scholarly journals Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Argyrios Periferakis ◽  
Georgios Tsigas ◽  
Aristodemos-Theodoros Periferakis ◽  
Ioana Anca Badarau ◽  
Andreea-Elena Scheau ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Primary Liver Cancer ◽  
Somatostatin Receptors ◽  
Metastatic Potential ◽  
Cancer Staging ◽  
Complete Evaluation ◽  
Specific Effects

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.

scholarly journals Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Haoting Sun ◽  
Chaoqun Wang ◽  
Beiyuan Hu ◽  
Xiaomei Gao ◽  
Tiantian Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Tumor Metastasis ◽  
Metastatic Potential ◽  
Functional Roles ◽  
Stat3 Phosphorylation ◽  
Hcc Cells

AbstractIntercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

scholarly journals The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1261 ◽  
Author(s):  
Lysann Tietze ◽  
Sonja M. Kessler
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Therapy ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Human Patient ◽  
In Vivo Models ◽  
Study Results ◽  
Novel Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The use of long noncoding (lnc) RNAs can widen the list of novel molecular targets improving cancer therapy. In hepatocarcinogenesis, the role of the lncRNA H19, which has been known for more than 30 years now, is still controversially discussed. H19 was described to work either as a tumor suppressor in vitro and in vivo, or to have oncogenic features. This review attempts to survey the conflicting study results and tries to elucidate the potential reasons for the contrary findings, i.e., different methods, models, or readout parameters. This review encompasses in vitro and in vivo models as well as studies on human patient samples. Although the function of H19 in HCC remains elusive, a short outlook summarizes some ideas of using the H19 locus as a novel target for liver cancer therapy.

The Promise of miRNA Replacement Therapy for Hepatocellular Carcinoma

2019 ◽  
Vol 19 (5) ◽  
pp. 290-304 ◽  
Author(s):  
Mahmoud Elhefnawi ◽  
Zeinab Salah ◽  
Bangly Soliman
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Mortality Rate ◽  
Tumor Suppressor ◽  
Noncoding Rnas ◽  
Efficient Delivery ◽  
Post Transcriptional Regulation ◽  
Tumor Suppressor Mirnas

Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate 94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of noncoding RNAs, which exhibit decreased or inhibited expression in the case of carcinogenesis. Therefore, the replacement of these molecules leads to post-transcriptional regulation of tens to hundreds of oncogenic targets and limiting the tumor. Interestingly, there is a group of tumor silencer miRNAs that have been highlighted in HCC and herein, our review will discuss the prominent examples of these miRs in terms of their efficient delivery using vectors, nano-delivery systems, their successful models either in vitro or in vivo and pre-clinical trials. Collectively, tumor suppressor miRNAs can act as novel therapeutics for HCC and more studies should be directed towards these promising therapeutics.

Glycyrrhizic Acid Modulates Apoptosis through Extrinsic/Intrinsic Pathways and Inhibits Protein Kinase B- and Extracellular Signal-Regulated Kinase-Mediated Metastatic Potential in Hepatocellular Carcinoma In Vitro and In Vivo

2020 ◽  
Vol 48 (01) ◽  
pp. 223-244
Author(s):  
Jai-Jen Tsai ◽  
Po-Jung Pan ◽  
Fei-Ting Hsu ◽  
Jing-Gung Chung ◽  
I-Tsang Chiang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Invasion ◽  
Glycyrrhizic Acid ◽  
Metastatic Potential ◽  
Signaling Transduction ◽  
Apoptotic Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

A previous study presented that glycyrrhizic acid as the hepatoprotective agent inhibits total parenteral nutrition-associated acute liver injury in rats. However, the anticancer effect and mechanism of glycyrrhizic acid in human hepatocellular carcinoma (HCC) is ambiguous. The purpose of the present study was to investigate the effect of glycyrrhizic acid on apoptosis dysregulation and metastatic potential in HCC in vitro and in vivo. Both SK-Hep1 and Hep3B cells were treated with different concentrations of glycyrrhizic acid for 24 or 48[Formula: see text]h. SK-Hep1/luc2 tumor-bearing mice were treated with vehicle or glycyrrhizic acid (50[Formula: see text]mg/kg/day by intraperitoneal injection) for 7 days. Tumor cells growth, apoptotic, and metastatic signaling transduction were evaluated by using MTT assay, digital caliper, bioluminescence imaging (BLI), flow cytometry, western blotting assay, and immunohistochemistry (IHC) staining. The results demonstrated glycyrrhizic acid significantly inhibits tumor cell growth, cell invasion, and expression of AKT (Ser473), extracellular-signal-regulated kinase (ERK), epidermal growth factor receptor (EGFR) phosphorylation, anti-apoptotic and metastatic proteins in HCC in vitro and in vivo. Glycyrrhizic acid also significantly triggered apoptosis and extrinsic/intrinsic apoptotic signaling transduction. In addition, PD98059 (ERK inhibitor) and LY294002 (AKT inhibitor) obviously reduced cell invasion and expression of metastasis-associated proteins. Taken together, these results indicated that glycyrrhizic acid induces apoptosis through extrinsic/intrinsic apoptotic signaling pathways and diminishes EGFR/AKT/ERK-modulated metastatic potential in HCC in vitro and in vivo.

