Overexpression of CIP2A is associated with poor prognosis in multiple myeloma

Xuewen Liu,Zheng Lu,Junnian Zheng,Wei Cao,Baofu Zhang,Yang Guo,Ying Dong,Shanshan Qin,Qian Cheng,Pinghong Ming,Te Zhang,Ying Liu

doi:10.1038/sigtrans.2017.13

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous protein phosphatase 2A (PP2A) inhibitor, has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer. However, the expression and the role played by CIP2A in the pathogenesis of multiple myeloma (MM) remain unclear. In this study, we showed that CIP2A was overexpressed in human MM cell lines and MM patients’ bone marrow tissues. Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow. Kaplan–Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. Moreover, CIP2A knockdown in MM cells resulted in attenuated proliferative abilities. In addition, CIP2A depletion sensitizes dexamethasone (Dex)-resistant cells to Dex. The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A, which in turn activated Akt. In vivo studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt. Taken together, our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM.

Highlights

As a neoplastic disorder of plasma cells characterized by clonal proliferation within the bone marrow (BM), multiple myeloma (MM) accounts for ~ 10% of all hematological cancers and ~ 1% of all cancer deaths.1 In 2017, the annual incidence of MM increased with the aging of the population worldwide
The results showed that Cancerous inhibitor of protein phosphatase 2A (CIP2A) is overexpressed in MM cell lines at the messenger RNA level
The evidence supporting that CIP2A is associated with Dex therapy and poor prognosis in MM was proposed at the very first time

Summary

Introduction

As a neoplastic disorder of plasma cells characterized by clonal proliferation within the bone marrow (BM), multiple myeloma (MM) accounts for ~ 10% of all hematological cancers and ~ 1% of all cancer deaths. In 2017, the annual incidence of MM increased with the aging of the population worldwide. As a neoplastic disorder of plasma cells characterized by clonal proliferation within the bone marrow (BM), multiple myeloma (MM) accounts for ~ 10% of all hematological cancers and ~ 1% of all cancer deaths.. An estimated 30 280 new cases (17 490 in men and 12 790 in women) of MM were diagnosed in 2017, and 12 590 deaths (6660 in men and 5930 in women) are estimated to occur from this disease in the United States.. Overall survival has improved in recent years. Patients are predicted to have a median survival of ~ 5 years.. Despite the improved therapeutic armamentarium, most patients experience relapse and refractory disease.

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