Prognostic Value of LC3A Protein Expression Patterns in Rectal Cancer Tumors

TL;DR

A specific pattern of LC3A protein in rectal cancer tumors is linked to worse survival outcomes, especially in advanced stages.

Contribution

Identifies a novel LC3A staining pattern as a potential prognostic biomarker for rectal cancer.

Findings

Stone-like LC3A structures in tumor periphery correlate with worse overall and disease-free survival.

The association is strongest in patients with advanced T3–T4 rectal cancer tumors.

Multivariate analysis confirms the prognostic significance of this LC3A pattern.

Abstract

Rectal cancers represent a growing proportion of colorectal cancer diagnoses, particularly in younger patients, and are associated with poor outcomes due to surgical challenges and an incomplete understanding of disease pathogenesis. Here, we investigated the relationship between rectal cancer outcomes and expression patterns of microtubule-associated protein 1 light chain 3 alpha (LC3A), a marker protein for the essential cellular self-degradation mechanism known as autophagy, in tumors from 243 rectal cancer patients. We found that a specific punctate pattern of LC3A staining in the tumor periphery, referred to as stone-like structures, was associated with worse overall survival and disease-free survival, particularly for patients with more advanced rectal cancer tumors (i.e., T3–T4). These findings suggest that the presence of “stone-like” formations comprising the autophagy marker LC3A at the peripheral regions of the tumor where metastasis is likely to begin is associated with rectal cancer malignancy and poor survival outcomes.

Background/Objectives: Autophagy is a conserved self-degradation process by which cells break down and recycle their cellular constituents. This process is activated by various stressors, including nutrient deprivation and DNA damage, and has also been associated with tumor progression. In the present study, we aimed to determine the expression patterns, clinicopathological significance, and prognostic value of the autophagy marker microtubule-associated protein 1 light chain 3 alpha (LC3A)—an essential component of autophagic vacuoles—in rectal cancer. Methods: LC3A reactivity was measured by immunohistochemistry in tumor samples from 243 patients who underwent surgery for rectal cancer. Results: Three distinct patterns of LC3A expression were identified: diffuse cytoplasmic, perinuclear, and stone-like structures (SLS). In Kaplan–Meier survival analyses, patients positive for the SLS pattern of LC3A staining in the tumor periphery (TP) had worse overall survival (OS; p = 0.001) and disease-free survival (DFS; p = 0.030) than those without SLSs in this region, as determined by the log–rank test. When patients were stratified by tumor stage, this result was significant in those with stage T3–T4 (OS, p < 0.001; DFS, p = 0.001) but not T1–T2 disease. Multivariate Cox regression analysis further showed an association between TP-localized LC3A SLS positivity and reduced OS for the overall cohort (hazard ratio [HR] = 2.6313, 95% confidence interval [CI]: 1.090–6.349, p = 0.031) and specifically those in the T3–T4 subgroup (HR = 3.347, 95% CI: 1.657–6.760, p = 0.001). Conclusions: Our findings suggest that positivity for SLSs in the TP may hold clinical value as a biomarker for survival prognosis in rectal cancer patients.

Figures