Characterization of PIMREG as a molecular marker of tumor progression and prognosis in glioma and its possible role in DNA damage response

Abstract

PIMREG is a proliferation marker that plays a role in cell cycle control and tumorigenesis. Its expression is induced by mitogens, varies according to the phases of the cell cycle and is directly related to the proliferative state of both tumor and normal cells. Recent studies showed elevated levels of its transcripts in tumor samples compared to the normal adjacent tissue of patients with different types of cancer, and the relationship of PIMREG as a possible marker for tumor progression and prognosis was proposed for breast cancer, renal cell carcinoma and pancreatic cancer. In normal adult tissue, PIMREG expression is restricted to a few tissues, while during embriogenesis it is widely distributed in the developing embryo, with marked expression in the central nervous system (CNS), suggesting its particular importance in this tissue. Preliminary data from our group showed that samples of patients with glioblastoma, one of the most commun primary brain tumours in adults, , have the highest levels of PIMREG, and it directly correlates with the degree of malignancy and inversely correlates with patient survival. In these samples, the genes associated with PIMREG expression, are enriched for cell cycle, DNA replication, pyrimidine metabolism, and various DNA repair pathways. In addition, PIMREG expression was induced in glioblastoma cells treted with genotoxic agents, suggesting that PIMREG responds to DNA damage caused by these drugs. Our hypothesis is that PIMREG participates in the signaling and / or repair of DNA lesions caused by genotoxic agents in glioblastoma cells. Thus, we aim to investigate whether PIMREG is, in fact, a marker of tumor progression and / or prognosis, if it plays a role in promoting malignant phenotype of brain tumor cell and if it participates in the signaling and / or response to DNA damage, and consequently, to resistance of these cells to treatment. Thus, we intend to (i) analyze PIMREG expression by immunohistochemistry in glioma samples and correlate with the classification, clinical data and patient survival; ii) modulate PIMREG expression in glioblastoma cell lines and evaluate the effects of its overexpression and inhibition for the malignant phenotype in vitro, as well as signaling response and DNA damage repair activities; and iii) investigate the protein interaction network established by PIMREG in glioblastoma cells, when it is upregulared upon treatment with genotoxic agent. (AU)