scholarly journals Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongbo Wang ◽  
Zaiming Lu ◽  
Xiangxuan Zhao
Keyword(s):  
Liver Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Liver Cancer ◽  
Signal Transmission ◽  
Clinical Applications ◽  
Research Progress ◽  
Treatment Regimens ◽  
Average Survival ◽  
Average Survival Rate

AbstractHepatocellular carcinoma (HCC, also called primary liver cancer) is one of the most fatal cancers in the world. Due to the insidiousness of the onset of HCC and the lack of effective treatment methods, the prognosis of HCC is extremely poor, and the 5-year average survival rate is less than 10%. Exosomes are nano-sized microvesicle and contain various components such as nucleic acids, proteins, and lipids. Exosomes are important carriers for signal transmission or transportation of material from cell to cell or between cells and tissues. In recent years, exosomes have been considered as potential therapeutic targets of HCC. A large number of reports indicate that exosomes play a key role in the establishment of an HCC microenvironment, as well as the development, progression, invasion, metastasis, and even the diagnosis, treatment, and prognosis of HCC. However, the exact molecular mechanisms and roles of exosomes in these processes remain unclear. We believe that elucidation of the regulatory mechanism of HCC-related exosomes and its signaling pathway and analysis of its clinical applications in the diagnosis and treatment of HCC can provide useful clues for future treatment regimens for HCC. This article discusses and summarizes the research progress of HCC-related exosomes and their potential clinical applications.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

scholarly journals Contextual Regulation of TGF-β Signaling in Liver Cancer

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1235 ◽  
Author(s):  
Tu ◽  
Huang ◽  
Huang ◽  
Luo ◽  
Yan
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Primary Liver Cancer ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Cancer Cell Survival

Primary liver cancer is one of the leading causes for cancer-related death worldwide. Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that signals through membrane receptors and intracellular Smad proteins, which enter the nucleus upon receptor activation and act as transcription factors. TGF-β inhibits liver tumorigenesis in the early stage by inducing cytostasis and apoptosis, but promotes malignant progression in more advanced stages by enhancing cancer cell survival, EMT, migration, invasion and finally metastasis. Understanding the molecular mechanisms underpinning the multi-faceted roles of TGF-β in liver cancer has become a persistent pursuit during the last two decades. Contextual regulation fine-tunes the robustness, duration and plasticity of TGF-β signaling, yielding versatile albeit specific responses. This involves multiple feedback and feed-forward regulatory loops and also the interplay between Smad signaling and non-Smad pathways. This review summarizes the known regulatory mechanisms of TGF-β signaling in liver cancer, and how they channel, skew and even switch the actions of TGF-β during cancer progression.

scholarly journals Exosomal MiR-1290 Promotes Angiogenesis of Hepatocellular Carcinoma via Targeting SMEK1

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Liver Cancer ◽  
Blood Vessel ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Primary Liver Cancer ◽  
Human Endothelial Cells ◽  
Direct Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

Chronic viral hepatitis and its association with liver cancer

2017 ◽  
Vol 398 (8) ◽  
pp. 817-837 ◽  
Author(s):  
Thomas Tu ◽  
Sandra Bühler ◽  
Ralf Bartenschlager
Keyword(s):  
Liver Cancer ◽  
Molecular Mechanisms ◽  
Hepatitis Virus ◽  
Primary Liver Cancer ◽  
Causative Factor ◽  
Metabolic Reprogramming ◽  
Model Systems ◽  
Cellular Stress Response ◽  
Viral Gene ◽  
Hepatitis Viruses

AbstractChronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.

scholarly journals Anticancer Activities and Underlying Molecular Mechanisms of Novel Mangostin Glycosides in Human Hepatocellular Carcinoma Hep3B Cells

