Emerging Regulatory Mechanisms of N6-Methyladenosine Modification in Cancer Metastasis

Zhao, Jing; Xu, Hao; Su, Yinghan; Pan, Junjie; Xie, Sun‐Zhe; Xu, Jianfeng; Qin, Lun–Xiu

doi:10.1007/s43657-021-00043-w

Cited by 19 publications

(23 citation statements)

References 115 publications

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“…Sorafenib is a multikinase inhibitor that mainly targets kinase activity in the RAF/MEK/ERK signaling pathway, which is heavily involved in tumor invasion and metastasis in HCC. Despite efforts to develop clinically effective strategies for targeting HCC ( Yang et al, 2023 , Zhao et al, 2023 ), sorafenib has remained a globally accepted first-line systemic therapy for HCC for over a decade. However, sorafenib acquired resistance has become an obstacle to extending the overall survival benefits to patients with HCC ( Bruix et al, 2021 , Llovet et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma

Kim,

Jung,

Kim

et al. 2024

Drug Resistance Updates

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Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma

Kim,

Jung,

Kim

et al. 2024

Drug Resistance Updates

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“…Metastasis is the principal cause of cancer death and involves critical interactions between tumor cells and the tumor microenvironment (TME). [ 1 , 2 , 3 , 4 ] Lung cancer is the leading cause of cancer‐related deaths worldwide. [ 5 ] Bone metastases occur in ≈50% of advanced‐stage NSCLC patients, with very limited treatment options.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic Exosomal circPLEKHM1‐Mediated Crosstalk between Tumor Cells and Macrophages Drives Lung Cancer Metastasis

Wang,

Jin

et al. 2024

Advanced Science

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Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell‐derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non‐small cell lung cancer (NSCLC) cells, a hypoxia‐induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1‐eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1‐targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA‐mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.

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Section: Introductionmentioning

confidence: 99%

“…Currently, because of ongoing advancements in new cancer detection technologies, N 6 -methyladenosine (m 6 A) modifications of RNA molecules (4), which exert significant effects on RNA stability, export, splicing, or translation (5), have come to prominence. The m 6 A modification is catalyzed by an installed complex composed of multiple methyltransferases as "writers," m 6 A RNA-binding proteins as "readers," and demethylases as "erasers." The well-established m 6 A writer methyltransferases include methyltransferase-like 3 (METTL3), METTL14, Wilms' tumor 1-associating protein (WTAP), RNA-binding motif protein 15 (RBM 15), and zinc finger CCCH-type containing 13 (ZC3H13).…”

Section: Introductionmentioning

confidence: 99%

The m6A-related gene signature stratifies poor prognosis patients and characterizes immunosuppressive microenvironment in hepatocellular carcinoma

Ma,

Li,

Shen

et al. 2023

Front. Immunol.

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BackgroundN6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m6A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m6A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive.MethodsDifferentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m6A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation.ResultsThe m6A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration.ConclusionThe m6A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies.

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Emerging Regulatory Mechanisms of N6-Methyladenosine Modification in Cancer Metastasis

Cited by 19 publications

References 115 publications

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma

Hypoxic Exosomal circPLEKHM1‐Mediated Crosstalk between Tumor Cells and Macrophages Drives Lung Cancer Metastasis

The m6A-related gene signature stratifies poor prognosis patients and characterizes immunosuppressive microenvironment in hepatocellular carcinoma

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