CDC14B is a favorable biomarker for recurrence and prognosis of GBM

Glioma is the most common malignant primary brain tumor in adults, and is classified from grade I to IV in WHO classification [1]. Glioblastoma (GBM) is the majority of WHO grade IV glioma, accounting for 57 % of all gliomas and 48 % of primary brain tumors [2]. The general incidence of GBM is 3.2 per 100,000 population in the United States, and the incidence increases dramatically with the age of patients and reaches a peak incidence of 15.24 per 100,000 between 75 and 84 years old [3]. The prognoses of many types of cancers have been extensively improved thanks to the development of chemotherapy, target therapy and immunotherapy, but the outcomes of GBM have not got significant progresses though many tumor-treatment approaches have been made such as the whole-brain radiation therapy. The prognosis of GBM is still very poor with the 5-year OS rate of GBM as low as 5 % partly because it is insensitive to these treatments in most cases [4].

Tyrosine phosphorylation is involved in almost all the cellular processes such as cell proliferation, differentiation and apoptosis [5]. The tyrosine residues are phosphorylated by tyrosine kinase and dephosphorylated by protein tyrosine phosphatases (PTPs) [6]. In PTP superfamily, there is a subgroup called dual specificity phosphatases (DUSPs) which dephosphorylate not only tyrosine residue, but also the serine and threonine residues of proteins. Compared to classic PTPs, substrates and exact regulatory mechanism of DUSPs are not fully studied, although DUSPs participate in the regulation of many cellular functions and signaling pathways [7]. CDC14 is a conserved DUSP functioning mainly, but not limited in DNA damage response and cell division [8], [9]. In budding yeast, CDC14 is essential in G1 phase entry by inactivating cyclin-dependent kinase (CDK) activity at the end of mitosis [10], [11]. CDC14 contains two homologs in human, CDC14A and CDC14B [12], which have different subcellular localizations and seemingly different cellular functions [13].

In human cells, CDC14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint [9]. The low CDK activity in G1 phase is essential for the initiation of DNA replication to enter S phase [14]. In tumor, CDC14B expression is aberrant or mutated in several cancer types such as medullary thyroid cancer and renal cell carcinoma, suggesting tumor-suppressive function of CDC14B [15], [16]. In GBM, the role of CDC14B is rarely studied and controversial. On one hand, CDC14B was shown to promoted the degradation of p53 and inhibit p53 activity in glioma cells with in vitro experiments [17]. On the other hand, CDC14B was identified to be a target of adenosine deaminase acting on RNA(ADAR) enzymes, which can inhibit GBM progression by promoting CDC14B expression and regulating CDC14B/Skp2/p21/p27 axis [18]. As to CDC14A, there is no study on the correlation between CDC14A and GBM, but CDC14A was reported to participate in cell cycle regulation during brain surgery and the progression of several other tumor types such as bladder cancer [19], [20]. In sum, CDC expression and clinical relevance in GBM are not fully investigated, and the prognostic significance of CDC family is still elusive.

In our study, we established a retrospective GBM cohort consisting of 135 patients who underwent the surgery and received standard treatment. We compared the expression of CDC14A and CDC14B in GBM and tumor-adjacent tissues by retrieving data from TCGA and qPCR. With immunohistochemistry (IHC), we detected the expression of CDC14B in the cohort, and analyzed the correlations between CDC14B and progression-free survival (PFS) rates, overall survival (OS) rates and clinicopathological factors including patients’ age, gender, KPS, tumor size, MGMT expression and IDH1 mutation(R132H).

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