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 5
Author(s):  
Kim ◽  
Han ◽  
Jung
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Primary Liver Cancer ◽  
Critical Role ◽  
Single Agent ◽  
Anticancer Activities ◽  
Parent Molecule ◽  
Hep3b Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In this study, for the first time, we evaluated the anticancer activities of mangostin-3-O-β-d-2-deoxyglucopyranoside (Man-3DG) and mangostin 6-O-β-d-2-deoxyglucopyranoside (Man-6DG), glycosides of mangostin, against human hepatoma Hep3B cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed growth and migration of Hep3B cells. In addition, they induced apoptosis of Hep3B cells by regulating apoptosis-related proteins of mitochondria. Noticeably, Man-3DG and Man-6DG also caused autophage, while cotreatment of the mangostin glycosides with an autophage inhibitor 3MA enhanced the inhibitory effect on Hep3B cell growth, compared to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway, which plays a critical role in the pathogenesis of liver cancer. Furthermore, the mangostin glycosides decreased tumor cell-induced angiogenesis in vitro through downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). These findings suggest that Man-3DG and Man-6DG might be promising anticancer agents for HCC treatment with superior pharmacological properties than parent molecule mangostin.

Treatment of Neurodegenerative Diseases with Bioactive Components ofTripterygium wilfordii

2019 ◽  
Vol 47 (04) ◽  
pp. 769-785 ◽  
Author(s):  
Jianheng Li ◽  
Jijun Hao
Keyword(s):  
Neurodegenerative Diseases ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Research Progress ◽  
Bioactive Components ◽  
Tripterygium Wilfordii Hook F ◽  
Autoimmune And Inflammatory Diseases ◽  
Tripterygium Wilfordii Hook

Tripterygium wilfordii Hook F. (TWHF), a traditional Chinese medicine, has been widely used to treat autoimmune and inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis in China. Recently, studies have demonstrated that the bioactive components of TWHF have effective therapeutic potential for neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis. In this paper, we summarize the research progress of triptolide and celastrol (the two major TWHF components) as well as their analogues in the treatment of neurodegenerative diseases. In addition, we review and discuss the molecular mechanisms and structure features of those two bioactive TWHF components, highlighting their therapeutic promise in neurodegenerative diseases.

scholarly journals Investigation of the Therapeutic Potential of Momelotinib on Hepatitis Virus-Associated Liver Cancer Is Through Suppressing Oncogenic/Stemnes IFNGR-JAK-STAT Pathway

2020 ◽  
Author(s):  
Jiann Ruey Ong ◽  
Chi-Tai Yeh ◽  
Ting-Yi Huang ◽  
Ming-Shou Hsieh ◽  
Wei-Hwa Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Liver Cancer ◽  
Therapeutic Potential ◽  
Hepatitis Virus ◽  
Signal Transmission ◽  
Tumor Burden ◽  
Poor Overall Survival ◽  
Invasive Property

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, accounting for more than 700,000 deaths annually. In this study, we hypothesized that momelotinib could regulate the progression of HCC by targeting Jak family related protein. The proteins of IFN gamma-related pathways are obviously activated after hepatitis virus infection. This result suggests the difference in signal transmission between viral liver cancer and general liver cancer. Based on this observation, we are linked to the relevant targets of the JAK family and the potential applications of targeted therapy inhibitors.Methods: We analyzed possible synergism between Momelotinib and Sorafenib in hepatitis virus-associated liver cancer. Immunostaining, colony formation Assay, cell invasion, migration, and tumorsphere-formation assay was used drug cytotoxicity, cell viability and possible molecular mechanism. Result: We found that Jak2 downstream gene STAT1 expression was correlated with poor prognosis and poor overall survival of patients with HCC. Treatment of momelotinib significantly inhibits Jak2, resultant in the reduction of the migratory, invasive property of vHCC cells. Interestingly, cell cycle arrest and inhibition of the stem cell-like phenotype of vHCC cells were also observed after the momelotinib treatment. Furthermore, the combined effect of momelotinib and sorafenib both at in-vitro and in-vivo synergistically suppresses the proliferation of vHCC cells and effectively reduces the tumor burden.Conclusion: Our results showed that momelotinib effectively suppressed the expression of Jak2, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes in vHCC cells, thus maximizing its therapeutic potential for patients with HCC.

scholarly journals HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1876 ◽  
Author(s):  
Yuan-Hsi Wang ◽  
Chao-Lien Liu ◽  
Wan-Chun Chiu ◽  
Yuh-Ching Twu ◽  
Yi-Jen Liao
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Liver Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Survival Rates ◽  
Normal Liver ◽  
Apoptosis Pathway ◽  
Tissue Arrays

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer.

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