Hepatocellular carcinoma (HCC) is third leading cause of cancer-related death globally. Evidence suggest that long non-coding RNAs (lncRNAs) have emerged as key regulators of tumorigenesis and metastasis in HCC. In this study, we investigated the functional significance of SNHG12 and explored whether SNHG12 can directly interact with miR-199a/b-5p in the progression of HCC. We determined the expression level of SNHG12 in HCC tissues with quantitative real-time PCR and then studied its clinical significance. The binding site between SNHG12 and miR-199a/b-5p was confirmed using dual luciferase assay and RNA immunoprecipitation (RIP) assay. SNHG12 was silenced through the siRNA transfection to determine whether SNHG12-siRNA is able to affect cell proliferation, invasion and metastasis. SNHG12 was significantly higher in the HCC tissues than that in the adjacent normal tissues. There were direct interactions between miR-199a/b-5p and the binding site of SNHG12. SNHG12 functioned as an endogenous sponge for miR-199a/b-5p to regulate the expression of MLK3 and affect the NF-κB pathway. SNHG12 may serve as a valuable biomarker and a potential therapeutic target for HCC.

Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8⁺ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8⁺ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.

Background: Immune function, nutrition status, and inflammation influence tumor initiation and progression. This was a retrospective multicenter cohort study that investigated the prognostic value and clinical relevance of immune-, inflammatory-, and nutritional-related biomarkers to develop a novel prognostic immune–inflammatory–nutritional score (PIIN score) for patients with intrahepatic cholangiocarcinoma (ICC).Methods: The clinical data of 571 patients (406 in the training set and 165 in the validation set) were collected from four large hepato-pancreatico-biliary centers of patients with ICC who underwent surgical resection between January 2011 and September 2017. Twelve blood biomarkers were collected to develop the PIIN score using the LASSO Cox regression model. The predictive value was further assessed using validation datasets. Afterward, nomograms combining the PIIN score and other clinicopathological parameters were developed and validated based on the calibration curve, time-dependent AUC curves, and decision curve analysis (DCA). The primary outcomes evaluated were overall survival (OS) and recurrence-free survival (RFS) from the day of primary resection of ICC.Results: Based on the albumin–bilirubin (ALBI) grade, neutrophil- to- lymphocyte ratio (NLR), prognostic nutritional index (PNI), and systemic immune- inflammation index (SII) biomarkers, the PIIN score that classified patients into high-risk and low-risk groups could be calculated. Patients with high-risk scores had shorter OS (training set, p < 0.001; validation set, p = 0.003) and RFS (training set, p < 0.001; validation set, p = 0.002) than patients with low-risk scores. The high PIIN score was also associated with larger tumors (≥5 cm), lymph node metastasis (N1 stage), multiple tumors, and high tumor grade or TNM (tumor (T), nodes (N), and metastases (M)) stage. Furthermore, the high PIIN score was a significant independent prognostic factor of OS and RFS in both the training (p < 0.001) and validation (p = 0.003) cohorts, respectively. A PIIN-nomogram for individualized prognostic prediction was constructed by integrating the PIIN score with the clinicopathological variables that yielded better predictive performance than the TNM stage.Conclusion: The PIIN score, a novel immune–inflammatory–nutritional-related prognostic biomarker, predicts the prognosis in patients with resected ICC and can be a reliable tool for ICC prognosis prediction after surgery. Our study findings provide novel insights into the role of cancer-related immune disorders, inflammation, and malnutrition.

Background: Hepatocellular carcinoma (HCC) is the world’s third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet. Methods: CEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of β-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2). Results: CEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of β-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and β-catenin, thus promoting the nuclear translocation of β-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis. Conclusions: Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/β-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/β-catenin axis may be used as a potential therapeutic target for HCC treatment.

