Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma

Abstract

The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating malignant tumor progression. However, the core effector molecules involved in TME modulation of kidney renal papillary cell carcinoma (KIRP) are poorly understood. To address this question, a cohort containing 233 KIRP patients was derived from The Cancer Genome Atlas (TCGA) database, and the data were processed using the ESTIMATE algorithm. We further evaluated the relationship between immune scores (ISs) and stromal scores (SSs) and disease progression and found that high SSs were associated with a poor prognosis in KIRP. Differentially expressed genes (DEGs) were therefore screened based on SS scores, resulting in 2509 DEGs, including 1668 mRNAs, 783 long noncoding (lnc)RNAs, and 58 micro (mi)RNAs. DEGs were then filtered using the random variance and subjected to hierarchical clustering using EPCLUST. Weighted gene co-expression network analysis (WGCNA) was used to assess the prognostic capacity of these DEGs and identify target ceRNA networks, and lncRNA GUSBP11/miR-432-5p/CAMK2B in the turquoise module was selected as a promising ceRNA network. From this analysis CAMK2B was selected as the core gene predicted to be involved in stromal TMA regulation. We therefore explored the expression and function of CAMK2B in vitro and in vivo and provide evidence that this protein promotes stromal TME remodulation and inhibits proliferation in KIRP. Lastly, we show that vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, and close homolog of L1 (CHL1) act as downstream effectors of CAMK2B in KIRP. Thus, in this study, we show that the TME determines prognosis of KIRP patients via the core effector molecule CAMK2B, which mediates both microenvironmental remodeling and tumor progression. Based on these findings, we propose that remodeling of the stromal microenvironment could represent an improved therapeutic approach relative to immunotherapy for KIRP.

Long Non-Coding RNAs as Novel Biomarkers in the Clinical Management of Papillary Renal Cell Carcinoma Patients: A Promise or a Pledge?

“…Through weighted gene co-expression network analysis (WGCNA), they identified the competitive endogenous RNA (ceRNA) network lncRNA GUSBP11/miR-432-5p/CAMK2B as a promising prognostic factor. The authors also showed that CAMK2B promotes stromal TME remodulation and inhibits proliferation in pRCC [139]. So, the stromal score related network lncRNA GUSBP11/miR-432-5p/CAMK2B showed prognostic potential in pRCC, and CAMK2B may represent an effective therapeutic target [139].…”

“…Thus, the latter might be upstream the miR140-3p/GPRIN1 axis in pRCC [138]. A complementary approach was investigated by Jia et al [139], who focused the analysis on the core effector molecules involved in tumor microenvironment modulation of pRCC. By analyzing a cohort of 233 pRCC patients, whose expression data were available in the TCGA database, they determined a stromal score and divided the patients according to high and low scores.…”

“…Data validation in tissue samples confirmed that levels of CAMK2B and GUSBP11 were lower, while those of miR-432-5p were higher in tumor tissue than in paired tumor-adjacent tissue, suggesting a protective role of the axis in pRCC. The cellular mechanism of action for CAMK2B relates to inhibiting proliferation and remodeling angiogenesis and fibrogenesis, likely through inhibiting downstream effector genes, including vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)β, and close homolog of L1 (CHL1) [139]. To investigate the regulatory potential of pRCC toward the infiltrating immune cells related to tumorigenesis, the evaluation of the ceRNA network was based on the 318 samples from TCGA, including 285 pRCC and 33 normal control samples [140].…”

“…In another study, Jia et al explored how the tumor microenvironment (TME) and in particular, the TME effector genes and their competitive endogenous RNA (ceRNA) networks (previously described in Section 7.1 of this review) affect pRCC tumor progression [139]. Analyzing gene transcript, miRNA, and lncRNA expression data of pRCC on the TCGA datasets, they performed estimation of stromal scores and immune scores and found that high stromal scores were associated with a poor prognosis in pRCC.…”

“…Analyzing gene transcript, miRNA, and lncRNA expression data of pRCC on the TCGA datasets, they performed estimation of stromal scores and immune scores and found that high stromal scores were associated with a poor prognosis in pRCC. They then identified 2509 differentially expressed genes in high stromal score tumors compared to low stromal score tumors, including 1668 mRNAs, 783 lncRNAs, and 58 miRNAs [139]. Through weighted gene co-expression network analysis (WGCNA), they identified the competitive endogenous RNA (ceRNA) network lncRNA GUSBP11/miR-432-5p/CAMK2B as a promising prognostic factor.…”