Lymphotoxin‐β receptor‐NIK signaling induces alternative RELB/NF‐κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer

Abstract

Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin‐β (LTβ), receptor LTβR, and NF‐κB‐inducing kinase (NIK), promote the aberrant activation of alternative NF‐κB2/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF‐kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LTβR is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LTβ, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LTβR, NIK, and RELB proteins. Recombinant LTβ, and siRNA depletion of endogenous LTβR and NIK, modulated expression of LTβR, NIK, and nuclear translocation of NF‐κB2(p52)/RELB as well as functional NF‐κB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]‐Iso‐Quinoline Dione) reduced the protein expression of NIK and NF‐κB2(p52)/RELB, and blocked LTβ induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LTβ‐induces expression of migration and metastasis related genes, including hepatocyte growth/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LTβ is expressed. Our findings show that LTβ/LTβR promotes activation of the alternative NIK‐NF‐κB2/RELB pathway to enhance MET‐mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.

The decreased mean platelet volume is associated with poor prognosis in patients with oropharyngeal cancer treated with radiotherapy

“…Despite several advances in the management of OPSCC including novel imaging as well as innovations in surgical and radiotherapeutic techniques, the overall survival of patients with OPSCC still remains around 50% at 5 years, primarily because of locoregional and/or systemic recurrence of disease [ 2 ]. In recent years, many efforts have been undertaken to identify novel molecular and cellular prognostic biomarkers in order to improve the prediction of the risk of OPSCC recurrence, however, high costs of analyses, time-consuming preparation and lack of standardization limit their application in routine clinical practice [ 3 ]. In addition, there is increasing data demonstrating that radiomics provides important prognostic information for the risk assessment of specific outcomes in head and neck cancer [ 4 , 5 ].…”

Head and Neck Cancers Promote an Inflammatory Transcriptome through Coactivation of Classic and Alternative NF-κB Pathways

“…In addition, genes involved in the alternative NF-κB pathway such as BIRC3 were highly inducible by LTβ in a HPV(+) cell line. The latter findings might guide future targeted and immune therapies in HPV(+) HNSCC, where inhibition of the alternative NF-κB pathway or prosurvival targets such as BIRC3 (IAP2) combined with activation of the death pathway by death receptor agonists could be more effective (12,(40)(41)(42).…”

“…The classical pathway plays an important role in cancer cell proliferation and survival, and in therapeutic resistance (4)(5)(6)(7). In HNSCC, we also showed that components of the alternative NF-κB pathway, RELB and NF-κB2 (p100/p52), are modulated by lymphotoxin-β (LTβ) and other ligands through the activation of NF-κB inducing kinase (NIK) and IKKα (CHUK) (11,12). The alternative pathway promotes tumor cell migration, an important feature underlying malignant spread and metastasis.…”

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

“…Early studies from our lab demonstrated that key components of the canonical NFκB pathway are aberrantly activated in HNSCC and are further activated by TNFα via the IKK complex [ 22 , 102 , 103 ]. Furthermore, recent studies have demonstrated the activation of non-canonical NFκB signalling, involving NIK and IKKα [ 104 , 105 , 106 ]. Both of the NFκB pathways have also been shown to interact with other pro-oncogenic signalling pathways, including the EGFR, STAT3, and AP-1 pathways [ 104 , 107 , 108 ].…”