Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas

Harish Shrikrishna Bharambe†,
Raikamal Paul†,
Pooja Panwalkar†,
Rakesh Jalali,
Epari Sridhar,
Tejpal Gupta,
Aliasgar Moiyadi,
Prakash Shetty,
Sadaf Kazi,
Akash Deogharkar,
Shalaka Masurkar,
Kedar Yogi,
Ratika Kunder,
Nikhil Gadewal,
Atul Goel,
Naina Goel,
Girish Chinnaswamy,
Vijay RamaswamyEmail author and
Neelam Vishwanath ShirsatEmail author

†Contributed equally

Acta Neuropathologica Communications20197:52

https://doi.org/10.1186/s40478-019-0697-3

Received: 30 January 2019
Accepted: 10 March 2019
Published: 3 April 2019

Abstract

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Low expression of miR-204 in the Group 3 / Group 4 tumors identify a highly aggressive subset of tumors having poor overall survival, in the two independent cohorts of medulloblastomas. Downregulation of miR-204 expression correlates with poor survival within the Group 4 as well indicating it as a valuable risk-stratification marker in the subgroup. Restoration of miR-204 expression in multiple medulloblastoma cell lines was found to inhibit their anchorage-independent growth, invasion potential and tumorigenicity. IGF2R was identified as a novel target of miR-204. MiR-204 expression resulted in downregulation of both M6PR and IGF2R that transport lysosomal proteases from the Golgi apparatus to the lysosomes. Consistent with this finding, miR-204 expression resulted in reduction in the levels of the lysosomal proteases in medulloblastoma cells. MiR-204 expression also resulted in inhibition of autophagy that is known to be dependent on the lysosomal degradation pathway and LC3B, a known miR-204 target. Treatment with HDAC inhibitors resulted in upregulation of miR-204 expression in medulloblastoma cells, suggesting therapeutic role for these inhibitors in the treatment of medulloblastomas. In summary, miR-204 is not only a valuable risk stratification marker in the combined cohort of Group 3 / Group 4 medulloblastomas as well as in the Group 4 itself, that has paucity of good prognostication markers, but also has therapeutic potential as indicated by its tumor suppressive effect on medulloblastoma cells.