L1TD1 promotes colorectal mucinous adenocarcinoma progression by enhancing ABCC3 mRNA stability

Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains underexplored. In this study, scRNA-seq analyses revealed that L1TD1 expression was significantly greater in MAC than in adjacent noncancerous tissues. L1TD1 is an RNA-binding protein that has been reported to regulate mRNA stability and stemness-associated transcriptional programs in cancer cells. Further experiments confirmed that L1TD1 expression was elevated in MAC compared to normal tissues and L1TD1 promoted mucus production and accelerated tumor cell proliferation and metastasis. Mechanistically, further analysis revealed the RNA recognition motif (RRM) domain of L1TD1 binds to the 3' untranslated region (3'-UTR) of ABCC3 mRNA, thus increasing its stability. In addition, ABCC3 inhibition reversed L1TD1 overexpression-induced mucus production and MAC progression. Collectively our findings demonstrate that L1TD1 binds to the GUGU motif within ABCC3 mRNA and upregulates ABCC3 expression, which subsequently activates the MAPK signaling pathway and promotes mucin production and accelerates MAC progression. These results also provide essential evidence for investigating the mechanisms of mucus production and tumor progression in MAC.