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ADRM1-Amplified Metastasis Gene in Gastric Cancer

2015-06-06 00:01:47

Genes, Chromosomes & Cancer; 6 June 2015; DOI: 10.1002/gcc.22262



Marlena S. Fejzo, Lee Anderson, Hsiao-Wang Chen, Adrian Anghel, Jiaying Zhuo, Ravi Anchoori, Richard Roden, Dennis J. Slamon



Abstract



The proteasome ubiquitin receptor ADRM1 has been shown to be a driver for 20q13.3 amplification in epithelial cancers including ovarian and colon cancer. We performed array-CGH on 16 gastric cancer cell lines and found 20q13.3 to be amplified in 19% with the minimal amplified region in gastric cancer cell line AGS spanning a 1 Mb region including ADRM1. Expression microarray analysis shows overexpression of only two genes in the minimal region, ADRM1 and OSBPL2. While RNAi knockdown of both ADRM1 and OSBPL2 led to a slight reduction in growth, only ADRM1 RNAi knockdown led to a significant reduction in migration and growth in soft-agar. Treatment of AGS cells with the ADRM1 inhibitor RA190 resulted in proteasome inhibition, but RNAi knockdown of ADRM1 did not. However, RNAi knockdown of ADRM1 led to a significant reduction in specific proteins including MNAT1, HRS, and EGFR. We hypothesize that ADRM1 may act in ADRM1-amplified gastric cancer to alter protein levels of specific oncogenes resulting in an increase in metastatic potential. Selective inhibition of ADRM1 independent of proteasome inhibition may result in a targeted therapy for ADRM1-amplified gastric cancer. In vivo models are now warranted to validate these findings.



INTRODUCTION



Gastric cancer is the fourth most common cancer and the second leading cause of cancer death worldwide. The disease is identified primarily in its advanced stage when it is largely incurable. New approaches for detection and therapy are warranted.



Chromosome band 20q13 is duplicated early in cancer and is believed to harbor a cancer-initiating gene. It is gained in as many as 97% of gastric cancers suggesting a critical gene in gastric pathogenesis maps within the region. In addition, 20q13 gains correlate with lymph node metastasis, and 13 genes have been associated with high malignant potential in several cancers including gastric cancer. Fine mapping has revealed 20q13.33 is the most significantly altered in all histological subtypes of gastric cancer. The 20q13.33 amplification target is unclear. Among the most recent studies, one study implicates TNFRSF6B due to its association with lymph node metastasis; another study points to C20ORF11 due to a correlation between overexpression and amplification; and a third study analyzed ADRM1 because it was one of six genes in 20q13 both amplified and overexpressed greater than twofold Herein we analyze the 20q13.3 amplicon in gastric cancer cell lines and perform functional analysis of candidate genes to confirm ADRM1 is the most likely amplification target and a critical driver of gastric cancer pathogenesis.




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