Chang Yu-Jung, Chen Kuan-Wei, Chen Linyi
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.
Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan;.
Cancers (Basel). 2020 Oct 1;12(10):2845. doi: 10.3390/cancers12102845.
Increased ROS proto-oncogene 1 (ROS1) expression has been implicated in the invasiveness of human oral squamous cell carcinoma (OSCC). The cellular distribution of ROS1 has long-been assumed at the plasma membrane. However, a previous work reported a differential cellular distribution of mutant ROS1 derived from chromosomal translocation, resulting in increased carcinogenesis. We thus hypothesized that cellular distribution of upregulated ROS1 in OSCC may correlate with invasiveness. We found that ROS1 can localize to mitochondria in the highly invasive OSCC and identified a mitochondria-targeting signal sequence in ROS1. We also demonstrated that ROS1 targeting to mitochondria is required for mitochondrial fission phenotype in the highly invasive OSCC cells. OSCC cells expressing high levels of ROS1 consumed more oxygen and had increased levels of cellular ATP levels. Our results also revealed that ROS1 regulates mitochondrial biogenesis and cellular metabolic plasticity. Together, these findings demonstrate that ROS1 targeting to mitochondria enhances OSCC invasion through regulating mitochondrial morphogenesis and cellular respiratory.
活性氧原癌基因1（ROS1）表达增加与人类口腔鳞状细胞癌（OSCC）的侵袭性有关。长期以来，人们一直认为ROS1在细胞膜上呈细胞分布。然而，先前的一项研究报道了源自染色体易位的突变型ROS1的细胞分布差异，导致致癌作用增强。因此，我们推测OSCC中上调的ROS1的细胞分布可能与侵袭性相关。我们发现ROS1可以定位于高侵袭性OSCC的线粒体中，并在ROS1中鉴定出一个线粒体靶向信号序列。我们还证明，ROS1靶向线粒体是高侵袭性OSCC细胞中线粒体分裂表型所必需的。表达高水平ROS1的OSCC细胞消耗更多氧气，细胞ATP水平升高。我们的研究结果还表明，ROS1调节线粒体生物发生和细胞代谢可塑性。总之，这些发现表明，ROS1靶向线粒体通过调节线粒体形态发生和细胞呼吸增强OSCC侵袭。
