CircRAPGEF5 acts as a modulator of RAS/RAF/MEK/ERK signaling during colorectal carcinogenesis
Zhipeng Yin,
Hao Li,
Heng Zhao,
Lutterodt Bentum-Ennin,
Yang Xia,
Zaibiao Wang,
Wanglai Hu,
Hao Gu,
Shangxin Zhang,
Guangyun Li
Affiliations
Zhipeng Yin
Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
Hao Li
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Heng Zhao
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Lutterodt Bentum-Ennin
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Yang Xia
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Genome Center, KingMed Center for Clinical Laboratory Co., Ltd., Hefei, China
Zaibiao Wang
Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
Wanglai Hu
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Translational Research Institute, People's Hospital of Zhengzhou University, Academy of Medical Science, Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Zhengzhou University, Zhengzhou, China
Hao Gu
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Corresponding author.
Shangxin Zhang
Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China; Corresponding author.
Guangyun Li
Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China; Corresponding author.
Mutations in oncogenes such as KRAS, NRAS and BRAF promote the growth and survival of tumors, while excessive RAS/RAF/MEK/ERK activation inhibits tumor growth. In this study we examined the precise regulatory machinery that maintains a moderate RAS/RAF/MEK/ERK pathway activation during CRC. Here, using bioinformatic analysis, transcriptomic profiling, gene silencing and cellular assays we discovered that a circular RNA, circRAPGEF5, is significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5-induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells suggesting that an upregulation of circRAPEF5 may suppress the expression of TNFRSF10A and aid CRC progression by preventing apoptosis, while the direct interactions between circRAPGEF5 and elements of the RAS/RAF/MEK/ERK pathway was not identified, which nevertheless can be the basis for future research. Moreover, EIF4A3, was observed to share a similar expression pattern with circRAPEF5 and demonstrated to be a major controller of circRAPGEF5 via the promotion of circRAPGEF5 circularization and its silencing reduced circRAPGEF5 levels. Taken together, our findings reveal a mechanism of accurate RAS/RAF/MEK/ERK signaling regulation during CRC progression maintained by upregulation of circRAPGEF5 which may be a plausible target for future clinical applications that seek to induce CRC cell apoptosis via the RAS/RAF/MEK/ERK signaling pathway.
