Transmembrane mucin 21 drives lung adenocarcinoma growth by suppressing retinoic acid receptor β signaling

Lung cancer remains the most prevalent and lethal malignancy worldwide, with non-small cell lung cancer accounting for >85% of cases and lung adenocarcinoma (LUAD) representing a predominant histological subtype. LUAD exhibits marked molecular heterogeneity, early dissemination, and a strong tendency for distant metastasis, but the key molecular circuits driving its progression remain unclear. This study aimed to elucidate molecular markers governing the growth of LUAD, along with their underlying mechanisms.

Mucin (MUC)21 expression was examined in LUAD patient tissues (16 paired fresh samples and 35 paraffin‑embedded cases) and cell lines (BEAS-2B, A549, NCI‑H838, NCI‑H1395) by qPCR, western blot, and immunohistochemistry. Stable knockdown (KD) and overexpression (OE) of MUC21 were established in LUAD cells to assess proliferation (CCK‑8, EdU), migration (wound healing), and invasion (Matrigel Transwell) in vitro. Xenograft models in nude mice were used to evaluate tumor growth in vivo. Mechanistic involvement of retinoic acid receptor β (RARβ) was tested via rescue experiments with RARβ co‑silencing.

MUC21 was significantly upregulated in LUAD tissues and cell lines, with membrane‑localized enrichment in tumors. High MUC21 expression correlated with poorer progression‑free survival in patients. Functionally, MUC21 OE promoted cell proliferation, migration, and invasion, while MUC21 KD suppressed these malignant traits. In the xenograft model, MUC21 OE accelerated tumor growth and increased the Ki-67 proliferation index, whereas its silencing restrained tumor growth and enhanced apoptosis. Mechanistically, dysregulated MUC21 influenced gene pathways associated with retinoic acid signaling. MUC21 negatively correlated with the nuclear receptor RARβ, with MUC21 KD increasing RARβ messenger ribonucleic acid (mRNA) and protein levels, coinciding with reduced proliferation and invasiveness, and MUC21 OE repressing RARβ expression. Notably, RARβ co-silencing partially rescued MUC21-KD-induced suppression of LUAD proliferation, migration, and invasion, positioning RARβ as a key downstream mediator.

These findings present the MUC21-RARβ regulatory axis as a critical regulator of LUAD malignant progression and highlight the therapeutic potential of MUC21, offering novel insights and linking MUC-driven membrane signaling with RARβ-associated nuclear differentiation programs.