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

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.

Plasma-derived exosomal long noncoding RNAs of pancreatic cancer patients as novel blood-based biomarkers of disease

“…LncRNAs are abnormally expressed in various types of cancers, and differentially expressed lncRNAs in plasma or serum have become an emerging focus area in noninvasive diagnostic applications [23], including intrahepatic cholangiocarcinoma [27], gallbladder carcinoma [28], glioblastoma [29], and prostate carcinoma [30]. Although the functions and molecular mechanisms of most lncRNAs are still unknown, increasing evidence has shown that lncRNAs may play important roles in the occurrence, progression, and metastasis of tumors [31,32]. Recently, an increasing number of lncRNAs have been found to be related to the prognosis of PaCa.…”

Lactobacillus plantarum Zhang-LL Inhibits Colitis-Related Tumorigenesis by Regulating Arachidonic Acid Metabolism and CD22-Mediated B-Cell Receptor Regulation

“…Another study showed that RNF6 increased STAT3 phosphorylation by promoting SHP-1 ubiquitination and degradation, demonstrating that the RNF6/SHP-1/STAT3 axis might be a potential treatment option for tumors. However, studies of the mechanism of action for mitigating CRC progression have been relatively concentrated in the signaling pathways associated with STAT3 and the recruitment of mediated immune cells [62,63]. Transcriptomic KEGG functional enrichment analysis showed that signaling pathways directly related to CRC progression, such as the Toll-like receptor, NOD-like receptor, mTOR, and Hippo signaling pathways, were significantly enriched after Zhang-LL intervention.…”

The functions and mechanisms of long non-coding RNA in colorectal cancer

“…Through RNA sequencing (RNA-seq) and mass spectrometry (MS) studies, it was discovered that in CRC cells, GMDS-AS1 physically interacts with the RNA-binding protein HuR. This interaction protects HuR from polyubiquitination and proteasomal degradation, highlighting a crucial mechanism by which GMDS-AS1 contributes to the stabilization of proteins involved in cancer cell proliferation ( 61 ). The lncRNA MNX1-AS1/PPFIA4 activates the downstream AKT/HIF-1α signaling pathway to promote COAD proliferation ( 166 ).…”

“…Additionally, the transcription factor’s binding to IGHM enhancer 3 (TFE3) increases the transcription of LINC01606 after being recruited to the promoter region of LINC01606 ( 155 ). Ye et al.’s study indicates that the lncRNA GMDS-AS1 and its direct target HuR constitutively activate the STAT3/Wnt signaling pathway and promote the stemness of CRC tumors ( 61 ). Sun et al.…”