Dynein Light Chain Protein Tctex1: A Novel Prognostic Marker and Molecular Mediator in Glioblastoma

Autor: Eileen Brouwer, Claudia A. Dumitru, Salvatore Nocerino, Ibrahim Erol Sandalcioglu, Meliha Karsak, Tamina Stelzer, Ludwig Wilkens, Sebastian Rading
Rok vydání: 2021
Předmět:
Zdroj: Cancers, Vol 13, Iss 2624, p 2624 (2021)
Cancers
Volume 13
Issue 11
ISSN: 2072-6694
DOI: 10.3390/cancers13112624
Popis: Simple Summary Glioblastoma (GBM) remains one of the deadliest solid cancers, with only a dismal proportion of GBM patients achieving 5-year survival. Thus, it is critical to identify molecular mechanisms that could be targeted by novel therapeutic approaches in this tumor type. Our study identified Tctex1/DYNLT1 as an independent prognostic marker for the overall survival of GBM patients. Importantly, Tctex1 promoted the aggressiveness of GBM cells by enhancing tumor proliferation and invasion. These effects of Tctex1 appeared to be modulated via phosphorylation of retinoblastoma protein (RB) and the release of matrix metalloprotease 2 (MMP2), respectively. As Tctex1 can potentially be inhibited in vivo, our study provides a rationale for novel, individualized therapeutic strategies in GBM patients. Abstract The purpose of this study was to determine the role of Tctex1 (DYNLT1, dynein light chain-1) in the pathophysiology of glioblastoma (GBM). To this end, we performed immunohistochemical analyses on tissues from GBM patients (n = 202). Tctex1 was additionally overexpressed in two different GBM cell lines, which were then evaluated in regard to their proliferative and invasive properties. We found that Tctex1 levels were significantly higher in GBM compared to healthy adjacent brain tissues. Furthermore, high Tctex1 expression was significantly associated with the short overall- (p = 0.002, log-rank) and progression-free (p = 0.028, log-rank) survival of GBM patients and was an independent predictor of poor overall survival in multivariate Cox-regression models. In vitro, Tctex1 promoted the metabolic activity, anchorage-independent growth and proliferation of GBM cells. This phenomenon was previously shown to occur via the phosphorylation of retinoblastoma protein (phospho-RB). Here, we found a direct and significant correlation between the levels of Tctex1 and phospho-RB (Ser807/801) in tissues from GBM patients (p = 0.007, Rho = 0.284, Spearman’s rank). Finally, Tctex1 enhanced the invasiveness of GBM cells and the release of pro-invasive matrix metalloprotease 2 (MMP2). These findings indicate that Tctex1 promotes GBM progression and therefore might be a useful therapeutic target in this type of cancer.
Databáze: OpenAIRE
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