New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis.

PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

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'.

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.

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.

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.

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.

Ectopic expression of fungal EcGDH improves nitrogen assimilation and grain yield in rice.

NADP(H)-dependent glutamate dehydrogenases (GDH) in lower organisms have stronger ammonium affinity than those in higher plants. Here we report that transgenic rice overexpressing the EcGDH from Eurotium cheralieri exhibited significantly enhanced aminating activities. Hydroponic and field tests showed that nitrogen assimilation efficiency and grain yields were markedly increased in these transgenic plants, especially at the low nitrogen conditions. These results suggest that EcGDH may have potential to be used to improve nitrogen assimilation and grain yield in rice.

Dynamic Monitoring of Erythrocyte Distribution Width (RDW) and Platelet Distribution Width (PDW) in Treatment of Acute Myocardial Infarction.

BACKGROUND This study investigated the role of erythrocyte distribution width (RDW) and platelet distribution width (PDW) in evaluating the treatment efficacy for acute myocardial infarction (AMI). MATERIAL AND METHODS A total of 120 AMI patients receiving conventional myocardial infarction treatment were included. The patients were divided into an effective group and an ineffective group based on treatment efficacy. The RDW and PDW were measured before and after treatment. We used the independent samples t test, chi-square test, logistic regression, and ROC curves for analysis. RESULTS The change and change rate of RDW and PDW were significantly improved (p<0.01) and the positive change rate of RDW, PDW, and RDW + PDW were significantly lower in the effective group compared with those in the ineffective group (p<0.01). The change and change rate of RDW and PDW are independent factors for treatment efficacy evaluation (p<0.05). ROC curve analysis showed that the changes and change rate of RDW and PDW were all significant in evaluating treatment efficacy (p<0.05). CONCLUSIONS The change and change rate of RDW and PDW or their combination can be used to evaluate treatment efficacy; however, the absolute value of RDW and PDW are not as significant.

Combination of 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity.

This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).

Over-expression of a glutamate dehydrogenase gene, MgGDH, from Magnaporthe grisea confers tolerance to dehydration stress in transgenic rice.

MAIN CONCLUSION: Heterologous expression of a fungal NADP(H)-GDH gene ( MgGDH ) from Magnaporthe grisea can improve dehydration stress tolerance in rice by preventing toxic accumulation of ammonium. Glutamate dehydrogenase (GDH; EC 1.4.1.2 and EC 1.4.1.4) may act as a stress-responsive enzyme in detoxification of high intracellular ammonia and production of glutamate for proline synthesis under stress conditions. In present study, a fungal NADP(H)-GDH gene (MgGDH) from Magnaporthe grisea was over-expressed in rice (Oryza sativa L. cv. 'kitaake'), and the transgenic plants showed the improvement of tolerance to dehydration stress. The kinetic analysis showed that His-TF-MgGDH preferentially utilizes ammonium to produce L-glutamate. Moreover, the affinity of His-TF-MgGDH for ammonium was dramatically higher than that of His-TF-OsGDH for ammonium. Over-expressing MgGDH transgenic rice plants showed lower water-loss rate and higher completely close stomata than the wild-type plants under dehydration stress conditions. In transgenic plants, the NADP(H)-GDH activities were markedly higher than those in wild-type plants and the amination activity was significantly higher than the deamination activity. Compared with wild-type plants, the transgenic plants accumulated much less NH4 (+) but higher amounts of glutamate, proline and soluble sugar under dehydration stress conditions. These results indicate that heterologous expression of MgGDH can prevent toxic accumulation of ammonium and in return improve dehydration stress tolerance in rice.

Postoperative hepatitis B virus reactivation and surgery-induced immunosuppression in patients with hepatitis B-related hepatocellular carcinoma.

