Opposite functions of GSN and OAS2 on colorectal cancer metastasis, mediating perineural and lymphovascular invasion, respectively

The present study aimed to identify molecules associated with lymphovascular invasion (LVI) and perineural invasion (PNI) and to examine their biological behavior in colorectal cancer (CRC). LVI- and PNI-associated molecules were identified and verified using sequential processes including (1) identification of 117 recurrence-associated genes differentially expressed on RNA-seq analysis using primary cancer tissues from 130 CRC patients with and without systemic recurrence; (2) analysis of molecules associated with LVI and PNI; (3) assessment of biological properties by measuring proliferation, anoikis, invasion/migration, epithelial-mesenchymal transition and autophagy flux; and (4) verification of disease-free survival using public datasets. Gelsolin (GSN) and 2'-5'-oligoadenylate synthetase 2 (OAS2) were associated with PNI and LVI, respectively. Invasion potential was >2-fold greater in GSN-overexpressing LoVo cells than in control cells (ppp = 0.038), whereas RFS was longer in patients with OAS2 overexpression than in those with underexpression (73.4% vs. 63.7%, p = 0.01). In conclusion, GSN and OAS2 were positively and negatively associated with recurrence, respectively, suggesting their potential value as predictors of recurrence or therapeutic targets in CRC patients.

本研究旨在鉴定结直肠癌（colorectal cancer, CRC）中与淋巴血管侵犯（lymphovascular invasion, LVI）及神经周围侵犯（perineural invasion, PNI）相关的分子，并探究其生物学行为。研究通过以下系列流程鉴定并验证与LVI、PNI相关的分子：(1) 纳入130例伴或不伴系统性复发的结直肠癌患者的原发癌组织，经RNA测序分析筛选出117个复发相关差异表达基因；(2) 分析与LVI及PNI相关的分子；(3) 通过检测细胞增殖、失巢凋亡、侵袭/迁移能力、上皮间质转化及自噬流评估生物学特性；(4) 利用公共数据集验证无病生存期（disease-free survival, RFS）。结果显示，凝溶胶蛋白（Gelsolin, GSN）与2'-5'-寡腺苷酸合成酶2（2'-5'-oligoadenylate synthetase 2, OAS2）分别与PNI及LVI相关。过表达GSN的LoVo细胞侵袭能力较对照组提升2倍以上（ppp=0.038）；而OAS2过表达患者的无复发生存期较低表达患者更长（73.4% vs. 63.7%, p=0.01）。综上，GSN与结直肠癌复发呈正相关，OAS2则呈负相关，提示二者有望作为结直肠癌患者复发预测标志物或治疗靶点。