Nectin-4 Tumor Expression as a Prognostic Factor and Potential Therapeutic Target in Stage II/III Rectal Cancer

BackgroundRectal cancer (RC) represents approximately one-third of all colorectal cancer, and its incidence has been increasing worldwide. Nectin-4 has demonstrated oncological effects on several human cancers and has attracted attention as a novel therapeutic target molecule. However, the clinical significance and underlying mechanism in RC remain largely unknown.MethodsTo investigate the prognostic impact of Nectin-4 in localized advanced RC, we first evaluated Nectin-4 expression in 135 tissues from patients with Stage II/III RC using immunohistochemistry. Patients were then categorized into 2 groups according to Nectin-4 status. Subsequently, we evaluated the clinical impact of Nectin-4 on oncological outcomes using survival calculations and uni-/multivariate analysis. Furthermore, we performed in-vitro assays to elucidate the underlying mechanisms of Nectin-4 in cell proliferation.ResultsPatients with high Nectin-4 expression exhibited worse postoperative prognosis than those with low (OS: <i>P</i> = 0.002, RFS: <i>P</i> = 0.002). Multivariate analysis revealed that Nectin-4 expression was a significant independent prognostic factor in RC (OS: <i>P</i> = 0.002, RFS: <i>P</i> = 0.002). In addition, the Nectin-4 status stratified post-recurrence survival in patients who received chemotherapy for postoperative relapse (<i>P</i> = 0.023). Nectin-4 silencing by siRNA significantly inhibited RC cell proliferation, furthermore, the combination of Nectin-4 silencing and 5-FU resulted in a synergistic antitumor effect.DiscussionWe have showcased the clinical impact and biological value of Nectin-4 in RC. Our findings could provide a guidepost for further clinical trials to establish individualized treatment for RC and act as a key to opening the door to genome-based precision medicine.