BACKGROUND: Hepatectomy in hepatocellular carcinoma (HCC) patients lead to postoperative hepatitis B virus (HBV) reactivation (PHR) as well as immunosuppression. METHODS: This prospective study involved 135 HBV-related HCC patients and 42 control hepatic hemangioma patients. RESULTS: Among HCC patients, 26 (19.3%) suffered PHR. Risk factors for PHR were HBV-cAg S1 positivity [hazard ratio (HR) = 404.82, P = 0.004], high preoperative total bilirubin level (HR = 186.38, P = 0.036), small preoperative proportions of CD3-CD16 + CD56 + cells (HR = 0.01, P = 0.014) and CD19 + B cells (HR = 0.02, P = 0.016), blood transfusion (HR = 157.03, P = 0.006) and high liver cirrhosis S score (HR = 270.45, P = 0.004). On postoperative day (POD) 3, PHR patients showed much greater immunosuppression than non-PHR patients based on proportions of T cells (CD3+, CD3 + CD4+, CD3 + CD8+), B cells (CD19+) and on levels of IgG, IgA antibodies, complement proteins C3, and C4. By POD 7, PHR patients had partially recovered but not as quickly as non-PHR patients: PHR patients still showed deficits in T cells (CD3+, CD3 + CD4+), CD3-CD16 + CD56+ cells and in levels of IgM, C3, C4, and C-reactive protein. CONCLUSION: PHR may be associated with resection-induced immunosuppression in patients with HBV-related HCC.

Systematic review comparing the safety and efficacy of conventional and drug-eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma.

AIM: Conventional transarterial chemoembolization (cTACE) is widely used for treating patients with inoperable hepatocellular carcinoma (HCC). A variation on the technique based on drug-eluting beads (DEB-TACE) has recently entered the clinic, but trials of its safety and efficacy have given conflicting results. This systematic review aimed to gain a current, comprehensive picture of how DEB-TACE compares with cTACE. METHODS: MEDLINE, EMBASE, the Cochrane Library, the Chinese National Knowledge Infrastructure database and clinical trial registries were searched through June 2014. Risk ratios (RR), hazard ratios (HR) and 95% confidence intervals (CI) were calculated. RESULTS: The analysis included four randomized controlled trials, one uncontrolled prospective study and one prospective case-control study, altogether involving 652 patients. Overall survival benefit was similar between cTACE and DEB-TACE patients (HR = 1.07, 95% CI = 0.82-1.40, P = 0.875). However, DEB-TACE was associated with a significantly higher objective tumor response rate (RR = 1.14, 95% CI = 1.01-1.29, P = 0.03) and a slightly lower incidence of adverse events. CONCLUSION: Though the available evidence suggests that although DEB-TACE is associated with better tumor response and potentially fewer adverse events, it does not provide greater survival benefit than cTACE. These results need to be validated in high-quality trials with large sample size.

Investigation of the causal relationship between breast cancer and thyroid cancer: a set of two-sample bidirectional Mendelian randomization study.

PURPOSE: A potential association between breast (BC) and thyroid cancer (TC) has been observed. We investigated if the relationship between BC and TC is causal using bidirectional Mendelian randomization (MR) in Asian and European populations. METHODS: BC-linked single nucleotide polymorphisms (SNPs) were acquired from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium and Biobank Japan. The most recent TC GWAS data were obtained from the FinnGen Project and National Biobank of Korea. We assessed the potential causal relationship between BC and TC using various MR methods, including inverse-variance-weighting (IVW). Sensitivity, heterogeneity, and pleiotropic tests were performed to assess reliability. RESULTS: We found a bidirectional causal association between BC and TC within Europeans (IVW, TC on BC: odds ratio [OR] 1.090, 95% confidence interval [CI]: 1.012-1.173, P = 0.023; BC on TC: OR 1.265, 95% CI: 1.158-1.381, P < 0.001). A one-way causal relationship between BC susceptibility and TC risk was found in Asians (IVW BC on TC: OR 2.274, 95% CI: 2.089-2.475, P < 0.001). Subsequently, we identified a noteworthy bidirectional causal relationship between estrogen receptor (ER)-positive BC and TC (IVW, TC on ER-positive BC: OR 1.104, 95% CI: 1.001-1.212, P = 0.038; ER-positive BC on TC: OR 1.223, 95%CI: 1.072-1.395, P = 0.003), but not ER-negative BC and TC in Europeans. CONCLUSION: We revealed a reciprocal causal association between ER-positive BC and TC. These findings establish a theoretical framework for the simultaneous surveillance and treatment of BC and TC.

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.

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.

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.

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.

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.

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.

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.