2. Academic Validation
  3. LncGMDS-AS1 promotes the tumorigenesis of colorectal cancer through HuR-STAT3/Wnt axis

LncGMDS-AS1 promotes the tumorigenesis of colorectal cancer through HuR-STAT3/Wnt axis

  • Cell Death Dis. 2023 Feb 27;14(2):165. doi: 10.1038/s41419-023-05700-8.
Deji Ye # 1 2,  Hanshao Liu # 2,  Guojun Zhao # 1,  Aijun Chen 3,  Yuhang Jiang 1 2,  Yiming Hu 1 2,  Dandan Liu 1 2,  Ningxia Xie 1 2,  Weifei Liang 1,  Xi Chen 2,  Haohao Zhang 1 2,  Cuifeng Li 1 2,  Jingyao Wang 1,  Donglin Sun 1,  Weifeng Chen 1,  Dan Tan 3,  Qi Wang 1 2,  Hongru Wang 4,  Dianping Yu 4,  Baojin Wu 5,  Mingliang Wang 3,  Shuzhong Cui 6,  Sanhong Liu 7,  Xiaoren Zhang 8 9
Affiliations

Affiliations

  • 1 The Sixth Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, Qingyuan People's Hospital, State Key Laboratory of Respiratory Disease, Qingyuan, 511518, Guangdong, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3 General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
  • 4 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 5 Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6 The Sixth Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, Qingyuan People's Hospital, State Key Laboratory of Respiratory Disease, Qingyuan, 511518, Guangdong, China. cuishuzhong@gzhmu.edu.cn.
  • 7 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. liush@shutcm.edu.cn.
  • 8 The Sixth Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, Qingyuan People's Hospital, State Key Laboratory of Respiratory Disease, Qingyuan, 511518, Guangdong, China. xrzhang@gzhmu.edu.cn.
  • 9 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. xrzhang@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 36849492 DOI: 10.1038/s41419-023-05700-8
Abstract

Chronic inflammation promotes the tumorigenesis and cell stemness maintenance of colorectal Cancer (CRC). However, the bridge role of long noncoding RNA (lncRNA) in linking chronic inflammation to CRC development and progression needs better understanding. Here, we elucidated a novel function of lncRNA GMDS-AS1 in persistently activated signal transducer and transcription activator 3 (STAT3) and Wnt signaling and CRC tumorigenesis. Interleukin-6 (IL-6) and Wnt3a induced lncRNA GMDS-AS1 expression, which was highly expressed in the CRC tissues and plasma of CRC patients. GMDS-AS1 knockdown impaired the survival, proliferation and stem cell-like phenotype acquisition of CRC cells in vitro and in vivo. We performed RNA Sequencing (RNA-seq) and mass spectrometry (MS) to probe target proteins and identify their contributions to the downstream signaling pathways of GMDS-AS1. In CRC cells, GMDS-AS1 physically interacted with the RNA-stabilizing protein HuR, thereby protecting the HuR protein from polyubiquitination- and proteasome-dependent degradation. HuR stabilized STAT3 mRNA and upregulated the levels of basal and phosphorylated STAT3 protein, persistently activating STAT3 signaling. Our research revealed that the lncRNA GMDS-AS1 and its direct target HuR constitutively activate STAT3/Wnt signaling and promote CRC tumorigenesis, the GMDS-AS1-HuR-STAT3/Wnt axis is a therapeutic, diagnostic and prognostic target in CRC.

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