Background LVI and PNI, recognized as major histological traces of metastatic CRC, have been recognized as a category I prognostic factor representing aggressive CRC. The primary aim of our study was to find out molecules associated with LVI and PNI and to examine their biological behavior with their prognostic significance.
Methods LVI- and PNI-associated molecules were identified and verified by utilizing (1) RNA-seq and selecting 117 genes by differential expression values in primary cancer samples of 130 patients with and without systemic recurrence (n = 72 and 58) (2) association analysis to extract six genes associated with LVI or PNI (3) assessment of biological property measuring proliferation, invasion/migration, epithelial-mesenchymal transition, and autophagy flux (4) verification of disease-free survival using public data sets of gene
Results GSN-overexpressing LoVo cells showed more than 2-fold greater invasion compared with control cells 5 (p < 0.001 - 0.005), whereas OAS2-overexpressing RKO cells showed a significantly reduced invasion compared with control cells (p < 0.001 - 0.005). GSN repressed expressions of E-cadherin, β-catenin, claudin-1, and snail, whereas it enhanced N-cadherin and ZEB1 expressions. Reverse findings were noticeably identified in OAS2-overexpression. Interestingly, expressions of multiple autophagy-related proteins including ATG5-12, ATG6/BECN1, ATG7, and ATG101 were decreased in GSN-overexpressing Lovo cells. In addition, accumulation of p62, a well-known substrate of autophagic degradation, suggested that an autophagic flux was also reduced in the GSN-overexpressing Lovo cells. In contrast to GSN overexpression, reverse findings of autophagy flux was identified in OAS2-overexpressing RKO cells. The 5-year RFS rates were significantly greater in the GSN underexpression group than in the overexpression group (73.6% and 64.7%, p = 0.038), whereas patients with OAS2 overexpression presented a greater RFS rate than those with underexpression (73.4% and 63.7%, p = 0.01).
Conclusion GSN and OAS2, as a recurrence promoter and suppressor, respectively, suggest their potential value as recurrence predictor or therapeutic targets in future clinical validation studies.
Citation Format: Jin Cheon Kim, Je Jin Ha, Ka Hee Tak, Seon Ae Roh, Chan Wook Kim, Yong Sik Yoon, Jong Lyul Lee, Seon-Kyu Kim, Ee Hong Kwon, Dong-Hyung Cho, Seon-Young Kim, Yong Sung Kim. Novel inverse functioning molecules, GSN as metastatic promoter and OAS2 as metastatic repressor in colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 96.