ATM-Mediated translocation of RanBPM regulates DNA damage response by stabilizing p21 in non-small cell lung cancer cells.

PURPOSE: Platinum-based chemotherapy remains a standard-of-care for most patients with advanced non-small cell lung cancer (NSCLC). DNA damage response (DDR) induced by platinum or Etoposide activated a panel of cell cycle-regulatory proteins including p21 through p53 pathway. Previous studies have reported that RanBPM has been involved in various cellular processes such as DDR by interacting with multiple proteins. However, the underlying mechanism remains unclear. METHODS: NSCLC tissue microarrays were used for assessing the expression of RanBPM by immunohistochemical staining. The roles of RanBPM in the DDR of NSCLC progression was examined in in vitro cell lines and in vivo animal models. The regulation of RanBPM on protein stability and ubiquitination levels were investigated by immunoblots and in vivo ubiquitylation assay. RESULTS: The level of p21 or RanBPM is lower in NSCLC than non-malignant tissues and has a highly positive correlation. Mechanistically, RanBPM protein physically interacts with p21, and RanBPM deubiquitinates p21 by recruiting a deubiquitinase USP11 to maintain protein stability of p21. RanBPM silencing significantly decreased p21 protein level. Conversely, RanBPM overexpression led to the accumulation of endogenous p21 protein regardless of p53 status. Functionally, RanBPM regulates DDR in a p21-dependent manner. Furthermore, DNA damage significantly promoted the nuclear translocation of RanBPM protein through ATM signaling pathways. CONCLUSION: RanBPM is a novel regulator of P21 protein stability, and plays a critical role in the regulation of DDR.

Specific gut microbiome signature predicts hepatitis B virus-related hepatocellular carcinoma patients with microvascular invasion.

BACKGROUND: We aimed to assess differences in intestinal microflora between patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) and those without MVI. Additionally, we investigated the potential of the microbiome as a non-invasive biomarker for patients with MVI. METHODS: We analyzed the preoperative gut microbiomes (GMs) of two groups, the MVI (n = 46) and non-MVI (n = 56) groups, using 16S ribosomal RNA gene sequencing data. At the operational taxonomic unit level, we employed random forest models to predict MVI risk and validated the results in independent validation cohorts [MVI group (n = 17) and non-MVI group (n = 15)]. RESULTS: ß diversity analysis, utilizing weighted UniFrac distances, revealed a significant difference between the MVI and non-MVI groups, as indicated by non-metric multidimensional scaling and principal coordinate analysis. We also observed a significant correlation between the characteristic intestinal microbial communities at the genus level and their main functions. Nine optimal microbial markers were identified, with an area under the curve of 79.76% between 46 MVI and 56 non-MVI samples and 79.80% in the independent verification group. CONCLUSION: This pioneering analysis of the GM in patients with operable HBV-HCC with and without MVI opens new avenues for treating HBV-HCC with MVI. We successfully established a diagnostic model and independently verified microbial markers for patients with MVI. As preoperative targeted biomarkers, GM holds potential as a non-invasive tool for patients with HBV-HCC with MVI.

PLK1 maintains DNA methylation and cell viability by regulating phosphorylation-dependent UHRF1 protein stability.

PLK1 is a key serine/threonine kinase as well as a master mitotic regulator, but it has never been reported that PLK1 regulates DNA methylation. In the present study, we for the first time found that PLK1 inhibition disrupted global DNA methylation and elevated the expression level of tumor suppressor genes. Mechanistically, we found that PLK1 interacts UHRF1 protein to induce its phosphorylation at serine 265. Phosphorylation is required for the maintenance of UHRF1 protein stability by recruiting a deubiquitinase USP7. Conversely, PLK1 inhibition decreases UHRF1 protein interaction with USP7 and activates the ubiquitin-proteasome pathway, thereby accelerating UHRF1 protein degradation. UHRF1 degradation decreases the recruitment of DNMT1 to chromatin, and decreases the level of genome-wide DNA methylation, thereby elevating the expression of tumor suppressor genes and decreasing cell viability. We here presented the first report on the novel role of PLK1 in DNA methylation maintenance through UHRF1-DNMT1 pathway, and revealed a novel anticancer mechanism of PLK1 inhibitors.

UHRF1 promotes spindle assembly and chromosome congression by catalyzing EG5 polyubiquitination.

