Functional Polymorphism of the CK2α Intronless Gene Plays Oncogenic Roles in Lung Cancer

Ming-Szu Hung,Il-Jin Kim,David M Jablons,Cheng-Ta Yang,Liang You,Jian-Hua Mao,Yu-Ching Lin,Zhidong Xu,Chun-Ming Wong

doi:10.1371/journal.pone.0011418

Abstract

Protein kinase CK2 is frequently up-regulated in human cancers, although the mechanism of CK2 activation in cancer remains unknown. In this study, we investigated the role of the CK2α intronless gene (CSNK2A1P, a presumed CK2α pseudogene) in the pathogenesis of human cancers. We found evidence of amplification and over-expression of the CSNK2A1P gene in non- small cell lung cancer and leukemia cell lines and 25% of the lung cancer tissues studied. The mRNA expression levels correlated with the copy numbers of the CSNK2A1P gene. We also identified a novel polymorphic variant (398T/C, I133T) of the CSNK2A1P gene and showed that the 398T allele is selectively amplified over the 398C allele in 101 non-small cell lung cancer tissue samples compared to those in 48 normal controls (p = 0.013<0.05). We show for the first time CSNK2A1P protein expression in transfected human embryonic kidney 293T and mouse embryonic fibroblast NIH-3T3 cell lines. Both alleles are transforming in these cell lines, and the 398T allele appears to be more transforming than the 398C allele. Moreover, the 398T allele degrades PML tumor suppressor protein more efficiently than the 398C allele and shows a relatively stronger binding to PML. Knockdown of the CSNK2A1P gene expression with specific siRNA increased the PML protein level in lung cancer cells. We report, for the first time, that the CSNK2A1P gene is a functional proto-oncogene in human cancers and its functional polymorphism appears to degrade PML differentially in cancer cells. These results are consistent with an important role for the 398T allele of the CSNK2A1P in human lung cancer susceptibility.

Highlights

Lung cancer is the leading cause of death from cancer in the United States [1]
We focused on the CSNK2A1P gene because we initially found it was minimally expressed in normal cells, but was predominantly expressed in several types of human cancer cell lines and tumor tissues, including the human T cell leukemia cell line Jurkat, which is known for its high CK2 activity
By semi-quantitative RT-PCR, we showed that the CSNK2A1P gene is over-expressed in three NSCLC lines: H1299, H322, and A549, but minimally expressed in normal cells and two lung cancer cell lines H1650 and H460 (Fig. 1A)

Summary

Introduction

Lung cancer is the leading cause of death from cancer in the United States [1]. Some of the somatic events involved in lung cancer have been well characterized, but some of them remain unknown [2,3]. Protein kinase CK2 (formerly known as casein kinase II) is a serine/threonine protein kinase that phosphorylates more than 300 proteins [4]. It degrades tumor suppressor proteins such as PML [5] and promotes the activity and stability of oncogenic proteins such as AKT [6]. CK2 promotes PML degradation and CK2 kinase activity is inversely correlated with PML protein levels in human lung cancer [5]. Multiple myeloma cell survival was shown to rely on the high activity of protein kinase CK2 [7]. CK2 affects several cell signaling pathways, including PI3K, NFkB, and Wnt pathways [8]

Methods

Results

Conclusion