Abstract
PDZ-binding kinase (PBK) is known to regulate tumor progression in some cancer types. However, its relationship to immune cell infiltration and prognosis in different cancers is unclear. This was investigated in the present study by analyzing data from TCGA, GEO, GETx, TIMER, CPTAC, GEPIA2, cBioPortal, GSCALite, PROGNOSCAN, PharmacoDB, STRING, and ENCORI databases. PBK was overexpressed in most tumors including adenocortical carcinoma (hazard ratio [HR] = 2.178, p < 0.001), kidney renal clear cell carcinoma (KIRC; HR = 1.907, p < 0.001), kidney renal papillary cell carcinoma (HR = 3.024, p < 0.001), and lung adenocarcinoma (HR = 1.255, p < 0.001), in which it was associated with poor overall survival and advanced pathologic stage. PBK methylation level was a prognostic marker in thyroid carcinoma (THCA). PBK expression was positively correlated with the levels of BIRC5, CCNB1, CDC20, CDK1, DLGAP5, MAD2L1, MELK, PLK1, TOP2A, and TTK in 32 tumor types; and with the levels of the transcription factors E2F1 and MYC, which regulate apoptosis, the cell cycle, cell proliferation and invasion, tumorigenesis, and metastasis. It was also negatively regulated by the microRNAs hsa-miR-101-5p, hsa-miR-145-5p, and hsa-miR-5694. PBK expression in KIRC, liver hepatocellular carcinoma, THCA, and thymoma was positively correlated with the infiltration of immune cells including B cells, CD4+T cells, CD8+ T cells, macrophages, monocytes, and neutrophils. The results of the functional enrichment analysis suggested that PBK and related genes contribute to tumor development via cell cycle regulation. We also identified 20 drugs that potentially inhibit PBK expression. Thus, PBK is associated with survival outcome in a variety of cancers and may promote tumor development and progression by increasing immune cell infiltration into the tumor microenvironment. These findings indicate that PBK is a potential therapeutic target and has prognostic value in cancer treatment.
Highlights
PDZ-binding kinase (PBK), known as T lymphokineactivated killer cell-derived protein kinase (TOPK), is a serinethreonine kinase of the mitogen-activated protein kinase (MAPKK) family that regulates cell survival, proliferation, growth, apoptosis, and inflammation (Abe et al, 2000; Gaudet et al, 2000; Zhao et al, 2020)
PBK is differentially expressed between cancer and normal tissues and modulates radiosensitivity in tumors, suggesting that patients can be treated with radiotherapy (Pirovano et al, 2017); and a recent retrospective analysis showed that PBK expression was negatively correlated with the prognosis of patients with oral squamous cell carcinoma treated with radiotherapy (Yu et al, 2021)
PBK expression was higher in adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), rectum adenocarcinoma (READ), prostate adenocarcinoma (PRAD), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS) but lower in acute myeloid leukemia (LAML) compared to normal tissues
Summary
PDZ-binding kinase (PBK), known as T lymphokineactivated killer cell-derived protein kinase (TOPK), is a serinethreonine kinase of the mitogen-activated protein kinase (MAPKK) family that regulates cell survival, proliferation, growth, apoptosis, and inflammation (Abe et al, 2000; Gaudet et al, 2000; Zhao et al, 2020). PBK knockdown was shown to result in cytokinesis defects in cancer cells (Park et al, 2010). PBK is overexpressed in a variety of active proliferating cells including malignant tumor cells as well as normal sperm cells. PBK directly phosphorylates extracellular signal-regulated kinase (ERK), histone H3 (Ser10), histone H2AX (Ser139), peroxide-reduced protein 1 (PRX1, Ser32), JNK1 (Thr183/Tyr185), and p53associated protein kinase (PRPK, Ser250) (Zykova et al, 2010; Roh et al, 2018) and activates downstream signaling pathways including MAPK, ribosomal S6 kinase (RSK), and transcription factors (TFs) such as activating protein 1 (AP-1) or nuclear factor kappa B (NF-κB) through phosphorylation, thereby promoting cell proliferation, migration, and invasion (Aksamitiene et al, 2010; Park et al, 2014; Ishikawa et al, 2018). PBK likely plays an important role in cancer development
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