Identification of cancer cell-intrinsic biomarkers associated with tumor progression and characterization of SFTA3 as a tumor suppressor in lung adenocarcinomas

Recent advancements in contemporary therapeutic approaches have increased the survival rates of lung cancer patients; however, the long-term benefits remain constrained, underscoring the pressing need for novel biomarkers. Surfactant-associated 3 (SFTA3), a long non-coding RNA predominantly expressed in normal lung epithelial cells, plays a crucial role in lung development. Nevertheless, its function in lung adenocarcinoma (LUAD) remains inadequately understood.

We developed a robust prognostic model and identified SFTA3 as a novel biomarker with potential applications in the diagnosis, prognosis, and personalized treatment of LUAD. Additionally, our findings offer new insights into the mechanisms underlying LUAD tumorigenesis and immune evasion.

Single-cell RNA sequencing data were utilized to identify novel cancer cell-intrinsic gene signatures associated with the progression of LUAD, and their roles in LUAD were comprehensively analyzed. Serum samples were collected to quantify the expression levels of SFTA3 in LUAD patients. Furthermore, a series of biological experiments, including cell viability assays, scratch wound healing assays, and colony formation assays, were conducted to demonstrate the tumor-suppressive effects of SFTA3. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SFTA3 in lung cancer cells.

We constructed a prognostic model comprising eight genes: ALDOA, ATP5MD, SERPINH1, SFTA3, SLK, U2SURP, SCGB1A1, and SCGB1A3. The model effectively stratified patients into high- and low-risk categories, revealing that low-risk patients experienced superior clinical outcomes, exhibited an immunologically hot tumor microenvironment (TME), and had a greater probability of responding to immunotherapy. In contrast, the high-risk group exhibited a cold TME and may benefit more from chemotherapy. Furthermore, our study revealed that a progressive decrease in SFTA3 expression in cancer cells was correlated with tumor advancement. Notably, the serum levels of SFTA3 significantly decreased in patients with LUAD, suggesting its potential utility in liquid biopsy for LUAD diagnosis. Additionally, the knockdown of SFTA3 enhances the proliferation and migration of lung cancer cells, whereas its overexpression inhibits these phenotypes. The epithelial-mesenchymal transition pathway was significantly enriched following SFTA3 silencing, suggesting that SFTA3 may impact tumor progression by modulating this process. We also identified key transcription factors and epigenetic mechanisms implicated in the downregulation of SFTA3 in LUAD.