Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas
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...
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BMC
2019-04-01
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Series: | Acta Neuropathologica Communications |
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Online Access: | http://link.springer.com/article/10.1186/s40478-019-0697-3 |
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author | 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 |
author_facet | 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 |
author_sort | Harish Shrikrishna Bharambe |
collection | DOAJ |
description | 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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spelling | doaj.art-aef8469f83e742e0adb6de2d5a4827ff2022-12-22T02:39:51ZengBMCActa Neuropathologica Communications2051-59602019-04-017111610.1186/s40478-019-0697-3Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomasHarish Shrikrishna Bharambe0Raikamal Paul1Pooja Panwalkar2Rakesh Jalali3Epari Sridhar4Tejpal Gupta5Aliasgar Moiyadi6Prakash Shetty7Sadaf Kazi8Akash Deogharkar9Shalaka Masurkar10Kedar Yogi11Ratika Kunder12Nikhil Gadewal13Atul Goel14Naina Goel15Girish Chinnaswamy16Vijay Ramaswamy17Neelam Vishwanath Shirsat18Shirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreDepartment of Radiation Oncology, Tata Memorial Hospital, Tata Memorial CentreDepartment of Pathology, Tata Memorial Hospital, Tata Memorial CentreDepartment of Radiation Oncology, Tata Memorial CentreDepartment of Surgical Oncology, Tata Memorial Hospital, Tata Memorial CentreDepartment of Surgical Oncology, Tata Memorial Hospital, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreBioinformatics Centre, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreDepartment of Neurosurgery, Seth G. S. Medical College & K. E. M. HospitalDepartment of Pathology, Seth G. S. Medical College & K. E. M. HospitalDepartment of Medical Oncology, Tata Memorial Hospital, Tata Memorial CentreDivision of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children and University of TorontoShirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial CentreAbstract 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.http://link.springer.com/article/10.1186/s40478-019-0697-3MedulloblastomaMiR-204Risk stratificationTumor-suppressionAutophagy |
spellingShingle | 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 Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas Acta Neuropathologica Communications Medulloblastoma MiR-204 Risk stratification Tumor-suppression Autophagy |
title | Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas |
title_full | Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas |
title_fullStr | Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas |
title_full_unstemmed | Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas |
title_short | Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas |
title_sort | downregulation of mir 204 expression defines a highly aggressive subset of group 3 group 4 medulloblastomas |
topic | Medulloblastoma MiR-204 Risk stratification Tumor-suppression Autophagy |
url | http://link.springer.com/article/10.1186/s40478-019-0697-3 |
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