The role of ACAA2 in colorectal caner patient with active glucose metabolism.

Abstract

e15522 Background: colorectal cancer(CRC) is third in incidence and mortality in worldwide with a 5-year survival rate is 65%. CRC patients(pts) with active glucose metabolism have a worse outcome. Molecular biological mechanisms in this subgroup have not been well uncovered. Here we identified ACAA2 has a significant prognostic role in CRC pts and more down-regulated in those with higher standardized uptake value(SUV). Then we focused on its functions and mechanisms behind it. Methods: Clinical and transcriptional data of pts with CRC obtained from GSE39582 dataset (n = 510) and a Zhongsh an Hospital Fudan University Cohort(ZHFUC) with CRC diagnosed at 6/2015-12/2018 were collected (n = 441). The ACAA2 protein expression of ZHFUC was evaluated by immunohistochemistry staining. Metabolic activity was evaluated by SUV. Overall survival (OS) was analyzed via Kaplan-Meier Curves with Log-rank test and multivariable Cox regression. Silencing (KD) and over-expression (OE) of ACAA2 were performed in CRC cells, respectively(KD: HCT116;RKO and OE: DLD1;RKO). The effect of ACAA2 was tested through CCK8, colony formation assays, cell cycle assays, seahorse for glucose metabolism and subcutaneous xenograft models. The potential mechanism under ACAA2 contribution was explored by RNA sequencing and western blot. Results: ACAA2 of ZHFUC was down-regulated in CRC compared to normal tissues. Pts divided into ACAA2 high (n = 226) and low (n = 215) with an evenly distribution in their clinicopathological features.Of 143 pts with available PETCT imaging took as a SUV-related group), 78 were identified as ACAA2 high and 65 were low. In comparison to ACAA2 high ones, pts in ACAA2 low showed an higher SUV (p < 0.05) and a significantly worse OS (total pts: p = 0.012; SUV-related group:p = 0.024; median OS is not reached). The multivariate analysis showed that ACAA2 low was independently associated with inferior OS [total pts: HR 1.99(95%CI: 1.2 ¨C 3.2), p < 0.001; SUV-related group: HR 2.51(95%CI: 1.1 ¨C 5.7), p =< 0.05]. Over-expression ACAA2 inhibited tumor growth both in vitro and in vivo, and lower glucose metabolism and arrested G0/G1 cell cycle were observed in HCT116-OE cells, while reversed effects in RKO-KD cells. gene expression profiling analysis and consistent results in western blot highlighted the role of AKT signaling pathway in those contributions of ACAA2. A AKT inhibitor could suppress cell proliferation causing by silencing ACAA2 both in vitro and in vivo. Conclusions: while ACAA2 expression was an independent prognostic factor for CRC pts. And those of them with an active glucose metabolism had a lower ACAA2 expression. The silencing and over-expression of ACAA2 expression in CRC cell lines promoted and inhibited cell proliferation and tumor growth in vitro and in vivo, oppositely. ACAA2 expression levels might classified a subtype of CRC pts, who might benefit from AKT inhibitors treatment.