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Published on: May 30, 2025
Antisense oligonucleotides targeting lncRNA AC104041.1 induces antitumor activity through Wnt2B/β-catenin pathway in
Mengwei Li1,2, Xu Ding3, Yinan Zhang1,2
1The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, P.R. China.
Abstract:
Long non-coding RNAs (lncRNAs) contribute to the initiation and progression of various tumors, including head and neck squamous carcinoma (HNSCC), which is a common malignancy with high morbidity and low survival rate. However, the mechanism of lncRNAs in HNSCC tumorigenesis remains largely unexplored. In this work, we identified a novel lncRNA AC104041.1 which is highly upregulated and correlated with poor survival in HNSCC patients. Moreover, AC104041.1 overexpression significantly promoted tumor growth and metastasis of HNSCC in vitro and in vivo. Mechanistically, AC104041.1 mainly located in the cytoplasm and could function as ceRNA (competing endogenous RNA) for miR-6817-3p, thereby stabilized Wnt2B, and consequently inducing β-catenin nuclear translocation and activation. Moreover, we demonstrate that salinomycin, which as a highly effective antibiotic in the elimination of cancer stem cells through the Wnt/β-catenin signaling, could enhance the inhibition of tumor growth by antisense oligonucleotides (ASO) targeting AC104041.1 in HNSCC cells and PDXs (patient-derived xenograft) model. Thus, our data provide preclinical evidence to support a novel strategy of ASOs targeting AC104041.1 in combination with salinomycin and may as a beneficial treatment approach for HNSCC.
Insights
A novel long non-coding RNA, AC104041.1, drives head and neck cancer growth by activating the Wnt/β-catenin pathway. Targeting AC104041.1 with salinomycin offers a promising new treatment strategy for HNSCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Long non-coding RNAs (lncRNAs) are implicated in various cancers, but their role in head and neck squamous cell carcinoma (HNSCC) tumorigenesis is not fully understood.
- HNSCC is a prevalent malignancy characterized by high morbidity and low survival rates, necessitating novel therapeutic targets.
Purpose of the Study:
- To identify and characterize novel lncRNAs involved in HNSCC development.
- To elucidate the molecular mechanisms underlying the function of a newly identified lncRNA, AC104041.1, in HNSCC.
- To evaluate the therapeutic potential of targeting AC104041.1 in combination with salinomycin for HNSCC treatment.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) to assess AC104041.1 expression in HNSCC tissues and cell lines.
- In vitro and in vivo experiments to evaluate the effects of AC104041.1 overexpression on HNSCC cell proliferation, migration, and invasion.
- Mechanism studies involving RNA immunoprecipitation (RIP) and Western blotting to investigate the interaction between AC104041.1, miR-6817-3p, Wnt2B, and β-catenin.
- Combination therapy studies using antisense oligonucleotides (ASOs) targeting AC104041.1 and salinomycin in HNSCC cell lines and patient-derived xenograft (PDX) models.
Main Results:
- AC104041.1 was found to be significantly upregulated in HNSCC and correlated with poor patient survival.
- Overexpression of AC104041.1 promoted HNSCC tumor growth and metastasis in vitro and in vivo.
- AC104041.1 functions as a competing endogenous RNA (ceRNA) for miR-6817-3p, stabilizing Wnt2B and activating the Wnt/β-catenin signaling pathway.
- Combination treatment with ASOs targeting AC104041.1 and salinomycin demonstrated enhanced inhibition of tumor growth in HNSCC models.
Conclusions:
- AC104041.1 is a novel oncogenic lncRNA that promotes HNSCC progression through the miR-6817-3p/Wnt2B/β-catenin axis.
- Targeting AC104041.1 with ASOs in combination with salinomycin represents a potential therapeutic strategy for HNSCC.
- Further preclinical studies are warranted to validate this combination therapy for HNSCC patients.
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