Abstract
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 (p<0.001–0.005), whereas OAS2-overexpressing RKO cells showed reduced invasion (p<0.001–0.005). GSN downregulated E-cadherin, β-catenin, claudin-1 and snail, and upregulated N-cadherin and ZEB1, whereas OAS2 overexpression had the opposite effects. Several autophagy-related proteins including ATG5-12, ATG6/BECN1, ATG7 and ATG101 were downregulated in GSN-overexpressing LoVo cells, whereas the opposite pattern was observed in OAS2-overexpressing RKO cells. Patients with low GSN expression had significantly higher 5-year recurrence-free survival (RFS) rates than those with GSN overexpression (73.6% vs. 64.7%, p = 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.
Highlights
25% of patients with colorectal cancer (CRC) have metastatic disease at the time of diagnosis, and 30–50% of CRC patients undergoing curative resection develop metastasis or recurrence during the follow-up period [1]
The 117 recurrence-associated genes identified based on the cutoff of log2 transcripts per million (TPM) of mean values were compared according to lymphovascular invasion (LVI) and perineural invasion (PNI) status in the initial 130 patients
LVI was closely associated with the expression of oligoadenylate synthetase 2 (OAS2) (p = 0.009), whereas PNI correlated with GSN (p = 0.029), UDP1A6 (p = 0.004), PALMD (p = 0.003), synuclein gamma (SNCG) (p = 0.004) and heat shock protein family B member 6 (HSPB6) (p = 0.002) (Table 1)
Summary
25% of patients with colorectal cancer (CRC) have metastatic disease at the time of diagnosis, and 30–50% of CRC patients undergoing curative resection develop metastasis or recurrence during the follow-up period [1]. Metastatic routes of spread are frequently associated with histological traces of lymphovascular invasion (LVI), perineural invasion (PNI), extramural vascular invasion and tumor budding. Among these parameters, LVI and PNI are recognised as category I prognostic factors representing aggressive CRC (AJCC cancer staging, 8th ed, https:// cancerstaging.org/). Several molecular markers were introduced to help identify key genes and pathways driving LVI. Among these markers, CDKN2A hypermethylation was identified in a meta-analysis as significantly associated with LVI in addition to lymph node metastasis and proximal tumor location [3]
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