ATP-citrate lyase regulates stemness and metastasis in hepatocellular carcinoma via the Wnt/β-catenin signaling pathway

Background: Hepatocellular carcinoma(HCC) is one of the most highly malignant tumors. Liver tumor-initiating cells(LTICs) have been considered to contribute to HCC progression and metastasis. ATP-citrate lyase(ACLY), as a key enzyme for de novo lipogenesis, has been reported to be upregulated in various tumors. However, its expression and role in HCC and LTICs remain unknown. Methods: The expressions of ACLY in HCC tissues were detected by quantitative real-time PCR(q RT-PCR), Western blotting and immunohistochemistry. Kaplan-Meier curves and Chi-square test were used to determine the clinical significance of ACLY expression in HCC patients. A series of assays were performed to determine the function of ACLY on stemness, migration and invasion of HCC cells. Luciferase reporter assay, Western blotting and immunoprecipitation were used to study the regulation of the Wnt/β-catenin signaling by ACLY. Rescue experiments were performed to investigate whether β-catenin was the mediator of ACLY-regulated stemness and migration in HCC cells. Results: ACLY was highly expressed in HCC tissues and LTICs. Overexpression of ACLY was significantly correlated with poor prognosis, progression and metastasis of HCC patients. Knockdown of ACLY remarkably suppressed stemness properties, migration and invasion in HCC cells. Mechanistically, ACLY could regulate the canonical Wnt pathway by affecting the stability of β-catenin, and Lys49 acetylation of β-catenin might mediate ACLY-regulated β-catenin level in HCC cells. Conclusions: ACLY is a potent regulator of Wnt/β-catenin signaling in modulating LTICs stemness and metastasis in HCC. ACLY may serve as a new target for the diagnosis and treatment of HCC.

p28^GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity

它一致地被看了那 oncoprotein p28GANK，它是在人的 hepatocellular 癌(HCC ) 的 overexpressed，在 HCC 的 tumorigenesis 起一个关键作用。然而，内在的机制仍然保持不清楚。这里，我们证明 p28GANK 在 endoplasmic 蜂窝胃导致的 HCC 房间禁止 apoptosis (嗯) 应力。在期间嗯应力， p28GANK 提高展开的蛋白质反应，支持嗯从翻译压抑的恢复，并且从而便于房间的能力应付压力条件。而且， p28GANK upregulates 调整葡萄糖的蛋白质 78 (GRP78 ) ，一把钥匙嗯女伴蛋白质，它随后提高合拢能力的 ER 并且支持恢复从嗯应力。我们也证明 p28GANK 增加 p38 激活 mitogen 的蛋白质 kinase 和 Akt phosphorylation，并且禁止原子因素 kappa B (NF-B ) 激活在下面嗯强调 upregulation，它接着贡献 GRP78。一起拿，我们的结果显示 p28GANK 禁止嗯在 HCC 房间的导致压力的 apoptosis，至少部分地，由提高适应反应和 GRP78 表示。我们建议 p28GANK 在 ER 压力条件下面为 HCC 前进有潜在的含意。

Transarterial chemoembolization versus percutaneous microwave coagulation therapy for recurrent unresectable intrahepatic cholangiocarcinoma:Development of a prognostic nomogram

Background:Transarterial chemoembolization(TACE)and percutaneous microwave coagulation therapy(PMCT)are commonly used to treat intrahepatic recurrent liver cancers.However,there is no informa-tion regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma(ICC)after resection.Methods:A total of 275 patients with localized recurrent ICC who received either TACE(n=183)or PMCT(n=92)were studied.A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT.Prognostic factors for TACE and PMCT were identified respectively.Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values.Results:Both TACE and PMCT provided curativeness in partial patients(5-year overall survival:21.4%and 6.1%,respectively),but TACE provided better survival benefit in both overall patients(hazard ratio[HR]=0.71;95%confidence interval[CI]:0.50–0.97;P=0.034)and propensity score matching analysis(HR=0.69;95%CI:0.47–0.98;P=0.041).Independent prognostic factors for TACE were tumor size>5 cm,poor differentiation,and major resection,whereas poor differentiation,hepatitis B virus infection,cholelithiasis,and lymph node metastasis were identified for PMCT.Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70,respectively.Conclusions:TACE provided better survival benefits compared to PMCT.However,there was a disparity in prognostic factors,suggesting evaluation of the two nomograms may be supportive in modality selection.Further prospective validation studies are required for the results to be applied in clinical medicine.

Gankyrin expression during mouse embryogenesis

Objective: To observe the gene expression of Gankyrin during mouse embryogenesis and reveal the gene biological significance during organs and tissues formation. Methods: The expressions of Gankyrin mRNA in various organs and tissues were detected by in situ hybridization at indicated times during embryogenesis. Results: The expression of Gankyrin mRNA in mouse day 12.5 embryo was mainly in midbrain, interbrain and endbrain; in mouse day 14.5 embryo mainly in midbrain, aorta, liver, gonad, cranium and rib; in mouse day 16.5 embryo mainly in cranium, rib and vertebra; and in mouse day 18.5 embryo mainly in cranium, rib and intestinal mucosa. Conclusion: Gankyrin gene probably participates in the development of the neural tissues (such as midbrain, interbrain and endbrain etc.), aorta, liver and gonad, intestinal mucosa and bone tissues, which may be closely associated with the function of the organs and tissues.

Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma

很少长期的发炎怎么贡献 hepatocellular 癌(HCC ) 的前进被知道，特别癌症的开始。揭开从长期的发炎的批评转变到在网络水平的 HCC 和分子的机制，我们用我们的动态网络 biomarker (DNB ) 分析了土拨鼠肝炎 virus/c-myc 鼠标和匹配年龄的 wt-C57BL/6 鼠标的时间系列 proteomic 数据模型。DNB 分析显示在转基因的老鼠的出生以后的第 5 月是癌症开始的批评时期，就在批评转变前，它与临床的症状一致。同时，联系 DNB 的网络在批评转变前后显示出蛋白质表示和 coexpression 层次的激烈的倒置。DNB， PLA2G6 和 CYP2C44 的二个成员，与他们的联系差别一起表示了蛋白质，被发现导致 arachidonic 酸新陈代谢的机能障碍，进一步通过短暂受体潜力隧道的煽动性的调停人规定激活煽动性的回答，并且最后导致肝 detoxification 和恶意的转变的缺陷到癌症。作为一个 c-Myc 目标， PLA2G6 断然在表示与 c-Myc 相关，显示出从减少到在 carcinogenesis 期间增加的一个趋势，与在批评转变的最小的点或付小费给的点。相应 PLA2G6 和 c-Myc 的如此的趋势也在人的 hepatocarcinogenesis 期间被观察，与在高级 dysplastic 小瘤(就在 carcinogenesis 前的一个阶段) 的最小的点。我们的学习暗示 PLA2G6 可能在 hepatocarcinogenesis 期间作为象著名 c-Myc 一样的 oncogene 工作，当 PLA2G6 和 c-Myc 的 downregulation 能是显示逼近的 carcinogenesis 的一个警告信号时。

HCCDB: A Database of Hepatocellular Carcinoma Expression Atlas

Hepatocellular carcinoma （HCC） is highly heterogeneous in nature and has been one of the most common cancer types worldwide. To ensure repeatability of identified gene expression patterns and comprehensively annotate the transcriptomes of HCC, we carefully curated 15 public HCC expression datasets that cover around 4000 clinical samples and developed the database HCCDB to serve as a one-stop online resource for exploring HCC gene expression with userfriendly interfaces. The global differential gene expression landscape of HCC was established by analyzing the consistently differentially expressed genes across multiple datasets. Moreover, a 4D metric was proposed to fully characterize the expression pattern of each gene by integrating data from The Cancer Genome Atlas （TCGA） and Genotype-Tissue Expression （GTEx）. To facilitate a comprehensive understanding of gene expression patterns in HCC, HCCDB also provides links to third-party databases on drug, proteomics, and literatures, and graphically displays the results from computational analyses, including differential expression analysis, tissue-specific and tumorspecific expression analysis, survival analysis, and co-expression analysis. HCCDB is freely accessible at http：//lifeome.net/database/hccdb.

Structural basis of interaction between protein tyrosine phosphatase PCP-2 and β-catenin

PCP-2 is a member of receptor-like protein tyrosine phosphatase of the MAM do- main family. To investigate which part of PCP-2 was involved in its interaction with β-catenin, we constructed various deletion mutants of PCP-2. These PCP-2 mutants and wild-type PCP-2 were co-transfected into BHK-21 cells with β-catenin individually. An in vivo binding assay revealed that the expression of wild-type PCP-2, PCP-2 ?C1C2 (deleted PCP-2 without both PTP domains) and PCP-2 ?C2 (deleted PCP-2 without the second PTP domain) could be immunoprecipitated by anti-catenin antibody in every co-transfection, but PCP-2 EXT (deleted PCP-2 without the juxtamembrane region and both PTP domains) was missing, which implied that PCP-2 and β-catenin could associate directly and the juxtamembrane region in PCP-2 was sufficient for the process.

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity

Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs(ceRNAs)bind to the same microRNAs.However,the contribution of such mechanisms in HCC has not been well studied.Herein,potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages,identifying the mT0RC2 component RICTOR as a potential HMGB1 ceRNA in HBV^(+)early stage HCC.Indeed,elevated HMGB1 mRNA was found to promote the expressio n of RICTOR mRNA through competitively bin ding with the miR-200 family,especially miR-429.Functio nal assays emplo ying overexpressi on or in terference strategies dem on strated that the HMGB1 and RICTOR 3zuntra nslated regions(UTR)epigenetically promoted the malignant proliferation,self-renewal,and tumorigenesis in HCC cells.Intriguingly,in terference agai nst HMGB1 and RICTOR in HCC cells promoted a stron ger an ti-PD-L1 immuno therapy resp on se,which appeared to associate with the production of PD-L1^(+)exosomes.Mechanistically,the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms,activating a positive feedback loop involving mT0RC2-AKT-C-MYC to upregulate glutamine synthetase(GS)expression,and inducing mTORCI signaling to derepress SIRT4 on glutamate dehydrogenase(GDH).Meanwhile,this crosstalk network could impede the efficacy of immunotherapy through mTORCI-P70S6K dependent PD-L1 production and PD-L1^(+)exosomes activity.In conclusion,our study highlights the non-coding regulatory role of HMGB1 with implicatio ns for RNA-based therapeutic targeting together with a predictio n of an ti-PD-L1 immuno therapy in HCC.

Infection with SARS-CoV-2 can cause pancreatic impairment

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.