UHRF1 is an epigenetic coordinator bridging DNA methylation and histone modifications. Additionally, UHRF1 regulates DNA replication and cell cycle, and its deletion induces G1/S or G2/M cell cycle arrest. The roles of UHRF1 in the regulation of G2/M transition remain poorly understood. UHRF1 depletion caused chromosome misalignment, thereby inducing cell cycle arrest at mitotic metaphase, and these cells exhibited the defects of spindle geometry, prominently manifested as shorter spindles. Mechanistically, UHRF1 protein directly interacts with EG5, a kinesin motor protein, during mitosis. Furthermore, UHRF1 induced EG5 polyubiquitination at the site of K1034 and further promoted the interaction of EG5 with spindle assembly factor TPX2, thereby ensuring accurate EG5 distribution to the spindles during metaphase. Our study clarifies a novel UHRF1 function as a nuclear protein catalyzing EG5 polyubiquitination for proper spindle architecture and faithful genomic transmission, which is independent of its roles in epigenetic regulation and DNA damage repair inside the nucleus. These findings revealed a previously unknown mechanism of UHRF1 in controlling mitotic spindle architecture and chromosome behavior and provided mechanistic evidence for UHRF1 deletion-mediated G2/M arrest.

AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer.

BACKGROUND: Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10-17% CRPC patients. The detailed mechanisms remain unclear.. METHODS: The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting. RESULTS: The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists. CONCLUSIONS: TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Prognostic factors and an innovative nomogram model for patients with hepatocellular carcinoma treated with postoperative adjuvant transarterial chemoembolization.

PURPOSE: The purpose of this study was to estimate the clinical efficacy and identify the best beneficiaries of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 749 HCC patients who underwent surgical resection (380 underwent PA-TACE, 369 had resection only) with a high risk of recurrence were reviewed retrospectively. Patients receiving PA-TACE were randomly split into development and validation cohorts. Univariate and multivariate analyses were performed in the development cohort. A novel model for PA-TACE-insensitivity prediction was built based on univariate and multivariate analysis and was multi-dimensionally validated in the validation set and all samples. RESULTS: After propensity score matching (PSM), in the early-recurrence group, no significant improvement in RFS was achieved with PA-TACE compared to radical hepatic resection alone. PA-TACE insensitive patients were considered as the PA-TACE non-benefit population and were associated with six clinicopathological factors: AFP, node number, tumor capsule, Ki-67 index, MVI, and complications in the development cohort. These factors were incorporated into a nomogram model, which reliably predicted PA-TACE insensitivity, with concordance indices of 0.874 and 0.897 for the development and validation cohort, respectively. In the overall sample, PA-TACE did not significantly improve patients' RFS and OS in the high-score group, while the low-score group had statistical significance. Recurrence pattern diversity was also found to be a factor leading to PA-TACE insensitivity. CONCLUSION: We constructed a new PA-TACE-insensitivity prediction model with potential clinical value. The good predictive performance and availability would allow this model to effectively screen PA-TACE beneficiaries.KEY MESSAGESThe independent influencing factors of PA-TACE insensitivity in patients who received PA-TACE were analyzed to construct a predictive model and its clinical application performance was verified with multi-dimensional methods.PA-TACE treatment should be avoided for patients with high scores according to this model, while it should be cautiously recommended for patients with low scores after multiple considerations.Compared with other related models, this model has obvious advantages in versatility and effectiveness. It can effectively screen the best benefit population of PA-TACE and provide a reliable reference for the selection of precise treatment plans for patients after radical resection of hepatocellular carcinoma.

Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization.

BACKGROUND: Postoperative transarterial chemoembolization (PA-TACE) is an effective adjuvant therapy for preventing early postoperative recurrence of hepatocellular carcinoma (HCC); however, many patients are insensitive to it. Therefore, the present study aimed to explore the in-depth reasons for PA-TACE resistance and provide a reliable basis for selecting patients who will benefit the most from PA-TACE. METHODS: The unique gene expression profiles of primary tumors from PA-TACE-sensitive or -insensitive patients were analyzed using microarray data. Combined differential expression analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were used to screen for potential drivers of PA-TACE insensitivity. The expression of ALDOB was silenced or overexpressed in hepatoma cell lines, and changes in glycolytic activity, cycle, apoptosis, and malignant biological phenotypes were observed under normoxia and hypoxia. Finally, an animal model was constructed to verify the effects of ALDOB dysregulation on the tumorigenic ability of HCC cells in vivo. RESULTS: The inhibition of ALDOB promoted the up-regulation of Ki67 expression, and glycolytic activity was significantly enhanced. Moreover, the proliferation, invasion, and migration capabilities were increased in HCC cells and even worse in hypoxia. This advantage of malignant behavior was also validated using in vivo models. CONCLUSION: Down-regulation of ALDOB may underlie the metabolic reprogramming observed in HCC by promoting the malignant behavior of HCC cells. Hypoxia and ALDOB down-regulation acted additively, which was closely related to PA-TACE insensitivity. The use of ALDOB and Ki67 as a combined marker has the potential to identify the 'PA-TACE beneficiary population'.

Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation.

Prostate cancer (PCa) represents the second cause of cancer death in adult men. Aberrant overexpression of UHRF1 has been reported in several cancer types, and is regarded as a novel drug target for cancer therapy. Nevertheless, no UHRF1-targeted small molecule inhibitor has been testing in clinical trials. Traditional Chinese medicine (TCM) prescriptions have a long history for the treatment of PCa in China, and Chinese herbal extracts are important resources for new drug discovery. In the present study, we first screened the potentially effective components from the commonly used TCMs for PCa treatment in clinic by using network pharmacology together with molecular docking. We identified diosgenin (DSG) as a small molecule natural compound specifically targeting UHRF1 protein. Furthermore, we validated the results by using the wet lab experiments. DSG, by directly binding UHRF1 protein, induced UHRF1 protein degradation through the ubiquitin-proteasome pathway. Importantly, DSG induced UHRF1 protein degradation by reducing the protein interaction with a deubiquitinase USP7. DSG reduced the level of genomic DNA methylation, and elevated the expression of such tumor suppressor genes as p21, p16 and LXN, thereby resulting in cell cycle arrest, cellular senescence and the inhibition of xenograft tumor growth. We here presented the first report that DSG specifically induced UHRF1 protein degradation, thereby revealing a novel anticancer mechanism of DSG. Altogether, this present study provided a promising strategy to discover new molecule-targeted drugs from small-molecule natural products.

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer.

Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.

Liver resection for large and huge hepatocellular carcinoma: Predictors of failure, recurrence patterns, and prognoses.

BACKGROUND: Characteristic symptoms and signs are often absent in patients with hepatocellular carcinoma (HCC). As a result, many patients are not diagnosed until their tumors have grown to large (> 5cm) or huge sizes (> 10cm). Liver resection has traditionally been reserved for patients with small HCC, but more recently it is being used for patients with large and huge tumors. The aim of this study was to determine risk predictors of recurrence, patterns of recurrence, and survival rates for large and huge HCC patients who underwent curative liver resection. MATERIALS AND METHODS: We retrospectively identified a subgroup of patients who underwent liver resection for HCC with diameters 5 cm or larger. Overall survival (OS) and recurrence-free survival (RFS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to investigate potential risk factors for recurrence and death. RESULTS: Among 897 patients, the median follow-up was 48 (range, 5-140) months. The 1-, 3-, and 5-year RFS rates were 51.6%, 36.1%, and 30.1%, respectively, and OS rates were 80.2%, 55.4%, and 47.7%, respectively. Significant independent predictors of recurrence were preoperative satellite nodule (HR = 2.25; 95% CI, 1.17-4.31; p = .02), preoperative AFP levels above 400 ng/ml (HR = 1.23; 95% CI, 1.04-1.45; p = .01), resection margins of 1 cm or less (HR = 1.21; 95% CI, 1.00-1.46; p = .047), cirrhosis (HR = 2.64; 95% CI, 2.13-3.28; p < .001), and microvascular invasion (HR = 1.71; 95% CI, 1.45-2.20; p < .001). All of these except narrow resection margin were also independent risk factors of OS. CONCLUSIONS: Hepatic resection for patients with large and huge HCC without hepatic vascular invasion, extrahepatic metastases, or severe chronic liver disease results in acceptable long-term outcomes.

Clinical implications and biological features of a novel postoperative recurrent HCC classification: A multi-centre study.

BACKGROUND & AIMS: The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine. METHODS: A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted. RESULTS: Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target. CONCLUSIONS: This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.

Gut microbiome dysbiosis in patients with hepatitis B virus-related hepatocellular carcinoma after extended hepatectomy liver failure.

