Pathogenesis Of Liver Cancer Research Articles

Multi-omics research contributes to early screening, diagnosis and treatment of liver cancer

In 2016, the World Health Organization set an ambitious goal of reducing viral hepatitis-related deaths by 65% by 2030. The key to this goal is to reduce viral hepatitis-related HCC deaths. Liver cancer is the fourth most common malignant tumor and the second leading cause of cancer death in China. The onset of HCC is insidious, and most patients are already in the middle and late stage when diagnosed. Despite the great progress on management of HCC, the therapeutic effect and prognosis of HCC are still unsatisfactory. Therefore, multi-dimensional and comprehensive analysis of the mechanism of liver cancer, improving the early screening, diagnosis and treatment rate of liver cancer are the key points of reducing the harm of liver cancer in China. In recent years, multi-omics studies have been widely applied in the field of liver cancer, providing a basis for the pathogenesis of liver cancer, early detection and diagnosis, development of individual treatment strategies and prognosis assessment. This issue will focus on the application of genomics, proteomics, metabolomics and imaging omics in early screening, diagnosis and treatment of liver cancer.

Inhibition of Arid1a increases stem/progenitor cell-like properties of liver cancer

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.

Elevated FOXA1 Expression Indicates Poor Prognosis in Liver Cancer due to Its Effects on Cell Proliferation and Metastasis.

Purpose Studying the pathogenesis of liver cancer is conducive to the exploration of effective diagnostic and prognostic biomarkers. In this study, we investigated the expression of FOXA1 and its oncogenic role in hepatocellular carcinoma (HCC). Methods Transcriptome data of HCC tissues were downloaded from The Cancer Genome Atlas (TCGA) and GEO databases and analyzed using R software. We also upregulated FOXA1 expression in HCC cells and investigated the role of FOXA1 in the proliferation and migration of HCC cells through proliferation, colony formation, wound healing, and Transwell assays. Results An analysis of the transcriptome data in TCGA database revealed found that FOXA1 is highly expressed in HCC tissues and that patients with low FOXA1 expression have a better prognosis. High FOXA1 expression was mainly associated with extracellular matrix organization, cancer, and mitosis. The results of an immunohistochemistry (IHC) assay showed that FOXA1 protein was highly expressed in HCC tissues, and patients with low FOXA1 expression showed longer disease-specific survival times and progression-free intervals. The results from quantitative reverse transcription–PCR (RT–qPCR) and Western blot experiments showed that the expression of FOXA1 in liver cancer cell lines was higher than that in immortalized human liver cell lines. Proliferation, wound healing, and Transwell experiments showed that FOXA1 enhanced the proliferation and migration abilities of liver cancer and immortalized human cell lines. Conclusion Our research suggests that FOXA1 plays an important role in promoting the recurrence and metastasis of HCC by increasing cell proliferation and metastasis.

Probing Iron-Mediated Synergistic Change of Cl- and HClO in Liver Cancer Cells with a Dual-Color Fluorescence Reporter.

The ambiguous molecular mechanism remains a leading cause for the high mortality rate of liver cancer. An evident iron overload has been unveiled in liver cancer cell proliferation, which is closely related to oxidative stress. However oxidative stress-regulated chloride intracellular channel protein 1 (CLIC1) obviously increases in liver cancer cells. Cl- is also involved in cell proliferation, and its downstream product, HClO, can induce cell carcinoma when over-generated. However, whether iron overload could mediate the variation of intracellular Cl- and HClO is still uncharted. Herein, we present a dual-responsive fluorescence reporter MQFL-NH2 for simultaneously visualizing the fluctuation of Cl-/HClO at the same spot in living cells. Electrostatic binding to Cl- effectively gave an attenuated signal with blue fluorescence, and HClO induced a sharp green fluorescence. In HL-7702 cells stimulated with iron, the blue/green dual fluorescence of MQFL-NH2 displayed that Cl- and HClO were elevated. In contrast, they were both reduced in iron-removed SMMC-7721 cells. Further results revealed that iron overload could promote the levels of Cl- and HClO by up-regulating CLIC1 and myeloperoxidase. Altogether, the work will energetically contribute to grasp the molecular mechanism in iron overload-mediated pathogenesis of liver cancer.

DNAJA1 Stabilizes EF1A1 to Promote Cell Proliferation and Metastasis of Liver Cancer Mediated by miR-205-5p.

