Characterization of SLC22A18 as a tumor suppressor and novel biomarker in colorectal cancer

Yeonjoo Jung,Hee-Young Lee,Yeonhwa Jung,Yong Beom Cho,Juhee Keum,Yeo Song Lee,Yukyung Jun,Jaesang Kim,Sanghyuk Lee,Suyeon Kim

doi:10.18632/oncotarget.4681

Yeonjoo Jung, Hee-Young Lee + Show 8 more

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https://doi.org/10.18632/oncotarget.4681

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Abstract

SLC22A18, solute carrier family 22, member 18, has been proposed to function as a tumor suppressor based on its chromosomal location at 11p15.5, mutations and aberrant splicing in several types of cancer and down-regulation in glioblastoma. In this study, we sought to demonstrate the significance of SLC22A18 as a tumor suppressor in colorectal cancer (CRC) and provide mechanistic bases for its function. We first showed that the expression of SLC22A18 is significantly down-regulated in tumor tissues using matched normal-tumor samples from CRC patients. This finding was also supported by publically accessible data from The Cancer Genome Atlas (TCGA). Functionally, SLC22A18 inhibits colony formation and induces of G2/M arrest consistent with being a tumor suppressor. Interestingly, suppression of KRAS by RNA interference promotes SLC22A18 expression, and expression of SLC22A18 in turn inhibits KRAS(G12D)-mediated anchorage independent growth of NIH3T3 cells indicating a mutual negative interaction. Finally, we evaluated diagnostic and prognostic values of SLC22A18 using clinical and gene expression data from TCGA which revealed a significantly worse long-term prognosis for patients with low level SLC22A18 expression. In sum, we established SLC22A18 as a tumor suppressor in colon epithelial cells and propose that SLC22A18 is potentially a marker of diagnostic and prognostic values.

Highlights

colorectal cancer (CRC) is currently the one of the highest-ranked cancers in terms of both mortality and incidence rates [1]
SLC22A18, a member of membrane bound solute carrier gene super family, has been proposed to be a tumor suppressor based on its chromosomal location in 11p15.5 as well as frequent mutations found in various tumors and was selected for further analyses
Multiple lines of evidence have suggested that SLC22A18 functions as a tumor suppressor

Summary

Introduction

CRC is currently the one of the highest-ranked cancers in terms of both mortality and incidence rates [1]. In the United States alone, nearly 140,000 new cases and over 50,000 deaths associated with CRC are projected for 2014 [2]. Such numbers signify a slight decline of colorectal cancer cases in United States, the incidence has been on the rise in other parts of the world including many populous Asian countries where colonoscopic screening for early detection is still limited [3, 4]. Novel molecular markers would be beneficial both for better diagnosis and prognosis and for characterizing the molecular mechanism of CRC development. We have previously reported isolation of novel markers of CRC from meta-analysis of publicly available gene expression data [5]. At least some of these genes (ECT2, ETV4, DDX21, RAN, S100A111, RPS4X, HSPD1, CKS2 and C9orf140), three of which have been shown to be activated by c-MYC or KRAS, likely contribute to oncogenic processes [5]

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