Umeda Daisuke, Harada Akikazu, Motooka Daisuke, Tahara Shinichiro, Kurashige Masako, Kido Kansuke, Takashima Tsuyoshi, Kiyokawa Hiroki, Ukon Koto, Matsui Takahiro, Matsumoto Shinji, Shintani Yasushi, Okuzaki Daisuke, Kikuchi Akira, Nojima Satoshi, Morii Eiichi
Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
Sci Rep. 2024 Dec 30;14(1):31642. doi: 10.1038/s41598-024-80280-x.
Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC.
微乳头腺癌（MPC）是肺腺癌（LUAD）的一种侵袭性组织学亚型。MPC由表现出极性倒置的小簇癌细胞组成。然而，其形成的潜在机制尚不清楚。在此，我们表明缺氧参与了MPC的形成。缺氧在使用A549人LUAD细胞的三维培养系统中诱导了MPC样结构（MLS）的形成，并且HIF-1α对于MLS的形成是不可或缺的。RNA测序分析表明，形成MLS的A549细胞表现出与肺MPC相似的基因表达特征。此外，MLS的形成增强了A549细胞对自然杀伤细胞细胞毒性的抗性。我们的研究结果表明，缺氧通过HIF-1α驱动肺MPC的形成，并且逃避自然杀伤细胞的免疫反应可能是MPC侵袭性的基础。
