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Hypoxia-Associated Alternative Polyadenylation of CARM1 and Tumor Microenvironment Alterations in Non-Small Cell Lung
Xinyu Qin1, Chunlong Zhang1, Sijia Wu2
1School of Computer Science and Artificial Intelligence, Northeast Forestry University, Harbin 150040, China.
Background:
Tumor hypoxia in non-small cell lung cancer (NSCLC) promotes malignant progression and treatment resistance by enhancing abnormal vasculature, invasiveness, and metastasis. However, the molecular mechanisms underlying hypoxia-driven tumor progression remain incompletely understood.
Methods:
In this study, patient samples, cell lines, single-cell transcriptomic data, and spatial transcriptomic data were comprehensively analyzed to investigate hypoxia-associated molecular alterations in NSCLC.
Results:
A global trend toward shortened 3' untranslated regions (3'UTRs) was observed in hypoxic tumors. Analysis of hypoxia-related alternative polyadenylation (APA) events revealed preferential usage of proximal polyadenylation sites (poly(A) sites, PASs) in CARM1. Shortening of the CARM1 3'UTR was associated with hypoxia and may serve as a candidate biomarker. This APA event may reduce putative microRNA (miRNA) binding sites and contribute to increased CARM1 expression, while potentially influencing the expression of hypoxia-related genes such as SELENBP1. Drug sensitivity analysis further suggested that patients with shorter CARM1 3'UTRs may exhibit differential responses to cisplatin chemotherapy. Moreover, single-cell and spatial transcriptomic analyses demonstrated enhanced interactions between hypoxic tumor cells and fibroblasts, highlighting a potential role for APA in remodeling the hypoxic tumor microenvironment.
Conclusions:
Our findings identify hypoxia-related APA features and characterize hypoxia-associated alterations within the NSCLC tumor microenvironmen, providing new insights into the molecular landscape of hypoxia-associated tumor progression.
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