The Role of Endoglin in Hepatocellular Carcinoma
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ABSTRACT:
SUBMITTER: Jeng K
PROVIDER: S-EPMC8004096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEndoglin (CD105) has been considered a prognostic marker for hepatocellular carcinoma (HCC), and widely used as an appropriate targeting for antiangenesis therapy in some cancers. Our aim was to evaluate the distribution and expression of CD105 in the liver of patients with HCC, and to discuss whether CD105 may be used as an appropriate targeting for antiangenesis therapy in HCC.MethodsThree parts of liver tissues from each of 64 patients with HCC were collected: tumor tissues (TT), adjacent non-tumor (AT) liver tissues within 2 cm, and tumor free tissues (TF) 5 cm far from the tumor edge. Liver samples from 8 patients without liver diseases served as healthy controls (HC). The distribution and expression of CD105 in tissues were evaluated by immunohistochemistry, Western blotting analysis, and real-time PCR. HIF-1alpha and VEGF165 protein levels in tissues were analyzed by Immunohistochemistry and Western blotting analysis or ELISA.ResultsCD105 was positively stained mostly in a subset of microvessels 'endothelial sprouts' in TT of all patients while CD105 showed diffuse positive staining, predominantly on hepatic sinus endothelial cells in the surrounding of draining veins in TF and AT. The mean score of MVD-CD105 (mean +/- SD/0.74 mm2) was 19.00 +/- 9.08 in HC, 153.12 +/- 53.26 in TF, 191.12 +/- 59.17 in AT, and 85.43 +/- 44.71 in TT, respectively. Using a paired t test, the expression of CD105 in AT and TF was higher than in TT at protein (MVD, p = 0.012 and p = 0.007, respectively) and mRNA levels (p < 0.001 and p = 0.009, respectively). Moreover, distribution and expression of CD105 protein were consistent with those of HIF-1alpha and VEGF165 protein in liver of patients with HCC. The level of CD105 mRNA correlated with VEGF165 level in TF (r = 0.790, p = 0.002), AT (r = 0.723, p < 0.001), and TT (r = 0.473, p = 0.048), respectively.ConclusionIt is demonstrated that CD105 was not only present in neovessels in tumor tissues, but also more abundant in hepatic sinus endothelium in non-tumor tissues with cirrhosis. Therefore, CD105 may not be an appropriate targeting for antiangenesis therapy in HCC, especially with cirrhosis.
| S-EPMC1941740 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.
2019-03-29 | PXD013095 | Pride
Project description:Hepatocellular carcinoma (HCC) remains a major health issue because of its increasing incidence and because of the complexity of its management. In addition to the traditional potentially curative treatments, i.e., liver transplantation and surgical resection, other new and emerging local therapies have been applied with promising results.Radiotherapy (RT) and interstitial treatments, such as radiofrequency ablation (RFA), microwave ablation (MWA), and irreversible electroporation (IRE), have recently opened new and interesting treatment scenarios for HCC and are associated with promising results in selected patients. Herein, we describe the emerging role of interventional oncology for the treatment of HCC and focus on the different Western and Eastern approaches.Modern RT and modern interstitial therapies, such as RFA, MWA, and IRE, should be considered for inclusion in HCC therapy guidelines.
| S-EPMC5159721 | biostudies-other
Project description:Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. MicroRNAs (miRs), small non-coding single-stranded RNAs of 19-24 nucleotides in length, negatively regulate the expression of many target genes at the post-transcriptional and/or translational levels and play a critical role in the initiation and progression of HCC. In this review we have summarized the information of aberrantly expressed miRs in HCC, their mechanism of action and relationship to cancer. The recent advances in HCC research reveal that miRs regulate expression of various oncogenes and tumor suppressor genes, thereby contributing to the modulation of diverse biological processes including proliferation, apoptosis, epithelial to mesenchymal transition and metastasis. From a clinical viewpoint, polymorphisms within miR-binding sites are associated with the risk of HCC. Polymorphisms in miR related genes have been shown to correlate with survival or treatment outcome in patients. Furthermore, the review focuses on the potential role of miRs as novel biomarkers and their translational applications for diagnosis and therapy in HCC. With further insights into miR deregulation in HCC, it is expected that novel miR-based therapeutics will arise. Also, we orient the readers to other reviews that may provide better understanding of miR research in HCC.
