If Artificial In Vitro Microenvironment Can Influence Tumor Drug Resistance Network via Modulation of lncRNA Expression?—Comparative Analysis of Glioblastoma-Derived Cell Culture Models and Initial Tumors In Vivo

• Published in: Cellular and molecular neurobiology 2022-05, Vol.42 (4), p.1005-1020
• Main Authors: Witusik-Perkowska, Monika, Jaskólski, Dariusz J., Liberski, Paweł P., Szemraj, Janusz
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Autophagy; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell culture; Cell Culture Techniques; Cell proliferation; Comparative analysis; Divergence; DNA repair; Drug resistance; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - pathology; Glioblastoma cells; Humans; MDR1 protein; Mesenchyme; Microenvironments; Multidrug resistance; Neoplasm Proteins - genetics; Neoplasm Proteins - therapeutic use; Neurobiology; Neurosciences; Non-coding RNA; Original Research; P-Glycoprotein; PTEN protein; RNA, Long Noncoding - genetics; TOR protein; Tumor Microenvironment; Tumors
• ISSN: 0272-4340; 1573-6830
• DOI: 10.1007/s10571-020-00991-3

The tumor resistance of glioblastoma cells in vivo is thought to be enhanced by their heterogeneity and plasticity, which are extremely difficult to curb in vitro. The external microenvironment shapes the molecular profile of tumor culture models, thus influencing potential therapy response. Our study examines the expression profile of selected lncRNAs involved in tumor resistance network in three different glioblastoma-derived models commonly utilized for testing drug response in vitro. Differential expression analysis revealed significant divergence in lncRNA profile between parental tumors and tumor-derived cell cultures in vitro, including the following particles: MALAT1, CASC2, H19, TUSC7, XIST, RP11-838N2.4, DLX6-AS1, GLIDR, MIR210HG, SOX2-OT. The examined lncRNAs influence the phenomenon of tumor resistance via their downstream target genes through a variety of processes: multi-drug resistance, epithelial–mesenchymal transition, autophagy, cell proliferation and viability, and DNA repair. A comparison of in vivo and in vitro expression identified differences in the levels of potential lncRNA targets, with the highest discrepancies detected for the MDR1 , LRP1 , BCRP and MRP1 genes. Co-expression analyses confirmed the following interrelations: MALAT1–TYMS, MALAT1–MRP5, H19–ZEB1, CASC2–VIM, CASC2–N-CAD; they additionally suggest the possibility of MALAT1–BCRP, MALAT1–mTOR and TUSC7–PTEN interconnections in glioblastoma. Although our results clearly demonstrate that the artificial ex vivo microenvironment changes the profile of lncRNAs related to tumor resistance, it is difficult to anticipate the final phenotypic effect, since this phenomenon is a complex one that involves a network of molecular interactions underlying a variety of cellular processes.