Background: Hepatitis B virus-related hepatocellular carcinoma (B-HCC) negatively affects the gut microbiome. This study aimed to investigate the gut microbiome profiles and functions post-hepatectomy liver failure (PHLF) after extended hepatectomy (e-PHLF) to obtain valuable insights, identify potential diagnostic biomarkers, and assist in the treatment of this disease. Methods: B-HCC patients who underwent extended hepatectomy were consecutively recruited and divided into Group A (n=15) and Group B (n=15) based on the presence and absence of e-PHLF, respectively. The relationships between gut microbiota and extended hepatectomy liver failure were explored using 16S ribosomal RNA (16S rRNA) gene sequencing data. Results: Following extended hepatectomy, the α-diversity of Group A was significantly higher than that of Group B (Shannon P=0.034 or Simpson P=0.031), and the ß-diversity differed significantly between Groups A and B (P=0.004, R=0.100). At the genus level, 10 bacterial genera (Bacteroides, Pantoea, Methylobacterium-Methylorubrum, Inquilinus, Mycobacterium, Allisonella, Helicobacter, GCA-900066575, IS-44, and Faecalibacterium) were significantly enriched in Group A, whereas five genera (Papillibacter, Scardovia, Turicibacter, Catabacter, and Senegalimassilia) were significantly enriched in Group B. The highly abundant genera Bacteroides, Pantoea, Faecalibacterium, and Turicibacter participated in multiple amino acid metabolism pathways, organic acid metabolism pathways, pyrimidine metabolism pathways, palmitate biosynthesis, and stearate biosynthesis. Redundancy analysis showed that four environmental factors (total bilirubin, international normalized ratio, prealbumin, and albumin) were significantly correlated with intestinal microorganisms. The formation of interaction networks between different gut microbiomes revealed important correlations between the gut microbiome, and there was a significant correlation between the highly abundant gut microbiome and main functions. Conclusions: The gut microbiota characteristics in B-HCC patients after extended hepatectomy liver failure might allow for the use of non-invasive biomarkers for disease diagnosis and treatment.

Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation.

Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.

Operable hepatitis B virus-related hepatocellular carcinoma: gut microbiota profile of patients at different ages.

Background: Age was important prognostic factors for operable hepatocellular carcinoma patients. The aim of the present study was to assess the difference in gut microbiota in patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) at different ages ; to investigate the features of the microbiota and its function associated with different ages; to provide a preliminary look at effects of the gut microbiota dimension on prognostic. Methods: From September 2020 to May 2021, patients with HBV-HCC were able to undergo liver resection and were recruited consecutively and divided into the younger age group (age <45 years) (Y.AG) (n=20), middle age group (age from 45 to 65 years) (M.AG) (n=13) 45-65 years, and older age group (age >65 years) (O.AG) (n=20). The relationships between gut microbiota and different ages were explored using 16S rRNA gene sequencing data. PICRUST2 was used to examine the metagenomic data in PHLF patients. Fisher's exact and Mann-Whitney U-test were used for the data analysis. Results: Pairwise comparison between the three groups showed that the α-diversity of Y.AG was significantly higher than that of O.AG (ACE Index, P=0.017; chao1 Index, P=0.031; observed_species Index, P=0.011; and goods_coverage Index, P=0.041). The ß-diversity in the 3 groups differed significantly (stress =0.100), while the composition (ß-diversity) differed significantly between the Y.AG and the M.AG (stress =0.090), the M.AG and the O.AG (stress =0.095), and the Y.AG and the O.AG (stress =0.099). At the genus level, 7 bacterial genera were significantly enriched in the O.AG compared with the Y.AG, of which Streptococcus, Blautia, Erysipelotrichaceae_UCG-003, and Fusicatenibacter represented the major variances in O.AG microbiomes. Eleven genera were significantly increased in the O.AG, of which Prevotella, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Ruminiclostridium, and Phascolarctobacterium represented the major variances in the O.AG. The Y.AG and the O.AG were predicted by PICRUSt2 analysis, which found 72 pathways related to differential gut microbiome at the genus level. Redundancy analysis showed that 7 environmental factors were significantly correlated with intestinal microorganisms, especially in the Y.AG compared with the O.AG. Conclusions: Analysis of gut microbiota characteristics in patients of different ages could ultimately contribute to the development of novel avenues for the treatment of HCC at different ages.

Outcomes of postoperative adjuvant transarterial chemoembolization for hepatocellular carcinoma according to the Ki67 index.

Aim: To assess whether Ki67 is related to the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in hepatocellular carcinoma patients at high risk of postsurgical recurrence. Methods: A total of 716 patients undergoing surgical resection with or without PA-TACE were retrospectively enrolled. Immunohistochemistry was used to analyze Ki67 expression. Results: There was no significant difference in tumor-free survival between patients who underwent resection with or without chemoembolization. However, chemoembolization was associated with significantly higher tumor-free survival rates among patients with 'low' (<30%) or 'moderate' (30-59%) levels of Ki67. Patients highly expressing Ki67 displayed higher rates of overall recurrence, earlier recurrence, multiple intrahepatic recurrence and extrahepatic metastasis. Conclusion: In patients with relatively high Ki67 levels, PA-TACE does not appear to improve outcomes.

