1. Bone and Joint Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
2. Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
3. Second Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
4. Department of Medicine, Rhode Island Hospital, Providence, RI 02903, USA.
Our understanding of coding gene functions in lung cancer leads to the development of multiple generations of targeted drugs. Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play a vital role in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of circFAT1 in lung adenocarcinoma (LUAD) progression and the potential impact of circFAT1 on LUAD treatment. We found that circFAT1 was one of the top expressed circRNAs in A549 cells by circRNA-seq and was significantly upregulated in human LUAD tissues. Multiple cellular assays with A549 and PC9 LAUD cell lines under both gain-of-function and loss-of-function conditions demonstrated that circFAT1 promoted proliferation of LUAD cells in vitro and in vivo. At molecular level, circFAT1 sequestered miR-7 to upregulate IRS2, which in turn regulated downstream ERK1/2 phosphorylation and CCND1 expression, ultimately promoting tumor progression. In addition, we showed that DDP treatment was much more effective in circFAT1 knockdown tumor cells in vitro and in a xenograft tumor model. Our results indicate that circFAT1 promote tumorigenesis in LUAD through sequestering miR-7, consequently upregulating IRS2-ERK1/2-mediated CCND1 expression, and can be a valuable therapeutic target and an important parameter for precision treatment in LUAD patients.
Keywords: circFAT1, miR-7-5p, IRS2, LUAD, DDP