Carcinoma-associated fibroblast-derived exosomes lncRNA RORA-AS1 facilitates radiotherapy resistance of oral squamous cell carcinoma through the IFITM1/STAT axis

We previously identified differentially expressed lncRNAs in carcinoma-associated fibroblasts (CAFs) using a lncRNA Chip. However, the molecular mechanisms by which CAFs-derived lncRNAs regulate radiotherapy resistance in Oral squamous cell carcinoma (OSCC) remain poorly understood. This study found that lncRNA RORA-AS1 (RORA-AS1) was markedly overexpressed in CAFs, exosomes derived from CAFs (CAFs-exo), and OSCC tissues. Notably, a RORA-AS1-based nomogram demonstrated robust predictive performance for OSCC patient survival. Moreover, RORA-AS1 showed a significant positive correlation with CAF infiltration. In in vitro experiments, both CAFs-CM and CAFs-exo enhanced Cal27 cell proliferation and upregulated RORA-AS1 and IFITM1 expression, while concurrently inhibiting Apoptosis, upon exposure to 8 Gy X-rays irradiation. RORA-AS1 Knockdown mitigated the radiotherapy resistance induced by CAFs-exo in Cal27 cells. Mechanistically, RORA-AS1 knockdown led to increased expression of p-STAT1, p21, and p53, alongside decreased levels of p-STAT3 and IFITM1 in Cal27 cells. RIP assay confirmed the physical association between RORA-AS1 and the IFITM1 RNA complex. In in vivo experiments, CAFs-exo enhanced tumor growth and RORA-AS1 and IFITM1 expression under radiotherapy conditions, which was mitigated by RORA-AS1 knockdown. In conclusion, CAF-derived exosome RORA-AS1 facilitates radiotherapy resistance in OSCC by activating the IFITM1/STAT signaling cascade. These findings identify RORA-AS1 as a potential biomarker for the diagnosis and treatment of OSCC.

Carcinoma-associated fibroblast; Exosome; LncRNA; Oral squamous cell carcinoma; Radiotherapy resistance.