Liver cancer is one of the most common and aggressive malignancies worldwide with poor prognosis. Studies on pathogenesis of liver cancer are urgently demanded to develop better treatment strategy. Here, we found that overexpression of DnaJ heat shock protein family (Hsp40) member A1 (DNAJA1) increased cell proliferation, invasion, and angiogenesis in Huh 7 and HepG2 cells, while depletion of DNAJA1 in MHCC-97H and HCC-M3 showed opposite effects. In vivo functional assays indicated that DNAJA1 promoted tumor growth and pulmonary metastasis in mice. Mechanistically, as a direct target of miR-205-5p, DNAJA1 promoted proliferation and metastasis of liver cancer cells by stabilizing eukaryotic elongation factor 1A1 (EF1A1). Moreover, DNAJA was markedly upregulated in liver cancer tissues (P < 0.05) and was significantly associated with poor prognosis. And its expression was correlated with differentiation (P < 0.001), dissemination (P < 0.001), and serum AFP (P = 0.029). The mRNA levels of miR-205-5p and DNAJA1 were negatively correlated in liver cancer. In conclusion, our study reveals that DNAJA1 acts as an oncogene in liver cancer via miR-205-5p/EF1A1 axis and might be a potential biomarker to predict the prognosis for liver cancer patients.

New and effective method to develop primary hepatocytes from liver cancer patients

Liver cancer (LC) is one of the most common malignant tumors worldwide. Since the mechanism of LC pathogenesis and metastasis cannot be carried out directly on the human body, it is particularly important to establish human liver cancer cell lines for research in vitro. In this study, tissue block adherence method combined with cell clumps digestion method was used to establish primary human hepatocytes (PHHs) with a successful rate of 60% (45/75). Short tandem repeat (STR) analysis proved the cells were derived from its paired tissues. These cells from hepatocellular carcinoma (HCC) expressed NTCP and secreted ALB and AAT as detected by western blot, and expressed hepatocyte-specific membrane protein ASGR1 as detected by flow cytometry. Liver cancer biomarkers like CK7 in ICC (intrahepatic cholangiocarcinoma), AFP, and GPC3 in HCC expressed of different degree as detected by immunohistochemical analysis. These cells displayed typical liver cancer cell morphological characteristics and can passage stably. In conclusion, we developed an effective method to establish PHHs. Further studies are necessary to study if these cells maintaining other liver function and reproduce the physiology of the tumors and how these cells behavior in the drug development.

Analyzing TCGA Data to Identify Gene Mutations Linked to Hepatocellular Carcinoma in Asians

Introduction: Liver cancer is the sixth most common and second most fatal type of cancer worldwide. Few treatment options are available as patients with liver cancer are often diagnosed in an advanced stage due to a lack of clinical symptoms. Effectively preventing and treating liver cancer relies heavily on early diagnosis; early diagnosis results from identifying and monitoring high-risk patients. Epigenetic risk factors, such as hepatitis B, hepatitis C, cirrhosis, nonalcoholic fatty liver disease, and alcohol/tobacco abuse, are highly prevalent in Asia and likely cause Asians to have a higher incidence and mortality rate of liver cancer. While these acquired risk factors are relatively well understood, the underlying genetic background of liver cancer in Asians has not been well established or correlated with clinical outcomes. Methods: In this study, we accessed The Cancer Genome Atlas (TCGA) hepatocellular carcinoma clinical and mutation data through TCGAbiolinksGUI. Results: We found that mutations in five genes (TP53, TTN, OBSCN, MUC5B, CSMD1) were statistically linked with increased mortality in Asians compared to non-Asians, four of which (TTN, OBSCN, MUC5B, CSMD1) were also more prevalent in the Asian population. Within the Asian cohort, two gene mutations (TTN, HMCN1) were statistically linked with worse outcomes. We also found that the TP53 mutation predicts worse outcomes within the non-Asian cohort but not within the Asian cohort. Discussion/Conclusion: Our findings can improve cancer care in the Asian population through better disease prognostication, evaluations for potential targeted therapy, and a deeper understanding of liver cancer pathogenesis.

