1) potently inhibited the in vitro migration and invasion, as well as, the in vivo metastasis of NPC cells via interacting with the IKBB protein. In addition, TSPAN1 was essential in preventing the overactivation of the NF-kB pathway in TSPAN1 overexpressing NPC cells. Furthermore, reduced TSPAN1 expression was associated with NPC metastasis and the poor prognosis of NPC patients. These results uncovered the suppressive role of TSPAN1 against NF-kB signaling in NPC cells for preventing NPC metastasis. Its therapeutic value warrants further investigation.

Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling.

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.

Correlated with better prognosis, CSTA inhibits metastasis of nasopharyngeal carcinoma cells via suppressing AKT signaling through promoting METTL3 degradation.

BACKGROUND: Metastasis is one of the main obstacles impeding the survival of nasopharyngeal carcinoma (NPC) patients, with the molecular mechanism underlying NPC metastasis still unclear. RESULTS: In this study, Cystatin A (CSTA) was found downregulated in NPC tissues with metastasis compared with those without metastasis. Shorter overall survival and distant metastasis-free survival were found in NPC patients with lower CSTA expression. Using functional assays, we found that CSTA prevented both the in vitro motility of NPC cells and their ability to metastasize in vivo. Transcriptome sequencing and western blot analysis revealed that CSTA inhibited the phosphorylation of AKT. Moreover, activating AKT using AKT agonist SG79 rescued the motility of CSTA-overexpressing NPC cells, whereas, treatment with AKT inhibitor MK2206 inhibited the motility of CSTA-knockdown NPC cells. Mechanically, immunoprecipitation coupled mass spectrometry found that CSTA interacted with the N6-adenosine-methyltransferase subunit METTL3 and promoted its ubiquitin-proteasome-mediated degradation following the upregulation of NKX3-1 and LHPP, which are negative regulators of AKT. Furthermore, knock-down of NKX3-1 and LHPP enhanced the motility of CSTA-overexpressing NPC cells. CONCLUSIONS: The inhibitory effect of CSTA upon NPC metastasis mainly depended on suppressing AKT signaling by the upregulation of NKX3-1 and LHPP expression resulting from the binding between CSTA and METLL3. Our study suggests that the CSTA-METLL3-NKX3-1/LHPP-AKT axis could be of therapeutic value for inhibiting NPC metastasis.