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S100A14 Suppresses Metastasis of Nasopharyngeal Carcinoma by Inhibition of NF-kB Signaling through Degradation of IRAK1

ABSTRACT: Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential, and distant metastasis is the main reason for treatment failure. The underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we have identified S100 calcium binding protein A14 (S100A14) as a functional regulator suppressed NPC metastasis via inhibiting NF-kB signaling and reversing epithelial-mesenchymal transition (EMT). S100A14 was downregulated in highly metastatic NPC cells and NPC tissues. Analyzing 202 NPC samples by immunohistochemical staining revealed that lower S100A14 expression significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS), serving as an independent unfavorable prognostic factor. Gain- and loss-of-function studies confirmed that S100A14 suppressed NPC cellular motility in vitro and in vivo. Mechanically, S100A14 promoted ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop, which can be disrupted by the IRAK1 inhibitor T2457. Overall, our study uncovers the S100A14-IRAK1 feedback loop is a theranostic target for NPC metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148481 | GEO | 2021/03/01

REPOSITORIES: GEO

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Project description:Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential. From genomic expression profiles comparing clones derived from the NPC cell line CNE-2, serglycin (SRGN) was identified as one of the most up-regulated genes in the high-metastasis clone. Serglycin protein was secreted by the high-metastasis clone, but not by any of the low-metastasis clones. Suppression of serglycin by shRNA diminished serglycin secretion and subsequently inhibited the migration and invasion of high-metastasis clone, and also reduced its metastasis rate in vivo. Overexpression of serglycin in low-metastasis cells resulted in an increased metastasis rate in vivo. Moreover, secreted serglycin promoted cellular motility in the wild-type low-metastasis cells. Interestingly, suppression of serglycin reduced the protein level of vimentin but did not influence the level of E-cadherin in high-metastasis clone. Proliferation was not influenced by serglycin in both high-and low-metastasis clones. Clinically, serglycin expression was significantly elevated in liver metastases from NPC relative to its expression in primary tumors. The prognostic value of serglycin was evaluated by immunohistochemical staining of tissue microarrays of NPC tissues from 263 patients, followed by multivariate analyses. A high level of serglycin expression in primary NPC was found to be an independent unfavorable indicator for distant-metastasis-free survival and disease-free survival. In summary, serglycin regulates NPC metastasis via autocrine and paracrine means without influencing proliferation, and it serves as a prognostic indicator of metastasis-free survival and disease-free survival for NPC patients. Keywords: Gene Expression experiment High-metastasis clone (S18) and low-metastasis clones (S22 and S26) together with their parental line CNE-2 were subjected for gene expression profiling to identify the genes highly expressed in high-metastasis clone. To explore the molecular mechanism(s) underlying this important biological behavior, we performed genomic expression profiling of these four cell lines from in vitro cultured cells, as well as in vivo xenograft tumors generated in nude mice by subcutaneous injection of the cells into the BALB/c (nu/nu) female mice. Briefly, 1 × 10^5 cells were subcutaneously injected into the left flank of a nude mouse, and the tumors were collected when their volume was 150-250 mm^3.

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S100A14 Suppresses Metastasis of Nasopharyngeal Carcinoma by Inhibition of NF-kB Signaling through Degradation of IRAK1

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