Molecular epidemiology of liver cancer: Liver cancer incidence and mortality pattern worldwide

Primary liver cancer was the sixth most prevalent cancer and third leading cause of cancer mortality worldwide. The highest rates of incidence and mortality were reported in Eastern Asia and it was 2 to 3 times more common than females in most regions. The summary estimates of the global trends in incidence rates of liver cancer indicated decreasing trends in many Asian high-risk countries, however increasing trends for North American and European countries. Understanding the several involved cells signaling pathways in liver cancer pathogenesis provide an opportunity to identify novel targets that can be utilized for therapeutic and diagnostic modalities. At this time there are only a few effective strategies to prevent or treat liver cancer, and, therefore, a great deal of research is being conducted on liver cancer early detection and prevention. There are no widely recommended screening tests for liver cancer in people who are at average risk at this time. But, testing might be recommended for some people at higher risk. However researchers are studying ways to prevent or treat hepatitis infections before they cause liver cancers. Research into developing a vaccine to prevent hepatitis C is ongoing. Since population-based methods for screening the disease have not been introduced, the greatest focus should be placed on the predominant risk factors for the disease in older men, further studies should be conducted and high-risk provinces should be spotlighted.

A systematic approach to decode the mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC)

Cornus Officinalis (Cornus), the dried pulp of mature Cornus, is used to treat liver diseases. However, the pharmacological mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC) has not been systematically studied. The chemical compounds and the bioactive chemical compounds of Cornus were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Cards database was used to explore the targets in liver cancer pathogenesis. The disease-drug Venn diagram was constructed using the VENN 2.1 and the STRING database was used to analyze protein-protein Interaction Network (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R package. Molecular docking was performed using Discovery Studio were assessed using Pymol and Discovery Studio 2016. Cell survival of BEL-7404 cells treated by Hydroxygenkwanin (HGK) were valued through CCK-8 assay. Expressions of caspase-3 and cleaved PARP was detected through Western blot. Pharmacological network diagrams of the Cornus compound-target network and HCC-related target network were successfully constructed. A total of 20 active compounds, 1841 predicted biological targets of Cornus, and 7100 HCC-related targets were identified. 37 target genes between Cornus and HCC were screened trough the network pharmacology. Molecular docking studies suggested that HGK has the highest affinity with caspase-3. HGK could induce apoptosis of HCC cells and significantly activate the caspase-3 protease activity in BEL-7404. This study systematically elaborated the mechanism of Cornus in the treatment of HCC and provided a new perspective to exploit Antineoplastic from Cornus.

MiR-513b-5p represses autophagy during the malignant progression of hepatocellular carcinoma by targeting PIK3R3.

Hepatocellular carcinoma (HCC) serves as a prevailing global malignancy with severe mortality and extremely unsatisfactory prognosis, in which autophagy is a fundamental process in liver cancer pathogenesis, but the mechanisms are poorly understood. MicroRNAs (miRNAs) serve as a type of well-recognized non-coding regulators and contribute to the modulation of liver cancer development, from the aspects of diagnosis, progression, and therapy. Here, we aimed to investigate the function of hsa_microRNA-513b-5p (miR-513b-5p) in regulating autophagy during HCC progression. Specifically, our data showed that miR-513b-5p mimic reduced the LC3-II and beclin1 expression but enhanced p62 expression in HCC cells. MiR-513b-5p repressed liver cancer cell proliferation, migration/invasion, and induced apoptosis in vitro. Crucially, miR-513b-5p attenuated tumor growth of liver cancer cells in vivo. In the mechanical investigation, we identified that PIK3R3 mRNA 3′UTR was targeted by miR-513b-5p and miR-513b-5p suppressed PIK3R3 expression. PIK3R3 overexpression partly reversed miR-513b-5p-mediated autophagy, proliferation, and apoptosis of liver cancer cells. Consequently, we concluded that miR-513b-5p repressed autophagy during the malignant progression of HCC by targeting PIK3R3. MiR-513b-5p may be applied as a therapeutic target for HCC.

Downregulation of HBx Restrains Proliferation, Migration, and Invasion of HepG2 Cells.

Liver cancer is a major contributor to cancer-related death with poor survival for sufferers. Meanwhile, Hepatic B virus X protein (HBx) and XB130 are likely to participate in the pathogenesis of liver cancer. However, the detailed mechanism of HBx/XB130 in liver cancer remains to be further investigated. Our study explored the effects of HBx/XB130 on liver cancer progression. HBx and XB130 expression was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Overexpression of HBx and XB130 was found in liver cancer tissues and cells. Mechanistic study revealed that HBx could bind to and positively regulate XB130 in HepG2 cells. Subsequently, HBx expression was knocked down, while XB130 was overexpressed in HepG2 cells in order to observe the specific role of HBx/XB130 in liver cancer in vitro. Results of CCK-8, Transwell, wound healing, and colony formation assays suggested that HBx could mediate biological function of HepG2 cells by activating the XB130-mediated PI3K/AKT pathway. In summary, our data illustrate that inhibition of HBx effectively suppressed proliferation and metastasis and induced apoptosis of liver cancer cells, which might be partially reversed by XB130. HBx and XB130 may be potential targets for liver cancer pathogenesis.

