MTDH is an oncogene in multiple myeloma, which is suppressed by Bortezomib treatment.

Chunyan Gu,Hongbao Yang,Ye Yang,Hailin Peng,Lang Feng,Zhenqing Feng

doi:10.18632/oncotarget.6610

Abstract

Metadherin (MTDH) is identified as an oncogene in multiple cancers including breast cancer, bladder cancer and endometrial cancer. However, the function of MTDH in multiple myeloma (MM) is still unexplored. In this study, we disclose that MTDH is an oncogene in MM. This is characterized by an elevation mRNA level of MTDH and chromosomal gain of MTDH locus in MM cells compared to normal samples. Moreover, MTDH expression significantly increased in MMSET translocation (MS) subgroup, one of the high-risk subgroups in MM, and was significantly correlated with MM patients' poor outcomes in Total Therapy 2 (TT2) cohort. Further knockdown of MTDH expression by shRNA in MM cells induced cell apoptosis, inhibited MM cells growth in vitro and decreased xenograft tumor formation in vivo. Interestingly, opposite to TT2, MM patients with high-MTDH expression showed favorable survival outcomes in the TT3 cohort, while Bortezomib treatment was the major difference between TT2 and TT3 cohort. Furthermore we proved that Bortezomib suppressed pre- and post-transcription levels of MTDH expression of MM cells in vitro and in vivo. Finally, our studies demonstrated that MTDH is a transcriptional gene of MMSET/NFκB /MYC signaling in MM cells, which is inhibited by Bortezomib treatment.

Highlights

Multiple myeloma (MM) is the second most common malignancy residing in the bone marrow, which exhibits gene expression changes and cytogenetic abnormalities commonly influencing the Immunoglobin locus [1,2,3,4]
Further analysis of array-based comparative genomic hybridization data collected from 115 MM patients revealed that the MTDH locus is frequently amplified in these MM patient samples (Figure 1B) [14] implying MTDH may behave as a tumor-initiating gene in MM
MTDH expression significantly increased in the relapsed MM patients from Total Therapy 2 (TT2) cohort compared to newly diagnosed patients in the same cohort (Figure 1C) [15]

Summary

Introduction

Multiple myeloma (MM) is the second most common malignancy residing in the bone marrow, which exhibits gene expression changes and cytogenetic abnormalities commonly influencing the Immunoglobin locus [1,2,3,4]. Many of these abnormalities like T(4;14) MMSET/FGFR3 translocation, 1q21 gain et al promote the development of drug resistance and aggressive disease. Continued research to identify innovative modes of action in MM and to develop its specific inhibition method are still in urgent requirement

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Results

Conclusion