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Tumor Discovery CK2 deregulation in non-small-cell lung cancer

CSNK2B-TSS1500/1stExon/5’UTR (Spearman: −0.26; in LUAD (Rho = 0.43) (Figure S7D-F). Overall, the
P = 9.54e-9) (Figure S3B). strongest and most significant correlations were observed
between CSNK2A1 and MDSC infiltration (Rho = 0.283,
3.3. Prognostic impact of CSNK2A1 and CSNK2B P = 1.49e-10) and between CSNK2B and MDSC infiltration
overexpression in LUAD (Rho = 0.43, P = 1.20e-23) in LUAD specimens.
We investigated whether the overexpression of CSNK2
subunits correlates with reduced OS in clinical cohorts of 3.5. Heightened CK-2 protein subunit levels and
NSCLC. Initially, we confirmed that CSNK2 mRNA levels enzymatic activity in LUAD and lung squamous
were consistently overexpressed across various tumor types, carcinoma specimens
including NSCLC, except for CSNK2A2 in LUAD (Figure S4). To assess CK2 protein subunit levels and enzymatic
Particularly, CSNK2A1 upregulation was substantially higher activity in NSCLC, we carried out IHC analysis on primary
than that of CSNK2A2 in LUAD (fold change: 1.40 vs. 0.95) LUAD and LUSC specimens from treatment-naive
and LUSC (fold change: 2.13 vs. 1.23) (Figure S4A and B), patients. CK2 subunit staining frequency and intensity
while CSNK2B displayed comparable expression levels in both varied across examined tissues but were consistently
LUAD and LUSC (LUAD: 1.35 vs. LUSC:1.40) (Figure S4C). higher than in tumor-matched para-neoplastic tissues
In alignment with CSNK2A1 and CSNK2B overexpression, a (Figures 5 and S8). CK2 subunits localized to both the
meta-analysis of mRNA expression versus OS indicated that nuclear and cytosolic compartments, while the Ki67
elevated of both subunits correlated with a poorer prognosis proliferation marker predominantly appeared in the
in LUAD but not LUSC patients (CSNK2A1: LUAD hazard nuclear region (Figure 5A).
ratio [HR] = 1.17, P < 0.01; LUSC HR = 1.07, P = 0.72; To quantify protein levels of CSNK2A1, CSNK2A2,
CSNK2B: LUAD HR = 1.11, P < 0.01; LUSC HR = 0.93, and CSNK2B in NSCLC tumors and corresponding
P = 0.16) (Figure 3). Conversely, CSNK2A2 overexpression para-neoplastic tissues, we applied a CIS incorporating
in LUAD was associated with improved OS (HR = 0.92, frequency and signal intensity (Table 1). CIS results for
P = 0.01) (Figure S5). Ki67 corroborated the aberrant growth of these tumors.
It is worth noting that, although data on metastatic The CIS analysis demonstrated that all CK2 protein
samples are limited and not stratified by NSCLC subtypes, subunits were significantly elevated in NSCLC tumors
preliminary findings suggest that CSNK2A1 (P = 1.28e-5) compared to para-neoplastic tissues (Table 1). To further
and CSNK2B (P = 1.33e-6), but not CSNK2A2 (P = 0.52), assess tumor specificity, we calculated CIS ratios (R) by
could be linked to lung metastasis (Figure S6). dividing tumor (T) score by para-neoplastic (PN) score, as
3.4. Correlation of CSNK2 subunit expression with shown in Equation I:
tumor infiltration by specific cell populations R = T/PN (1)
The oncogenic potential of CK2 has been linked to both The ratio served as an indicator for tumor-specific
tumor-intrinsic and tumor-extrinsic factors. Using marker association. The CSNK2A1 subunit exhibited
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various metrics to quantify the infiltration of immune and nearly two-fold higher tumor specificity (R = 3.9) than
stromal cells in tumors, we found that elevated CSNK2A1 CSNK2B (R = 2.1) and CSNK2A2 (R = 1.7) (Figure 6A).
mRNA expression levels were correlated with increased This specificity was further reinforced by analyzing samples
infiltration of cancer-associated fibroblasts (CAF) and with positive-to-strong positive (++/+++) staining, where
myeloid-derived suppressor cells (MDSC) across multiple CSNK2A1 showed a significantly higher tumor specificity
tumor subtypes (Figure 4A). (R = 18.3) than CSNK2A2 and CSNK2B (R = 3.1 – 3.2)
Tumor infiltration by CAFs showed a positive correlation (Figure 6A).
with CSNK2A1 mRNA overexpression according to Subsequently, we correlated the CIS values for each
three out of four metrics in both LUAD (CAF_TIDE, CK2 subunit with selected pathophysiological features
Rho = 0.185) and LUSC (CAF_TIDE, Rho = 0.164). MDSC in NSCLC patients (Tables S1 and S2). Protein levels
infiltration showed a stronger correlation with CSNK2A1 of the CSNK2A1 subunit showed a positive correlation
in LUAD (MDSC_TIDE, Rho = 0.283) compared to LUSC with smoking habit, tumor histology, tumor size, and
(MDSC_TIDE, Rho = 0.212) (Figure 4B and C). In contrast, clinical stage (Table S1). In contrast, elevated levels of the
weaker correlations were observed for CSNK2A2 in both CSNK2A2 subunit correlated only with tumor histology
LUAD and LUSC (Figure S7A-C). In addition, CSNK2B (Table S2). Notably, the catalytic CK2 subunits, CSNK2A1
expression levels correlated with MDSC infiltration in and CSNK2A2, were more highly expressed in LUSC than
both NSCLC subtypes, with a relatively high correlation LUAD samples (Figure 6B; Tables S1 and S2).

Volume 3 Issue 4 (2024) 6 doi: 10.36922/td.4571