In a breakthrough study, researchers have revealed a new understanding of the role played by RNA modification in the progression of pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer-related deaths. The research pinpoints how the long non-coding RNA (lncRNA), LINC00901, and its N6-methyladenosine (m6A) modification, contribute to the disease, offering a potential new avenue for therapeutic interventions.

Chemical modifications of RNA molecules, such as m6A, can critically impact gene expression, influencing various aspects of cancer development and progression. However, while studies into m6A modification of messenger RNA (mRNA) have been extensive, exploration of its impact on lncRNAs, especially within the context of PDAC, has been relatively limited.

In an innovative study published in the Genes & Diseases journal, a team from the The Children's Hospital, Zhejiang University School of Medicine, People's Hospital of Hangzhou Medical College and University of Mississippi Medical Center employed a methylated RNA immunoprecipitation (MeRIP) strategy to uncover the role of LINC00901, an m6A-modified long noncoding RNA (lncRNA), in promoting the proliferation, survival, and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells, thus leading to tumor growth. Intriguingly, the study suggests that the m6A reader protein YTHDF1 negatively regulates LINC00901 expression. The team identified two m6A sites on LINC00901 essential for its interaction with YTHDF1. Their function was underscored when mutations at these sites reduced interaction, thereby emphasizing the significance of m6A modification in LINC00901's oncogenic role. The study further unveils a critical LINC00901-IGF2BP2-MYC axis, driving PDAC progression in an m6A-dependent manner, thereby illuminating a potential new therapeutic target. The researchers suggest the m6A machinery as a promising therapeutic avenue, hinting at the potential for improved patient response to treatment through combining a checkpoint inhibitor with YTHDF1 deficiency. Moreover, with m6A modification implicated in the regulation of both innate and adaptive immune cells, the possibility of developing immunotherapies targeting this pathway emerges.

This study marks a significant advancement in understanding how RNA modifications, such as m6A, impact gene expression and contribute to cancer development. These findings offer fresh insights into the role of m6A modification in lncRNA in the context of PDAC, enhancing our understanding of the disease's progression and opening up potential new pathways for treatment. By exploring this RNA modification, the research expands the horizon of possibilities for targeted cancer therapies.

Reference

Images

Image title: LINC00901 is an m6A-modified lncRNA and its high level is associated with poor prognosis of PDAC patients.

Image caption: LINC00901 is an m6A-modified lncRNA and its high level is associated with poor prognosis of PDAC patients. (A) MeRIP and lncRNA profiling identified five candidate lncRNAs in MIA PaCa-2 cells, among them LINC00901 is a top candidate. BC200 and GAPDH were used as internal controls. (B) Validation of lncRNA profiling results in both MIA PaCa-2 and AsPC-1 cells by MeRIP and qRT-PCR assay. (C) Detection of interaction of LINC00901 with m6A antibody in MIA PaCa-2 and AsPC-1 cells. In vivo expressed S1m-tagged LINC00901 or vector control (S1m) was first pulled down by streptavidin beads and then incubated with m6A antibody overnight. The signals bound to the membrane were detected by donkey anti-mouse antibody conjugated with IRDye® 680RD. HC, heavy chain; LC, light chain. (D) RNA m6A methylation level of LINC00901 as determined by EpiQuik m6A RNA Methylation Quantification Kit. In vivo expressed S1m-tagged LINC00901 or vector control (S1m) was pulled down by streptavidin beads and then the bound S1m-tagged RNA was isolated from the precipitates by phenol/chloroform extraction. The m6A level of purified RNA was measured per the manufacturer's instruction. (E, F) The data obtained from the Kaplan–Meier plotter database (http://kmplot.com/analysis/) suggests poor overall survival (OS) and relapse-free survival (RFS) with high expression levels of LINC00901, compared with those in the low expression levels. Values are mean ± S.D., n = 3, ∗∗P < 0.01; ns, no significant.

Image credit: The authors

Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304222000708-gr1_lrg.jpg

License type: CC BY-NC-ND

Image title: LINC00901 regulates MYC signaling pathway.

Image caption: LINC00901 regulates MYC signaling pathway. (A) LINC00901 level is significantly associated with MAPK signaling pathway. Bulb map of KEGG pathway analysis of differentially expressed genes in MIA PaCa-2 LINC00901 overexpression or KO cells compared with vector control cells. X-axis represented the ratio of enriched differential genes in each pathway. Y-axis indicated names of statistics of pathway enrichment. The area of each node represented the number of enriched differential genes. The p-values were indicated by different color changes from blue to red. (B) GSEA analysis indicates that LINC00901 is involved in MAPK signaling. NES, normalized enrichment score. (C) Association between the enrichment of MYC targets and LINC00901 expression by GSEA analysis. (D, E) The expression of MYC regulated genes related to cell cycle and EMT in LINC00901 overexpression (D) or KO cells (E) was detected by qRT-PCR. Values are mean ± S.D., n = 3; ∗∗P < 0.01.

Image credit: The authors

Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304222000708-gr5_lrg.jpg  

License type: CC BY-NC-ND

Funding information

National Natural Science Foundation of China (82072703, 81772575, 81972455),

US Department of Defense (CA170314).

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