Hypoxia-induced long non-coding RNA HIF1A‑AS2 regulates stability of MHC class I protein in head and neck cancer
Abstract
Intratumoral hypoxia not only promotes angiogenesis and invasiveness of cancer cells, but also creates an immunosuppressive microenvironment that facilitates tumor progression. However, the mechanisms by which hypoxic tumor cells disseminate immunosuppressive signals remain unclear. In this study, we demonstrate that a hypoxia-induced long non-coding RNA (lncRNA) HIF1A Antisense RNA 2 (HIF1A-AS2) is upregulated in both hypoxic tumor cells and hypoxic tumor-derived exosomes (TEXs) in head and neck squamous cell carcinoma (HNSCC). Hypoxia-inducible factor 1 alpha 1 (HIF-1α) was found to directly bind to the regulatory region of HIF1A-AS2 to enhance its expression. HIF1A-AS2 reduced the protein stability of major histocompatibility complex class I (MHC-I) by promoting the interaction between the autophagy cargo receptor Neighbor of BRCA1 gene 1 protein (NBR1) and MHC-I, thereby increasing the autophagic degradation of MHC-I. In HNSCC samples, the expression of HIF1A-AS2 was found to correlate with hypoxic signatures and advanced clinical stages. Patients with high HIF-1α and low HLA-ABC expression showed reduced infiltration of CD8+ T cells. These findings define a mechanism of hypoxia-mediated immune evasion in HNSCC through downregulation of antigen-presenting machinery via intracellular or externalized hypoxia-induced lncRNA.
此論文探討頭頸癌細胞在低氧環境下，如何通過釋放信號分子促進癌細胞的免疫逃逸機制。研究顯示，在低氧環境下，頭頸癌細胞除了活化長鏈非編碼核糖核酸(lncRNA) HIF1A-AS2 的表現外，還增加了腫瘤源性外泌體中 HIF1A-AS2 的含量，並將 HIF1A-AS2 傳遞至周邊細胞。HIF1A-AS2 的表現量增加可促進 NBR1 與 MHC-I 的相互作用，進而促使 MHC-I 的自噬降解，導致癌細胞的免疫逃逸。