| S-EPMC3761096 | biostudies-literature
Project description:Increasing noncoding RNAs (ncRNAs) were found to show abnormal expression patterns in various human cancers. Based on their length, ncRNAs are briefly divided into two categories. Transcripts that are shorter than 200 nucleotides are recognized as short/small noncoding RNAs and greater than 200 nucleotides as long noncoding RNAs (lncRNAs). Short/small noncoding RNAs include microRNAs, piRNAs, snoRNAs, and endogenous siRNAs. Numerous studies have revealed that these short/small ncRNA play important roles in multiple biological processes and tumorigenesis. In contrast to small ncRNAs, long noncoding RNAs are much less known concerning their functions in human cancers especially in hepatocellular carcinoma (HCC). In this review, we highlight recent progress regarding HCC development, tumorigenesis, metastasis, clinical implication, as well as the role in the risk of HBV infection.
| S-EPMC4115723 | biostudies-other
Project description:To investigate the specific roles of SIRT1 in the development of hepatocellular carcinoma, we employed large-scale gene expression analysis to identify the molecular signature that may affect enabling characteristics of cancer cells. Differentially expressed genes were analyzed on the SNU-182 cells transfected with SIRT1 siRNA and recapitulated molecular signatures that related to hallmarks of cancer. SIRT1 expression in hepatocellular carcinoma was analyzed by RT-PCR and western blot. RNA interference-mediated protein knockdown method was used to investigate oncogenic potential of SIRT1 in hepatocelluar carcinoma
2012-03-01 | E-GEOD-32066 | biostudies-arrayexpress
Project description:Endoglin (ENG) is a coreceptor of the transforming growth factor-? (TGF?) family signaling complex, which is highly expressed on endothelial cells and plays a key role in angiogenesis. Its extracellular domain can be cleaved and released into the circulation as soluble ENG (sENG). High circulating levels of sENG contribute to the pathogenesis of preeclampsia (PE). Circulating bone morphogenetic protein 9 (BMP9), a vascular quiescence and endothelial-protective factor, binds sENG with high affinity, but how sENG participates in BMP9 signaling complexes is not fully resolved. sENG was thought to be a ligand trap for BMP9, preventing type II receptor binding and BMP9 signaling. Here we show that, despite cell-surface ENG being a dimer linked by disulfide bonds, sENG purified from human placenta and plasma from PE patients is primarily in a monomeric form. Incubating monomeric sENG with the circulating form of BMP9 (prodomain-bound form) in solution leads to the release of the prodomain and formation of a sENG:BMP9 complex. Furthermore, we demonstrate that binding of sENG to BMP9 does not inhibit BMP9 signaling. Indeed, the sENG:BMP9 complex signals with comparable potency and specificity to BMP9 on human primary endothelial cells. The full signaling activity of the sENG:BMP9 complex required transmembrane ENG. This study confirms that rather than being an inhibitory ligand trap, increased circulating sENG might preferentially direct BMP9 signaling via cell-surface ENG at the endothelium. This is important for understanding the role of sENG in the pathobiology of PE and other cardiovascular diseases.
| S-EPMC6731690 | biostudies-literature
Project description:To investigate the specific roles of SIRT1 in the development of hepatocellular carcinoma, we employed large-scale gene expression analysis to identify the molecular signature that may affect enabling characteristics of cancer cells. Differentially expressed genes were analyzed on the SNU-182 cells transfected with SIRT1 siRNA and recapitulated molecular signatures that related to hallmarks of cancer.
2012-03-01 | GSE32066 | GEO
Project description:The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway.The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model.Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade.MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.
| S-EPMC2678688 | biostudies-literature
Project description:PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, ?-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in ?-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.
| S-EPMC5143759 | biostudies-literature