Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis Through N6‐Methyladenosine mRNA Methylation‐Dependent Mechanism

Abstract

BaCKgRoUND aND aIMS:The dynamic N6methyladenosine (m 6 A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote HCC progression; however, whether m 6 A machinery is involved in IRFA-induced HCC recurrence remains open for study. appRoaCH aND ReSUltS: Using an IRFA HCC orthotopic mouse model, we detected a higher level of m 6 A reader YTH N6-methyladenosine RNA binding protein 1-3 (YTHDF1) in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m 6 A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model, and patients' HCC tissues. Functionally, gain-of-function/lossof-function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases epidermal factor growth receptor (EGFR) m 6 A modification in the vicinity of the 5′ untranslated region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethalheat-induced up-regulation of EGFR level was further confirmed in the IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CoNClUSIoNS:The m 6 A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m 6 A machinery combined with EGFR inhibitors to suppress HCC metastasis after RFA. (Hepatology 2021;74:1339-1356). R adiofrequency ablation (RFA) is now recommended as one of the curative therapies for early-stage HCC by guidelines of the American Association for the Study of Liver

M6a Regulator-Associated Methylation Modification Patterns Shape Tumor Microenvironment Characteristics in Hepatocellular Carcinoma

“…The role of RNA m6A modi cation has been increasingly recognized in various biological activities, such as stem cell development, immune response, and malignant progression, through affecting gene expression (36-40). Unexceptionally, evidence accumulated con rms that m6A modi cation involves every stage of HCC, ranging from tumor initiation to tumor growth and, nally, to metastatic dissemination (41)(42)(43). Our works further con rmed the ndings of mounting studies concluding the reliable role of m6A genes in predicting survival outcomes of cancer patients (44)(45)(46)(47).…”

Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma

“…Theoretically, genetic changes occur in the cancer cells around the ablation site when cells are subjected to thermal stimulation, and the cancer cells of incomplete ablation show more aggressive progression than untreated cells. The previous publications have proven that this experiment can imitate the biological properties similar to residual liver tumor observed clinically [22][23][24][25]. Following another 24-h culture, HepG2 xenografts were removed and immediately protected by RNAsafer Stabilizer Reagent (OMEGA, Guangzhou, China) for RNA-seq detection.…”

m6A-Related lncRNAs Are Potential Biomarkers for the Prognosis of Metastatic Skin Cutaneous Melanoma

“…m6A modification has been found that plays an important role in the occurrence and development of tumor. For example, sublethal heat treatment increases EGFR m6A modification near the 5′UTR region and promotes its binding to YTHDF1, thereby enhancing the translation of EGFR mRNA and promoting hepatocellular carcinoma progression (Su et al, 2021). METTL3 dependent m6A modification could regulate the differentiation of T follicle helper cells (Yao et al, 2021).…”