Abstract

Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes’ copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.

Highlights

  • Chordomas are rare malignant tumors that develop from persistent notochord tissue

  • These were miR-608, which has potential binding sites in the 39UTR of EGFR and BclxL mRNAs and miR-34a which is predicted to target MET [21,22,23]

  • MiR-196a has been studied for its oncogenic roles in glioblastoma, pancreatic adenocarcinoma, breast cancer, oesophageal adenocarcinoma, and colorectal cancer, and shown to target HOX family genes (HOXA7, HoxB7, HOXC8, HOXB8, HOXD8), ERG, HMGA2, ANXA1, S100A9, SPRR2C, KRTS [25] [26,27,28,29,30,31]. miR-196a associates with worse survival in glioblastoma and pancreatic adenocarcinoma [31,32]. miR-22 has been reported to play an important role in tumorigenesis in a cell-type specific manner

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Summary

Introduction

Chordomas are rare malignant tumors that develop from persistent notochord tissue. These tumors typically occur in the midline skeleton, most commonly in the skull base and spine. Despite the most advanced skull base surgical techniques, chordomas are extremely difficult to eradicate by surgery because of the need to preserve adjacent vital structures and recurrence rates are high (40%) [1] [2]. When resection and radiotherapy have been exhausted, patients are left without further therapeutic options. The development of new therapeutic options is hampered by a very limited knowledge of the molecular basis of chordoma. This study uncovers for the first time microRNA dysregulation as an important regulator of RTKs and chordoma malignancy

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