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LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis
Yi-Ling Chen1,2, Yi-Nan Liu2, Yen-Ting Lin1,2,3
1Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Background:
Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms.
Methods:
A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1.
Results:
SLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion.
Conclusion:
These findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer.
Insights
The long non-coding RNA SLCO4A1-AS1 inhibits lung cancer metastasis by disrupting the TOX4/NTSR1 signaling pathway. This discovery offers a promising therapeutic target for lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastasis, a key hallmark of cancer malignancy, involves cancer cell migration and invasion.
- Long non-coding RNAs (lncRNAs) are critical regulators of metastatic processes.
- The role of lncRNA SLCO4A1-AS1 in cancer metastasis requires further elucidation.
Purpose of the Study:
- To investigate the function of lncRNA SLCO4A1-AS1 in cancer metastasis.
- To identify the molecular mechanisms underlying SLCO4A1-AS1's role in metastasis.
- To explore the therapeutic potential of targeting the SLCO4A1-AS1 pathway in lung cancer.
Main Methods:
- Bioinformatic analysis of GEO database for metastasis-associated lncRNAs.
- In vitro (Transwell assays) and in vivo (mouse model) assessment of cancer cell migration and invasion.
- High-throughput screening (Mass Spectrometry, RNA-seq) and molecular assays (RT-qPCR, Western blotting, RIP, FISH, ChIP) to identify and validate targets and mechanisms.
Main Results:
- SLCO4A1-AS1 significantly reduced cancer cell migration and invasion, correlating with improved patient survival in lung adenocarcinoma.
- SLCO4A1-AS1 directly inhibited TOX4-mediated migration and invasion by acting as a decoy for TOX4.
- Neurotensin receptor 1 (NTSR1) was identified as a convergent downstream target, with SLCO4A1-AS1 preventing TOX4-induced NTSR1 transcription.
Conclusions:
- SLCO4A1-AS1 antagonizes the TOX4/NTSR1 signaling pathway, playing a crucial role in regulating lung cancer cell migration and invasion.
- Targeting the SLCO4A1-AS1/TOX4/NTSR1 axis presents a promising therapeutic strategy for lung cancer intervention.
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