Background: N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined.Methods: Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitroandin vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429.Results: KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3′ UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as acis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3.Conclusion: Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.

Rationale: circular RNAs (circRNAs) have been demonstrated to play a crucial role in cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. The aim of present study is to investigate the role of circular RNAs in KIAA1429-mediated HCC progression.

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.

Understanding the roles of noncoding RNAs (ncRNA) in tumorigenesis and metastasis would establish novel avenues to identify diagnostic and therapeutic targets. Here, we aimed to identify hepatocellular carcinoma (HCC)–specific ncRNA and to investigate their roles in hepatocarcinogenesis and metastasis. RNA-seq of xenografts generated by lung metastasis identified long noncoding RNA small nucleolar RNA host gene 10 (SNHG10) and its homolog SCARNA13 as novel drivers for the development and metastasis of HCC. SNHG10 expression positively correlated with SCARNA13 expression in 64 HCC cases, and high expression of SNHG10 or SCARNA13 was associated with poor overall survival. As SCARNA13 showed significant rise and decline after overexpression and knockdown of SNHG10, respectively, we hypothesized that SNHG10 might act as an upstream regulator of SCARNA13. SNHG10 and SCARNA13 coordinately contributed to the malignant phenotype of HCC cells, where SNHG10 served as a sponge for miR-150-5p and interacted with RPL4 mRNA to increase the expression and activity of c-Myb. Reciprocally, upregulated and hyperactivated c-Myb enhanced SNHG10 and SCARNA13 expression by regulating SNHG10 promoter activity, forming a positive feedback loop and continuously stimulating SCARNA13 expression. SCARNA13 mediated SNHG10-driven HCC cell proliferation, invasion, and migration and facilitated the cell cycle and epithelial–mesenchymal transition of HCC cells by regulating SOX9. Overall, we identified a complex circuitry underlying the concomitant upregulation of SNHG10 and its homolog SCARNA13 in HCC in the process of hepatocarcinogenesis and metastasis.Significance: These findings unveil the role of a noncoding RNA in carcinogenesis and metastasis of hepatocellular carcinoma.

Background and Aims: IL‐6–induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL‐6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown. Approach and Results: High‐throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL‐6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up‐regulated by IL‐6 treatment in a time and concentration‐dependent manner. The biogenesis of cGGNBP2 was regulated by RNA‐binding protein DEx‐H Box Helicase 9, which was also mediated by IL‐6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2‐184aa encoded by cGGNBP2. cGGNBP2‐184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2‐184aa directly interacted with signal transducers and activators of transduction‐3 (STAT3), phosphorylated STAT3^Tyr705, and played a positive regulatory role in modulating IL‐6/STAT3 signaling. IL‐6/cGGNBP2‐184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL‐6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis. Conclusions: Our study demonstrates that cGGNBP2‐184aa, a protein encoded by IL‐6–induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL‐6/STAT3‐targeting treatments in ICC.

Tumor-associated tertiary lymphoid structures (TLS) play a critical role in the progression of various tumors. However, the dynamics of lymphocyte recruitment during hepatocellular carcinoma (HCC) clinical progression have not been fully elucidated. In the present study, tissue microarrays and hematoxylin-eosin staining were used to evaluate the existence and degree of TLS in HCC patients. Nine immune biomarkers in intratumoral tissues were examined by immunohistochemical staining. A total of 462 patients were recruited for the study. Kaplan-Meier analysis showed that TLS was inversely correlated with the risk of early tumor recurrence (P=0.014), whereas no association was found between TLS and overall survival. Cox regression analysis identified TLS as an independent prognostic factor for early HCC recurrence (P=0.005). In addition, TLS was associated with increased intratumoral CD3+, CD8+, CD20+, and decreased infiltration of Foxp3+ and CD68+ cells. A lower density of PD1+, TIM3+, and LAG3+ were found in TLS+ cases. Sub-analysis revealed the prognostic value of TLS on early-stage HCC (BCLC 0-A, TNM stage I-II) and HCC with solitary nodule. The validation cohort verified the prognostic value of TLS in early-stage HCC patients. These results suggest that TLS-targeted immune-modulating therapies may be a potential strategy for effective immune-mediated tumor suppression.