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N6-methyladenosine (m6A) alteration is an epigenetic regulator widely involved in the tumorigenicity of hepatocellular carcinoma (HCC). The role of YTH N6-methyladenosine RNA binding protein F3 (YTHDF3), an m6A reader in HCC, requires further investigation. Here, we aim to explore the biological properties of YTHDF3 in HCC and its potential mechanisms. The predictive risk model for HCC was developed by analyzing the expression of genes associated with m6A in HCC using online datasets. WB and qPCR were employed to assess YTHDF3 expression in HCC and its correlation with the disease's clinicopathological characteristics. Both in vitro and in vivo methods were utilized to evaluate the biological effects of YTHDF3 in HCC. The potential targets of YTHDF3 were identified and confirmed using RNA-seq, meRIP-seq, and linear amplification and sequencing of cDNA ends (Lace-seq). We confirmed that YTHDF3 is overexpressed in HCC. Patients with higher YTHDF3 expression had a greater risk of cancer recurrence. In both in vitro and in vivo settings, YTHDF3 boosts the migration and invasion capabilities of HCC cells. Through multi-omics research, we identified YTHDF3's downstream target genes as NKD inhibitors of the WNT signaling pathway 1 (NKD1) and the WNT/β-catenin signaling pathway. With m6A modification, YTHDF3 suppresses the transcription and translation of NKD1. Additionally, NKD1 inhibited tumor growth by blocking the WNT/β-catenin signaling pathway. The investigation found that the oncogene YTHDF3 stimulates the WNT/β-catenin signaling pathway by m6A-dependently suppressing NKD1 expression in HCC cells. Our findings suggest that YTHDF3 regulates hepatocarcinogenesis, providing fresh perspectives on potential biomarkers and therapeutic targets for HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recent evidences have demonstrated that long non-coding RNAs (lncRNAs) act as key regulators of tumor development and progression including HCC. In the study, we showed that the expression level of HNF1A-AS1 was up-regulated in HCC cell lines. Furthermore, CCK-8 cell proliferation assays and cell cycle analysis showed that HNF1A-AS1 over-expression facilitated HCC cell proliferation by promoting the cell proliferation and S-phase progression, whereas HNF1A-AS1 knockdown had the opposite effect. Western-blotting analysis revealed that knockdown of HNF1A-AS1 inhibited the cycle-relative protein cyclin-D1 and PCNA expression in HCC cells. Mechanism, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays showed that by interacting with enhancer of zeste homolog 2 (EZH2), HNF1A-AS1 promoted HCC cell proliferation by repressing the NKD1 and p21 expression. These results suggested that HNF1A-AS1 may contribute to HCC progression, which may be an effective therapeutic target for patients., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Naked cuticle 1 (NKD1), a negative regulator of the Wnt signaling pathway, is abnormally expressed in many types of malignant tumors. Yet the role and mechanism of NKD1 in hepatocellular carcinoma (HCC) cell proliferation and its relationship with HCC patients' prognosis have been poorly characterized. In the present study, real-time polymerase chain reaction (PCR) was used to examine the mRNA expression patterns of NKD1 in the tissues of 60 patients with HCC and corresponding adjacent non-tumor tissues and found that NKD1 mRNA expression in HCC tissues was relatively lower than that in non-tumor tissues and negatively correlated with tumor size. Kaplan-Meier survival curves uncovered that patients with lower NKD1 expression had a poorer post-operative prognosis than those with higher expression. In addition, over-expression of NKD1 inhibited the HCC cell proliferation ability, whereas knockdown of NKD1 had the opposite effect. In vivo assays showed that mice injected with SMMC-7721 + control cells had bigger tumor nodules than those injected with SMMC-7721 + NKD1. Mechanism studies demonstrated that NKD1 repressed HCC cell proliferation by inducing p53 expression. Taken together, our study revealed that NKD1 mRNA expression was downregulated in HCC tissues and correlated with a poor prognosis. NKD1 inhibited HCC cell proliferation by inducing p53 expression.

It has been reported that NKD1 was an antagonist of the canonical Wnt/β-catenin pathway. While there is little information regarding NKD1 expression pattern in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinicopathologic significance and expression pattern of NKD1 in HCC. NKD1 protein expressions in 69 paired HCC cancer/adjacent non-cancerous tissues were detected by Western blot. Immunohistochemical studies were performed on 58 cases of HCC with integrated clinical information. NKD1 protein expression was divided into normal and low expression group and correlations between NKD1 protein expression and clinicopathologic factors were then evaluated. Western blot results showed that NKD1 protein levels were significantly lower in cancerous tissues compared with corresponding normal tissue (p < 0.05). In addition, we found that the level of NKD1 protein expression in HCC was significantly associated with tumor size (p = 0.011), intra or extra-hepatic metastasis (p = 0.010) and differentiation (p = 0.003). This is to our knowledge the first report investigating NKD1 protein expression pattern in HCC. Our data show that decreased NKD1 protein expression is associated with clinicopathologic factors, and suggest that NKD1 may play an important role in the development of HCC and could serve as a novel biomarker for HCC after further investigation., (© 2015 APMIS. Published by John Wiley & Sons Ltd.)

The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens., (Copyright © 2014. Published by Elsevier Inc.)