Casein kinase-2 (CK2) is a constitutively active kinase that supports neoplastic properties. Although there is an extensive body of preclinical research on CK2, translational and clinical information remains limited and sparse. In this study, we interrogated clinical multiomics databases to examine CK2 deregulation across various cancers. Specifically, we analyzed the mutational frequency, copy-number alterations (CNA), and mRNA expression of CK2 catalytic (CSNK2A1 and CSNK2A2) and regulatory (CSNK2B) subunits across two major cancer genomic repositories (The Cancer Genome Atlas/International Cancer Genome Consortium). These genomic and transcriptomic analyses were further focused on lung cancer and complemented by in situ assessments of CK2 protein subunits and enzymatic activity in biopsies from non-small-cell lung cancer (NSCLC). Our findings indicate that gene mutations and CNA do not account for the elevated mRNA levels and enzymatic activity of CK2 subunits in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Particularly, the upregulation of CSNK2A1 and CSNK2B mRNA was associated with a worse prognosis and showed a direct correlation with the infiltration of myeloid-derived suppressor cells in LUAD. At the protein levels, all CK2 subunits and enzymatic activity were markedly elevated in LUAD (n = 103) and LUSC (n = 31) biopsies; however, only CSNK2A1 expression correlated positively with tumor size and disease stage. Finally, CSNK2A1 appeared to be more tumor-specific than CSNK2A2, suggesting that targeted therapies against this catalytic subunit or its homotetramer may offer a more favorable therapeutic window in NSCLC.

Alarmins are endogenous molecules that alert the immune system to circumvent the invading antigens in the host. They are basically sensed by specific cellular receptors, leading to recruitment and activation of dendritic cells to mount innate and adaptive immune responses. However, a dual role of alarmins as mediators in either antitumor immunity or tumor progression has been also reported. Here, we investigated the status of the HMGB-1 alarmin and the alarmin-like NPM/B23 in 162 debut NSCLC patients and 60 age-matched healthy individuals as control. NSCLC patients exhibited lower median values of circulating HMGB-1 compared to control (30.04 versus 37.30 ng/ml, p=0.02), but higher levels of HMGB-1 were positively correlated with tumor size > 2.0 cm (p=0.004) irrespectively of tumor histology. Otherwise, circulating NPM/B23 levels were significantly increased in NSCLC patients respect to control (812 versus 551 pg/ml, p=0.00027). Likewise, patients with tumors > 2 cm exhibited higher levels NPM/B23. Strong association was observed between HMGB-1 and NPM/B23 in serum of NSCLC patients (r=0.679 p=0.0001) compared to healthy individuals who exhibited a weaker correlation (r=0.278 p=0.031). However, the strongest correlation between both alarmins was observed in patients with STAS and tumors ≤ 2 cm (r=0.900 p=0.0001). Co-expression of HMGB-1 and NPM/B23 was also observed in tumor tissues although to a lesser extent. Our data unveil that concomitant circulating HMGB-1 and NPM/B23 could serve as a putative alarmin-based biomarker of NSCLC disease progression.