Abstract 4858: AK4 promotes colorectal cancer progression and metastasis

Abstract

Abstract Metastatic colorectal cancer (CRC) is a fatal disease with a poor prognosis. It is crucial to understanding the underlying pathogenesis to battle this dismal condition. We previously identified that AK4, a gene on chromosome 1p31.3 encoding a member of adenylate kinase family enzymes, was progressively up-regulated from normal colon, primary CRC to metastasis by mRNA gene expression microarray of paired CRC samples. This study was aimed to validate the overexpression of AK4 and explore in-vitro effects in CRC. We firstly examined the mRNA expression level of AK4 in a panel of CRC cell lines. AK4 mRNA expression was higher in CRC cell lines (n=8) than normal colon cell line, and significantly higher in advanced stage cell lines (n=4, Dukes’ C and D) than early stage ones (n=4, Dukes’ A and B) (P=0.03). We further evaluated expression level of AK4 in two different cohorts of clinical samples. The first cohort consisted of 18 paired primary CRCs and its corresponding normal colonic mucosa, and 27 metastatic CRC (including 15 cases with paired primary CRC and normal colonic mucosa). AK4 mRNA level was significantly higher in metastatic CRC than normal colon (P<0.001), and metastatic CRC than primary CRC (P<0.001). Among 15 cases with paired primary and metastatic tumors, 14 (93.3%) demonstrated higher AK4 in metastatic tumors than their primary counterparts(P<0.05). The second cohort composed of 190 consecutive primary CRCs. Upregulation of AK4 protein expression evaluated by immunohistochemistry was found in 68.4% of CRC, and associated with advanced AJCC stage (P<0.001), poorer overall survival (P=0.002) and worse disease-free survival (P<0.001). To evaluate functional properties of AK4 in CRC, we knocked down AK4 on a CRC cell lines with high endogenous AK4 expression (DLD1, HCT116 and SW620) by siRNA. knockdown of AK4 significantly reduced anchorage-dependent colony forming ability (P<0.05) and eliminated migratory (P<0.05) and invasive (P<0.05) abilities. In conclusion, AK4 is a potential oncogene upregulated in metastatic CRC and exhibiting in-vitro oncogenic properties. AK4 may play an important role in tumor progression and metastasis. Citation Format: Yau Hei Yu, Joanna Hung Man Tong, Yi Pan, Raymond Wai Ming Lung, Ka Fai To, Anthony Wing Hung Chan. AK4 promotes colorectal cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4858. doi:10.1158/1538-7445.AM2017-4858