Bioinformatics screening of biomarkers related to liver cancer

BackgroundLiver cancer is a common malignant tumor in China, with high mortality. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, mRNA quantification and the clinical data of liver cancer. However, the hub genes, which can be served as biomarkers for diagnosis and treatment of early liver cancer, are not well screened.ResultsHere we present a new method for getting 6 key genes, aiming to diagnose and treat the early liver cancer. We firstly analyzed the different expression microarrays based on TCGA database, and a total of 1564 differentially expressed genes were obtained, of which 1400 were up-regulated and 164 were down-regulated. Furthermore, these differentially expressed genes were studied by using GO and KEGG enrichment analysis, a PPI network was constructed based on the STRING database, and 15 hub genes were obtained. Finally, 15 hub genes were verified by applying the survival analysis method on Oncomine database, and 6 key genes were ultimately identified, including PLK1, CDC20, CCNB2, BUB1, MAD2L1 and CCNA2. The robustness analysis of four independent data sets verifies the accuracy of the key gene’s classification of the data set.ConclusionsAlthough there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new method to identify the 6 key genes for diagnosis and treatment of early liver cancer, and these key genes can help us understand the pathogenesis of liver cancer more deeply.

Hsa_circ_0008537 facilitates liver carcinogenesis by upregulating MCL1 and Snail1 expression via miR‑153‑3p.

The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ_0008537 (circ_0008537) in liver cancer pathogenesis remain undetermined. In the present study, circ_0008537 expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ_0008537 exhibited a poor prognosis. In addition, circ_0008537 overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ_0008537 knockdown exhibited opposite effects. circ_0008537 acted as a sponge of microRNA-153-3p (miR-153-3p), and a negative correlation was observed between circ_0008537 and miR-153-3p expression in liver cancer. Transfection with miR-153-3p further abolished the effects of circ_0008537 on the malignant behavior of liver cancer cells. Furthermore, circ_0008537 indirectly affected the expression levels of pro-survival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR-153-3p in liver cancer cells. In conclusion, the data indicated that circ_0008537 facilitated liver carcinogenesis by indirectly regulating miR-153-3p and leading to the release of MCL1 and Snail1.

In Vivo Imaging of the Macrophage Migration Inhibitory Factor in Liver Cancer with an Activity-Based Probe.

The macrophage migration inhibitory factor (MIF), a vital cytokine and biomarker, has been suggested to closely associate with the pathogenesis of liver cancer. However, a simple and effective approach for monitoring the change and distribution of cellular MIF is currently lacking and urgently needed, which could be helpful for a better understanding of its role in the progression of cancer. Herein, we report a novel activity-based probe, TPP2, which allows for direct labeling and imaging of endogenous MIF activity within live cells, clinical tissues, and in vivo in a mouse model of liver cancer. With this probe, we have intuitively observed the dynamic change of intracellular MIF activity by both flow cytometry and confocal imaging. We further found that TPP2 permits the identification and distinguishing of liver cancer in vitro and in vivo with high sensitivity and selectivity toward MIF. Our observations indicate that TPP2 could provide a promising new imaging approach for elucidating the MIF-related biological functions in liver cancer.

Improving the efficacy of traditional Chinese medicine in treatment of primary liver cancer based on etiology and pathogenesis

At present, the of primary liver cancer is mainly based on modern medicine. Studies have found that traditional Chinese medicine (TCM) can promote the apoptosis of hepatoma cells and regulate the immunity of human body by affecting multiple critical pathways involved in the development and progression of tumor. TCM plays an irreplaceable role in the of liver cancer, and the focus on the etiology and pathogenesis of liver cancer is the key to achieving good efficacy. Although there are still no ideal anti-HBV drugs in TCM, intervention on the etiologies of dampness, heat, phlegm, toxin, stasis, and deficiency and the change in struggle between vital Qi and pathogen during each stage of disease progression may delay or even prevent disease progression, which is the based on etiology and pathogenesis and is the theory that treatment should focus on the principal cause of a disease. In clinical practice, modern medical combined with TCM can improve patients' quality of life and reduce tumor recurrence, and TCM combined with sorafenib has stronger efficacy and fewer side effects. Meanwhile, further studies are needed to explore how integrated traditional Chinese and Western medicine therapy exerts a therapeutic effect on liver cancer and the detailed mechanism of action of TCM in the of liver cancer.

