Acta Neuropathologica Communications (Apr 2019)

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 Ramaswamy,
  • Neelam Vishwanath Shirsat

DOI
https://doi.org/10.1186/s40478-019-0697-3
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 16

Abstract

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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.

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