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1476-45982012021Dec04Molecular cancerMol CancerA novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression.15815815810.1186/s12943-021-01457-wCircular RNA (circRNA), a subclass of non-coding RNA, plays a critical role in cancer tumorigenesis and metastasis. It has been suggested that circRNA acts as a microRNA sponge or a scaffold to interact with protein complexes; however, its full range of functions remains elusive. Recently, some circRNAs have been found to have coding potential.To investigate the role of circRNAs in gastric cancer (GC), parallel sequencing was performed using five paired GC samples. Differentially expressed circAXIN1 was proposed to encode a novel protein. FLAG-tagged circRNA overexpression plasmid construction, immunoblotting, mass spectrometry, and luciferase reporter analyses were applied to confirm the coding potential of circAXIN1. Gain- and loss-of-function studies were conducted to study the oncogenic role of circAXIN1 and AXIN1-295aa on the proliferation, migration, invasion, and metastasis of GC cells in vitro and in vivo. The competitive interaction between AXIN1-295aa and adenomatous polyposis coli (APC) was investigated by immunoprecipitation analyses. Wnt signaling activity was observed using a Top/Fopflash assay, real-time quantitative RT-PCR, immunoblotting, immunofluorescence staining, and chromatin immunoprecipitation.CircAXIN1 is highly expressed in GC tissues compared with its expression in paired adjacent normal gastric tissues. CircAXIN1 encodes a 295 amino acid (aa) novel protein, which was named AXIN1-295aa. CircAXIN1 overexpression enhances the cell proliferation, migration, and invasion of GC cells, while the knockdown of circAXIN1 inhibits the malignant behaviors of GC cells in vitro and in vivo. Mechanistically, AXIN1-295aa competitively interacts with APC, leading to dysfunction of the "destruction complex" of the Wnt pathway. Released β-catenin translocates to the nucleus and binds to the TCF consensus site on the promoter, inducing downstream gene expression.CircAXIN1 encodes a novel protein, AXIN1-295aa. AXIN1-295aa functions as an oncogenic protein, activating the Wnt signaling pathway to promote GC tumorigenesis and progression, suggesting a potential therapeutic target for GC.© 2021. The Author(s).PengYinYGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.XuYidanYGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.ZhangXiaojingXGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.DengShiqiSGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.YuanYuanYGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.LuoXiaonuanXGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.HossainMd TofazzalMTUniversity of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China.Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518000, People's Republic of China.Department of Statistics, Bangabandhu Sheikh Mujibur Rahaman Science and Technology University, Gopalganj, 8100, Bangladesh.ZhuXiaohuiXGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.DuKainingKGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.HuFanFGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.ChenYangYGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.ChangShanshanSGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.FengXianlingXGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.FanXinminXGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China.AshktorabHassanHDepartment of Medicine and Cancer Center, Howard University, College of Medicine, Washington, DC, 20060, USA.SmootDuaneDDepartment of Medicine, Meharry Medical Center, Nashville, TN, 37208, USA.MeltzerStephen JSJDepartment of Medicine/GI Division, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA.HouGangqiangGDepartment of Medical Image Center, Kangning Hospital, Shenzhen, Guangdong, 518000, People's Republic of China.WeiYanjieYUniversity of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China.LiSongSShenzhen Science & Technology Development Exchange Center, Shenzhen Science and Technology Building, Shenzhen, Guangdong, 518055, People's Republic of China. lisong@pkusz.edu.cn.QinYingYDepartment of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China. 1900pq@163.com.JinZheZGuangdong Provincial Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, 3688 Nanhai Avenue, Nanshan, Shenzhen, Guangdong, 518060, People's Republic of China. zhejin@szu.edu.cn.engU54 MD007597MDNIMHD NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov't20211204
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