Abstract B68: Role of MELK, STMN1, and FANCC in human astrocytoma

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and the standard treatment consists of surgical resection of the tumor followed by radiation and chemotherapy with temozolomide. Among the genes with increased expression in GBMs compared to pilocytic astrocytomas, we have previously identified MELK (Marie et al., 2008), which codes for Maternally Embryonic Leucine Zipper Kinase with a role in various cellular processes such as proliferation and cell cycle, apoptosis, gene expression control, hematopoiesis, and oncogenesis. Further microarray and proteomic analyses were performed to identify proteins associated with MELK pathway in astrocytomas. These studies showed high MELK and STMN1 expression levels in astrocytoma of different malignant grades, and identified STMN1 downstream MELK pathway (Marie et al., 2016). Stathmin 1 (coded by STMN1), also known as oncoprotein 18, is an important cytosolic protein that destabilizes microtubules and plays a critical role in mitosis by regulating microtubule dynamics. Also, STMN1 is involved in a variety of other biologic processes, such as cell cycle progression and cell migration, through the phosphorylation of its four serines (Ser16, Ser25, Ser38, and Ser 63). Specific phosphorylation of each serine causes the activation of STMN1, weakening its binding to the tubulin molecules. When the tubulins are free in the cytoplasm, they associate to form microtubules, and participate in biologic processes fundamental to tumor progression, such as formation of mitotic spindle (cell cycle progression) and cytoskeleton remodeling for cell migration. Amongst several proteins that phosphorylate STMN1, FANCC (Fanconi anemia complementation group C) phosphorylates STMN1 at Ser16 and Ser38. Thus, FANCC participates in the regulation of cellular division and is involved in a signaling network that assures the safeguard of chromosomes. The aim of this study was to analyze MELK, STMN1, and FANCC expression levels in our GBM cohort. Additionally, these data were validated in silico in larger GBM cohorts of The Cancer Genome Atlas (TCGA) and The Repository of Molecular Brain Neoplasia Data (Rembrandt) database. We have previously described decrease of STMN1 expression level when MELK was knocked down with siRNA. Interestingly, FANCC expression was also diminished in this condition, indicating a possible involvement of FANCC in MELK pathway. FANCC have higher expression levels in diffusely infiltrative astrocytomas compared to non-neoplastic brain tissue samples. MELK and STMN1 expressions are positively correlated in our GBM series (r=0.678 and p<0.0001 – Spearman-rho test). MELK and FANCC expression levels also correlated (r=0.340 and p=0.0006 – Spearman-rho test). Nonetheless, no correlation was found for expression levels of STMN1 and FANCC. The correlations of MELK and STMN1 and MELK and FANCC were further corroborated on TCGA database (r=0.213 and p=<0.0059, r=0.689 and p=<0.0001, respectively) and Rembrandt database (r=0.17 and p=<0.0083, r=0.414 and p=<0.0001, respectively). In summary, our results suggest that the three genes, STMN1, MELK, and FACC, participate in a signaling pathway related to cytoskeleton remodeling involved in cell cycle, and cell migration, both biologic functions relevant to tumor progression. Further functional studies are worthwhile to search for novel therapeutic targets in GBM. Citation Format: Fernanda Oliveira Serachi, Sr., Sueli Mieko Oba Shinjo, Sr. Role of MELK, STMN1, and FANCC in human astrocytoma [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B68.