Heterogeneous nuclear ribonucleoprotein C deficiency compromises extracellular matrix-receptor interaction and induces apoptosis in esophageal cancer by targeting transcripts with complex structures

Esophageal cancer (EC) is a highly aggressive malignancy associated with high rates of recurrence and metastasis, and the five-year survival rate remains only 20–30%. N6-methyladenosine (m6A), the most abundant mRNA modification, plays a pivotal role in regulating gene expression and disease pathogenesis. As an m6A “reader,” heterogeneous nuclear ribonucleoprotein C (HNRNPC) binds RNA through its recognition motif and has been shown to contribute to the progression of several cancers, including colorectal, breast, and non-small cell lung cancer. However, its function and mechanism in EC remain unclear. In this study, we demonstrated that HNRNPC was upregulated in EC and correlated with poor prognosis, based on analyses of public databases and a clinical cohort. Using the xenograft mouse model, we found that HNRNPC knockdown suppressed EC tumor growth in vivo . Interestingly, mechanistic studies revealed that HNRNPC depletion promoted cell apoptosis without affecting proliferation, thereby inhibiting tumor growth. At the molecular level, HNRNPC deficiency selectively influenced transcripts with complex structures, such as CD44, OLFML2A, and PCSK6, and subsequently disrupted extracellular matrix–receptor interactions, leading to impeded tumor progression. HNRNPC deficiency selectively influenced transcripts with complex structures, such as CD44, OLFML2A, and PCSK6, and subsequently disrupted extracellular matrix–receptor interactions, leading to enhanced apoptosis and inhibited migration. • HNRNPC is highly expressed in EC and associates with poor prognosis. • Silencing HNRNPC inhibits EC tumor growth in vitro and in vivo . • HNRNPC depletion promotes cell apoptosis without affecting proliferation. • HNRNPC deficiency selectively affects transcripts with complex structures in EC. • The collective dysregulation of CD44, OLFML2A, and PCSK6 disrupts ECM-receptor crosstalk in EC.