1. Academic Validation
  2. circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop

circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop

  • Mol Cancer. 2022 Jun 23;21(1):135. doi: 10.1186/s12943-022-01600-1.
Xiaomin Li  # 1 2 Jianjun Wang  # 3 Weihao Lin  # 1 2 Qinzi Yuan 1 2 Yanxia Lu 1 2 Haowei Wang 1 2 Yujia Chen 1 2 Lixia Chen 1 2 Peiling Dai 1 2 Huaicheng Long 1 2 Xuenong Li 4 5
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
  • 2 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
  • 3 Department of Histology and Embryology, Wannan Medical College, Wuhu, 241002, Anhui Province, China.
  • 4 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. nfydlxn@126.com.
  • 5 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. nfydlxn@126.com.
  • # Contributed equally.
Abstract

Background: In recent years, an increasing number of studies have indicated that circular RNA plays crucial roles in regulating tumor development and chemoresistance. Using two high-throughput RNA sequence datasets, we previously found that circEXOC6B was downregulated in colon Cancer. However, its role and mechanism in colorectal Cancer (CRC) remained unknown.

Methods: Real-time quantitative PCR was used to examine the expression of circEXOC6B in CRC tissues. In vivo and in vitro functional experiments were performed to determine the suppressor role of circEXOC6B in CRC progression. RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, fluorescence in situ hybridization, and immunofluorescence were applied to investigate the possible mechanisms connecting circEXOC6B to CRC growth and 5-fluorouracil-induced Apoptosis. Chromatin immunoprecipitation, dual-luciferase assay, western blot, and immunohistochemistry were used to explore the mechanisms underlying the HIF1A regulation of RRAGB transcription.

Results: circEXOC6B was downregulated in CRC tissues, and its lower expression was associated with poor prognosis of patients. Functional experiments showed that circEXOC6B inhibited growth and increased the 5-fluorouracil-induced Apoptosis of CRC cells in vitro and in vivo. Mechanistically, circEXOC6B inhibited the heterodimer formation of RRAGB by binding to it, thereby suppressing the mTORC1 pathway and HIF1A level. In addition, HIF1A upregulated the transcription of RRAGB by binding to its promoter region. Altogether, the results demonstrated that a HIF1A-RRAGB-mTORC1 positive feedback loop drives tumor progression in CRC, which could be interrupted by circEXOC6B.

Conclusions: circEXOC6B inhibits the progression of CRC and enhances the chemosensitivity of CRC cells to 5-fluorouracil by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop. circEXOC6B is a possible therapeutic target for CRC treatment.

Keywords

Circular RNA; Colorectal cancer; RRAGB; circEXOC6B; hsa_circ_0009043.

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