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer.

The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.

PIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro‐tumorigenic effect of PIDDosome‐mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence‐free survival in HCC patients.

Integrated in silico‐in vitro analysis of systematic kinase gatekeeper mutation effects on pan‐kinase inhibitors in targeted liver cancer therapy

AbstractKinase‐targeted therapy has been established as a widely used strategy to treat liver cancer. However, a number of kinase gatekeeper mutations are clinically observed to cause acquired drug resistance during the therapy, which can be overcome by pan‐kinase inhibitors. Here, we create a systematic profile of pan‐kinase inhibitors against clinical kinase gatekeeper mutations in liver cancer pathogenesis by integrating computational modeling and experimental assay. With the profile we are able to identify those gatekeeper mutations that can potentially cause resistance or confer sensitivity to certain pan‐kinase inhibitors. The nine inhibitors are clustered into three groups in terms of their response profile across the investigated mutations. The group‐I and group‐II inhibitors are generally sensitized and caused with resistance by most mutations, respectively, while the group‐III inhibitors exhibit divergent response to different mutations. Structural and energetic analyses reveal that the sensitizing mutations can form additional favorable chemical forces with inhibitor ligands, while the resistant mutations would address unfavorable steric effect and conformational change on inhibitor binding. The marine natural product Hymenialdisine is found to have a general sensitivity for kinase gatekeeper mutations, which could be explored as a novel molecular lead scaffold to develop the wild type‐sparing inhibitors of kinase gatekeeper mutants.

Synergistic anti-liver cancer effects of curcumin and total ginsenosides.

BACKGROUNDLiver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality. The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment. New therapeutic agents for liver cancer, which can control inflammation and restore cellular immunity, are required. Curcumin (Cur) is a natural anti-inflammatory drug, and total ginsenosides (TG) are a commonly used immunoregulatory drug. Of note, both Cur and TG have been shown to exert anti-liver cancer effects.AIMTo determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer.METHODSA subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line. Animals were treated with Cur (200 mg/kg per day), TG (104 mg/kg per day or 520 mg/kg per day), the combination of Cur (200 mg/kg per day) and TG (104 mg/kg per day or 520 mg/kg per day), or 5-fluorouracil combined with cisplatin as a positive control for 21 d. Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1 (PD-L1), inflammatory indicators Toll like receptor 4 (TLR4) and nuclear factor-κB (NF-κB), and vascular growth-related factors nitric oxide synthases (iNOS) and matrix metalloproteinase 9 were analyzed by Western blot analysis. CD4+CD25+Foxp3+ regulatory T cells (Tregs) were counted by flow cytometry.RESULTSThe combination therapy of Cur and TG significantly inhibited the growth of liver cancer, as compared to vehicle-treated animals, and TG showed dose dependence. Cur combined with TG-520 markedly decreased the protein expression of PD-L1 (P < 0.0001), while CD4+CD25+Foxp3+ Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1. Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB (P < 0.0001), thus inhibiting the TLR4/NF-κB signalling pathway (P = 0.0088, P < 0.0001), which is associated with inflammation and acts on PD-L1. It also inhibited the NF-κB-MMP9 signalling pathway (P < 0.0001), which is associated with tumor angiogenesis.CONCLUSIONCur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.

Long Noncoding RNAs: Potential Mediators of Liver Cancer Metastasis.

Liver cancer (LC) is the most common high-mortality malignancy, due to its aggressive nature, heterogeneity, and metastasis. Recent studies have recognized long noncoding RNAs (lncRNAs) as mediators of LC pathogenesis and metastasis. This review describes the role of lncRNAs in molecular mechanisms of tumorigenicity, metastasis, stem-cell maintenance, drug resistance, and tumor immunity. We present recent updates on therapeutic targeting of lncRNAs in LC as well as lncRNA's potential for LC diagnosis. Overall, we provide a new perspective on the role of lncRNAs for LC treatment and diagnosis.