Medulloblastoma is the most common malignant paediatric brain tumour. Current treatments are often insufficient and lead to severe side effects. There is a critical need for improved therapies and new diagnostic and prognostic biomarkers. This study focuses on the role of the RNA-binding proteins LIN28A and LIN28B, which are known to regulate cancer invasion, but their roles in Medulloblastoma were previously unexamined. The study evaluated the expression and function of these proteins in Medulloblastoma patient samples and cell lines.
Using R2 Genomics Analysis and Visualisation Platform, the researchers found that while LIN28A expression remained unchanged, LIN28B was significantly upregulated in tissues from medulloblastoma patients compared to normal brain tissues. This upregulation, which was not observed in other brain tumours, was specific for the aggressive medulloblastoma subgroups (molecular subgroups 3 and 4) and significantly correlated with patient survival and metastasis rates. Using BrainSpan Atlas, assessment of gene expression in the cerebellum of the developing brain at different time points, indicated that while LIN28A expression remained steady, LIN28B showed higher levels in the newborn brain that gradually decreased to very low or non-detectable levels at 37 weeks of age, which remained at this level into adulthood. LIN28B mRNA levels were higher in Group 3 cells (D341 cell line) compared to cell lines belonging to SHH (Daoy) and Group 4 (CHLA-01 and CHLA-01R), and protein levels were higher in Group 3 (D341) and Group 4 (CHLA-01) cells compared to the other lines.
Functionally, pharmacological inhibition of LIN28 activity concentration‐dependently reduced LIN28B expression, as well as the growth of D283 Medulloblastoma cells. While LIN28 inhibition did not affect the levels of intracellular ATP, it reduced the expression of the stemness marker CD133 in D283 cells and the sphere formation of CHLA‐01R cells. Supported by proteomics analysis and cell-based assays, silencing of LIN28B reduced the viability of Medulloblastoma cells, as well as ribosomal biogenesis, and promoted cellular lipid accumulation.
In conclusion, LIN28B is identified as a potential diagnostic and prognostic biomarker for Medulloblastoma and may be a valuable therapeutic target for inhibiting Medulloblastoma cell growth, especially in high-risk subgroups.