Postoperative adjuvant transarterial chemoembolization (PA-TACE), as an adjuvant treatment to surgery, is widely recommended in patients with high-risk factors for recurrence. Nevertheless, some studies challenge whether it actually improves prognosis, thus the influence of PA-TACE on prognosis remains controversial. The present research indicated that the ability of PA-TACE to help inhibit hepatocellular carcinoma recurrence is conditionally restrictive, and it appears to be beneficial only in those patients with a low or moderate Ki67 index (<60%). For patients with high Ki67 expression, compared with PA-TACE, 'adjuvant immunotherapy' may be a potential alternative option. This finding suggests a valuable reference to identify the best beneficiaries of PA-TACE for individualized treatment.

Integrated omics analysis: the relationship between significantly increased Klebsiella post-hepatectomy and decreased hub-metabolite 3-methyl-2-oxobutanoic acid is associated with induced liver failure.

Background: This study sought to evaluate the association between intestinal Klebsiella and post-hepatectomy liver failure (PHLF) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (B-HCC), and identify the inner relationship. Methods: Patients with B-HCC were divided into Groups A and B based on the presence or absence of PHLF. 16S ribosomal ribonucleic acid surveys were used to identify gut microbiome alterations. PICRUST2 was used to examine the metagenomic data in PHLF patients. Fecal and serum samples were processed by chromatography-mass spectrometry based non-targeted metabonomics, then comprehensively analyzed to obtain hub metabolites. A Spearman correlation analysis was then conducted to find any associations between fecal differential metabolites and the relative abundance of differential microbes. Results: Hepatectomies were significantly associated with a gut microbial imbalance in B-HCC patients, and a significant elevation of Klebsiella abundance was observed in PHLF patients. Klebsiella appears to act on 13 amino acid-related pathways, especially significantly observed in branched-chain amino acid (BCAA) metabolic pathways. Additionally, Klebsiella was found to be highly correlated with 3-methyl-2-oxobutanoic acid shared by feces and serum in the BCAA metabolic pathway. Conclusions: Hepatectomy can lead to an imbalance of intestinal microflora in B-HCC patients. Due to its potential connections with 3-methyl-2-oxobutanoic acid in the BCAA pathway, significantly increased Klebsiella has the potential to be an evaluation indicator of PHLF in B-HCC patients. Moreover, 3-methyl-2-oxobutanoic acid has research value in PHLF-targeted treatments.

Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ-stimulated antitumor immunity.

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-γ/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whsc1 diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.

UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications.

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.

The potential mechanism of miR-130b on promotion of the invasion and metastasis of hepatocellular carcinoma by inhibiting Notch-Dll1.

Introduction: This study aimed to elucidate the regulatory role and molecular regulation mechanism of miR-130b gene in the process of invasion and metastasis of hepatocarcinoma, and provide a theoretical basis for seeking of effective prevention and treatment of new targets for hepatocellular carcinoma.Materials and methods: The expression level of miR-130b gene in hepatocarcinoma tissues was determined by qRT-PCR. The biological function and mechanism of miR-130b gene were verified by cell and animal models, and the target gene was verified by double luciferase assay.Results: In the liver cancer tissues of patients with metastasis, the expression level of miR-130b gene was increased, and the difference was significantly significant (p < 0.05). Evaluation of independent risk factors for overall survival showed significant difference (p < 0.01). Up-regulation of miR-130b in MHCC97L- subpopulation cells significantly enhanced the invasion and migration ability, and the difference was statistically significant (p < 0.05). The invasion and migration ability of MHCC97H + subpopulation cells with increased expression of miR-130b was significantly decreased, and the difference was notably significant (p < 0.05). When the expression of miR-130b in MHCC97H + subpopulation cells was inhibited, the expressions of Notch-Dll1 and SOX2, Nanog and E2F3 proteins in transplanted tumor tissues were significantly higher than those in other groups (p < 0.05). When miR-130b in MHCC97L- subpopulation cells was up-regulated, the expressions of Notch-Dll1 and Bcl-2, CCND1, Nanog and MET proteins in transplanted tumor tissues were significantly increased than those in other groups (p < 0.05). The prediction results of bioinformatics data suggest that the target gene of miR-130b may be Notch-Dll1 gene. The experiment of luciferase reporter gene confirmed that miR-130b gene can be inhibited and contains fluorescent reporter gene with complementary binding site, lost activity.Conclusion: The miR-130b gene can inhibit the protein expression of Notch-Dll1, and it can promote the invasion and metastasis of liver cancer cells.