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长链非编码RNA RASAL2-AS1在头颈部鳞状细胞癌的增殖和进展中促进METTL14介导的m6A甲基化。

LncRNA RASAL2-AS1 promotes METTL14-mediated m6A methylation in the proliferation and progression of head and neck squamous cell carcinoma.

作者信息

Rong Meiting, Zhang Ming, Dong Feihong, Wu Ke, Cai Bingkun, Niu Jinrui, Yang Le, Li Zhongyan, Lu Hui-Yi

机构信息

The Second Affiliated Hospital of Dalian Medical University, #467 Zhongshan Road, Dalian, 116023, China.

Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.

出版信息

Cancer Cell Int. 2024 Mar 25;24(1):113. doi: 10.1186/s12935-024-03302-8.

DOI:10.1186/s12935-024-03302-8
PMID:38528591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10962181/
Abstract

BACKGROUND

Long non-coding RNAs (lncRNAs) are key regulators of the 6-methyladenosine (m6A) epigenetic modification, playing a role in the initiation and progression of tumors. However, the regulatory mechanisms in head and neck squamous cell carcinoma (HNSCC) remain elusive. In this study, we investigated the molecular regulatory mechanisms of the lncRNA RASAL2-AS1 in the occurrence and development of HNSCC tumors.

METHODS

A bioinformatics analysis was conducted to analyze the expression level of RASAL2-AS1 in HNSCC and normal tissues. RASAL2-AS1 mRNA and protein levels were detected using RT-PCR and Western blotting. Wound healing, transwell assays, flow cytometry, M6A dot blot, and RNA immunoprecipitation experiments were conducted to explore the regulatory role of the RASAL2-AS1 and downstream targets METTL14/LIS1 signaling pathway in HNSCC. Immunohistochemical examination was conducted to evaluate the expression of METTL14 and LIS1 in HNSCC and normal tissues. A tumor xenograft model of BALB/c nude mice was established to assess the impact of RASAL2-AS1 on cell proliferation and growth.

RESULTS

RASAL2-AS1 high expression in HNSCC and cells deteriorated with survival rates of HNSCC. RASAL2-AS1 overexpression in HNSCC accelerated cell migration, colony formation, cell proliferation, cell cycle in S stage, while RASAL2-AS1 knockdown in HNSC cells inhibited cell cycle in G1 stage. After silencing METTL14, the above effects induced by overexpression of the RASAL2-AS1 were reversed. RASAL2-AS1 overexpression prompted LIS1 expression, whereas RASAL2-AS1 silencing reduced LIS1 levels in HNSCC cells, which was confirmed by immunohistological staining. Results demonstrated elevated expression of METTL14 or LIS1 in tongue cancer tissues. Overexpression of RASAL2-AS1 promoted tumor weight and tumor volume, which was counteracted by pcDNA3.1 RASAL2-AS1 plus silencing METTL14 and METTL14 and LIS1 were significantly decreased.

CONCLUSION

Our study highlights the functional importance of the LncRNA RASAL2-AS1 in HNSCC and might assist in the development of a prognostic stratification and therapeutic approach. Which regulates HNSCC with the dependence of m6a manner.

摘要

背景

长链非编码RNA（lncRNAs）是6-甲基腺嘌呤（m6A）表观遗传修饰的关键调节因子，在肿瘤的发生和发展中起作用。然而，头颈部鳞状细胞癌（HNSCC）中的调控机制仍不清楚。在本研究中，我们调查了lncRNA RASAL2-AS1在HNSCC肿瘤发生和发展中的分子调控机制。

方法

进行生物信息学分析以分析RASAL2-AS1在HNSCC和正常组织中的表达水平。使用RT-PCR和蛋白质印迹法检测RASAL2-AS1的mRNA和蛋白质水平。进行伤口愈合、Transwell实验、流式细胞术、m6A斑点印迹和RNA免疫沉淀实验，以探讨RASAL2-AS1和下游靶点METTL14/LIS1信号通路在HNSCC中的调控作用。进行免疫组织化学检查以评估METTL14和LIS1在HNSCC和正常组织中的表达。建立BALB/c裸鼠肿瘤异种移植模型，以评估RASAL2-AS1对细胞增殖和生长的影响。

结果

RASAL2-AS1在HNSCC中高表达，且随着HNSCC生存率的降低而恶化。RASAL2-AS1在HNSCC中的过表达加速了细胞迁移、集落形成、细胞增殖、S期细胞周期，而在HNSC细胞中敲低RASAL2-AS1则抑制了G1期细胞周期。沉默METTL14后，RASAL2-AS1过表达诱导的上述效应被逆转。RASAL2-AS1过表达促使LIS1表达，而RASAL2-AS1沉默降低了HNSCC细胞中LIS1的水平，这通过免疫组织化学染色得到证实。结果表明舌癌组织中METTL14或LIS1的表达升高。RASAL2-AS1的过表达促进了肿瘤重量和肿瘤体积，而pcDNA3.1 RASAL2-AS1加沉默METTL14可抵消这种作用，且METTL14和LIS1显著降低。

结论

我们的研究突出了LncRNA RASAL2-AS1在HNSCC中的功能重要性，并可能有助于开发预后分层和治疗方法。其以m6A方式依赖性地调节HNSCC。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/c12b87227a13/12935_2024_3302_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/c3828981da49/12935_2024_3302_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/c12b87227a13/12935_2024_3302_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/139f724486a1/12935_2024_3302_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/6bb1a8e0d3d3/12935_2024_3302_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/c3828981da49/12935_2024_3302_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a1/10962181/c12b87227a13/12935_2024_3302_Fig7_HTML.jpg

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