Purpose: To comprehensively investigate the implications of lymph node dissection (LND) and the prognostic impact of the number of lymph node (LN) metastases on survival in intrahepatic cholangiocarcinoma (ICC) using a large‐scale study.Methods: Patients who underwent surgical resection for ICC between 2004 and 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) registries. The Kaplan–Meier and log‐rank tests were used to compare cancer‐specific survival (CSS) and overall survival (OS) between different groups. Propensity score matching (PSM) and subgroup analyses were performed to balance potential confounding factors. A multivariate Cox proportional hazards regression model was used to identify prognostic factors of survival outcomes. Restricted cubic splines fitted in the Cox proportional hazard regression models were also conducted to examine associations between continuous variables and outcomes.Results: In all, 1028 patients were enrolled. There were 652 (63.4%) patients undergoing LND, with lymph node metastasis (LNM) confirmed in 212 (32.5%) cases. Patients receiving LND did not show better survival outcomes than those receiving non‐LND (NLND). We divided the LND group into two subgroups: patients with LNM (+) and those without LNM (−). Among these three groups, patients with LNM experienced the worst CSS and OS, while NLND patients had similar survival times to LNM (−) patients. Restricted cubic spline analysis indicated that an increased number of LNM was associated with a decreased chance of survival (p < 0.001). Patients who received LND were further categorized as having no nodal metastasis (N0), 1–2 LNM (N1), or ≥3 LNM (N2) according to the number of LNM. The Kaplan–Meier curves showed that the mortality risk of patients with N0, N1, and N2 disease (median CSS, N0 50.0 vs. N1 22.0 vs. N2 14.0 months; median OS, N0 46.0 vs. N1 21.0 vs. N2 14.0 months, all p < 0.01) increased significantly, except for patients who had <6 LNs harvested. On multivariable survival analysis, a higher nodal stage (N1 vs. N0: CSS, hazard ratio [HR] 2.135, 95% CI 1.636–2.788, p < 0.001; OS, HR 2.100, 95% CI 1.624–2.717, p < 0.001; N2 vs. N0: CSS, HR 4.027, 95% CI 2.791–5.811, p < 0.001; OS, HR 3.678, 95% CI 2.561–5.282, p < 0.001) was an independent prognostic risk factor for survival.Conclusions: Despite the lack of a clear survival benefit of LND in patients with ICC, a significant positive association between the number of LNM and poor outcomes was observed. We still suggest adequate LND by examining at least six LNs to ensure precise staging. On this basis, the recently proposed nodal classification of N0, N1, and N2 stages may also allow better prognostic stratification of ICC patients.

Background: Lactate’s perception of lactate has changed over the last 30 years from a straightforward metabolic byproduct to a complex chemical with important biological activities, such as signal transduction, gluconeogenesis, and mitochondrial respiration. In addition to its metabolic contributions, lactate has far-reaching repercussions. This review highlights the role of lactate in the course of cancer by highlighting lactylation as a unique epigenetic alteration. The purpose of this review is to clarify the functions of lactate in the biology of tumors, with a particular focus on the translational potential of lactylation pathways in cancer diagnosis and treatment approaches.Methods: This review summarizes research on the relationship between lactate and cancer, with an emphasis on histone lactylation, its effect on gene expression, and its influence on the tumor microenvironment. By establishing a connection between metabolic byproducts and epigenetic gene regulation, we investigated how lactylation affects immune regulation, inflammation, and cellular repair.Findings: Histone lactylation, or the addition of lactate to lysine residues on histone proteins, increases transcriptional activity and facilitates the expression of genes involved in homeostasis and repair. These findings have important implications for cancer treatment. Lactylation, for example, activates genes such as Arg1, which is a hallmark of the M2 macrophage phenotype implicated in immunosuppression and tumor growth. The ability of lactate to dynamically alter gene expression is further supported by its function as a histone deacetylase(HDAC)inhibitor and its impact on histone acetylation. Its wide-ranging involvement in cellular metabolism and epigenetic control has been demonstrated by the discovery of particular lactylation sites on histones in various cell types, including cancer cells.