Bevanda Danijel, Racetin Anita, Kelam Nela, Filipović Natalija, Bevanda Mateo, Rudan Dimlić Marina, Budimir Jelena, Bevanda Glibo Daniela, Bevanda Ivana, Ramljak Danica, Vukojević Katarina
Department of Gastroenterology, School of Medicine, University of Mostar, University Hospital Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina.
Department of Anatomy, Histology and Embryology, Laboratory for Early Human Development, University of Split School of Medicine, Šoltanska 2A, 21000 Split, Croatia.
Cancers (Basel). 2025 Jan 7;17(2):166. doi: 10.3390/cancers17020166.
BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) remains a significant health burden, and its delayed diagnosis at advanced stages leads to poor survival outcome. Detection of known and novel prognostic markers is essential. In this study, the status of likely prognostic markers-the apoptotic inducing factor (AIFM3), vestigial-like family member 4 (VGLL4), and WNT4-was evaluated.
AIFM3, VGLL4, and WNT4 expression in CRC tissues across different stages (Dukes A-D) were analyzed using histological immunofluorescence staining and RNA sequencing analyses.
In advanced CRC stages, progressive loss of normal crypt architecture, reduction of goblet cells, and necrotic debris were detected along with differential expression patterns of AIFM3, VGLL4, and WNT4. AIFM3 exhibited high reactivity in the lamina propria of healthy tissue and Dukes A, but this was diminished in advanced CRC stages. VGLL4 expression, initially confined to the lamina propria, increased significantly in the epithelium of Dukes B and C, with a cytoplasmic localization pattern. WNT4 expression was elevated in the CRC epithelium across all stages, contrasting with a significant reduction in lamina propria reactivity. RNA sequencing corroborated these findings, showing significant downregulation of AIFM3 and WNT4 and upregulation of VGLL4 in CRC tissues compared to controls. Expression of AIFM3 and WNT4 showed no correlation with survival outcome, while low VGLL4 expression was correlated with better survival outcome.
The results suggest distinct roles for AIFM3, VGLL4, and WNT4 in CRC progression, highlighting only VGLL4 as a potential prognostic marker. Further evaluation of VGLL4 and its specific role in CRC progression remains to be elucidated.
背景/目的：结直肠癌（CRC）仍是一项重大的健康负担，其晚期的延迟诊断导致生存结局不佳。检测已知和新的预后标志物至关重要。在本研究中，对可能的预后标志物——凋亡诱导因子（AIFM3）、类 vestigial 家族成员 4（VGLL4）和 WNT4 的状态进行了评估。
使用组织学免疫荧光染色和 RNA 测序分析，对不同分期（Dukes A - D）的结直肠癌组织中 AIFM3、VGLL4 和 WNT4 的表达进行分析。
在晚期结直肠癌阶段，检测到正常隐窝结构逐渐丧失、杯状细胞减少和坏死碎片，同时伴随着 AIFM3、VGLL4 和 WNT4 的差异表达模式。AIFM3 在健康组织和 Dukes A 期的固有层中表现出高反应性，但在晚期结直肠癌阶段这种反应性降低。VGLL4 的表达最初局限于固有层，在 Dukes B 和 C 期的上皮中显著增加，呈细胞质定位模式。WNT4 的表达在所有阶段的结直肠癌上皮中均升高，与固有层反应性的显著降低形成对比。RNA 测序证实了这些发现，显示与对照组相比，结直肠癌组织中 AIFM3 和 WNT4 显著下调，VGLL4 上调。AIFM3 和 WNT4 的表达与生存结局无关，而低 VGLL4 表达与更好的生存结局相关。
结果表明 AIFM3、VGLL4 和 WNT4 在结直肠癌进展中具有不同作用，仅突出 VGLL4 作为潜在的预后标志物。VGLL4 及其在结直肠癌进展中的具体作用仍有待进一步阐明。