scholarly journals Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Lu-Yu Yang ◽  
Qin Luo ◽  
Lu Lu ◽  
Wen-Wei Zhu ◽  
Hao-Ting Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Inflammatory Response ◽  
Metastatic Potential ◽  
Underlying Mechanism ◽  
Mice Model ◽  
Extracellular Traps ◽  
Inflammatory Conditions ◽  
Hcc Cells

Abstract Background The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. Methods The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. Results NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. Conclusions NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

scholarly journals Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320716
Author(s):  
Runze Shang ◽  
Xinhua Song ◽  
Pan Wang ◽  
Yi Zhou ◽  
Xinjun Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Efficacy ◽  
Checkpoint Inhibitor ◽  
Primary Liver Cancer ◽  
Combined Treatment ◽  
Tumour Regression ◽  
Liver Tumours ◽  
Multikinase Inhibitor

ObjectiveHepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo.DesignHuman HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody.ResultsCabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested.Conclusionc-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.

scholarly journals Assessment of Current Gene Therapy Practices in Hepatocellular Carcinoma

2020 ◽  
Vol 2 (4) ◽  
pp. 469-480
Author(s):  
Bryan Mckiver ◽  
Mohamad Imad Damaj ◽  
Devanand Sarkar
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Therapy ◽  
Late Stage ◽  
Viral Vectors ◽  
Primary Liver Cancer ◽  
Treatment Options ◽  
Diagnostic Tools ◽  
In Vivo Models

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the fifth most common cancer worldwide. HCC is recognized as the fourth most common cause of cancer related deaths worldwide due to the lack of effective early diagnostic tools, which often leads to individuals going undiagnosed until the cancer has reached late stage development. The current FDA approved treatments for late stage HCC provide a minimal increase in patient survival and lack tumor specificity, resulting in toxic systemic side effects. Gene therapy techniques, such as chimeric antigen receptor (CAR)-T Cells, viral vectors, and nanoparticles, are being explored as novel treatment options in various genetic diseases. Pre-clinical studies using gene therapy to treat in vitro and in vivo models of HCC have demonstrated potential efficacy for use in human patients. This review highlights genetic targets, techniques, and current clinical trials in HCC utilizing gene therapy.

scholarly journals Long non-coding RNA BZRAP1-AS1 silencing suppresses tumor angiogenesis in hepatocellular carcinoma by mediating THBS1 methylation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Weiwei Wang ◽  
Guoyong Chen ◽  
Bing Wang ◽  
Zhenhua Yuan ◽  
Guangbo Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Methyltransferase ◽  
Primary Liver Cancer ◽  
Potential Effect ◽  
Loss Of Function ◽  
Specific Pcr ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Background Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer associated with a high mortality. Long non-coding RNAs (lncRNAs) have recently emerged as regulators in the development and progression of several cancers, and therefore represent an opportunity to uncover new targets for therapy. In the present study, we aimed to investigate the potential effect of lncRNA BZRAP1-AS1 on the angiogenesis of HCC. Methods Microarray-based data analysis was initially employed to screen genes and lncRNAs that are differentially expressed in HCC and the candidate BZRAP1-AS1 was identified as a hit. The expression of BZRAP1-AS1 and thrombospondin-1 (THBS1) in HCC tissues and cells were then determined using RT-qPCR. The gene methylation level was measured by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) assays. Next, the interactions between BZRAP1-AS1, DNA methyltransferase 3B (DNMT3b), and THBS1 were assessed by RIP, RNA pull-down and ChIP assays. Finally, the roles of BZRAP1-AS1, DNMT3b and THBS1 in angiogenesis in vitro as well as tumorigenesis in vivo were evaluated by a battery of the gain- and loss-of function experiments. Results BZRAP1-AS1 was identified as a highly expressed lncRNA in HCC tissues and cells. Down-regulation of BZRAP1-AS1 in HCC cells inhibited HUVEC proliferation, migration and angiogenesis. By interacting with DNMT3b, BZRAP1-AS1 induced methylation of the THBS1 promoter and inhibited the transcription of THBS1, resulting in promoted angiogenesis of HUVECs. Moreover, silencing of BZRAP1-AS1 repressed the angiogenesis as well as the tumor growth of HCC in vivo via up-regulating THBS1. Conclusion This study provides evidence that angiogenesis in HCC is hindered by silencing of BZRAP1-AS1. Thus, BZRAP1-AS1 may be a promising marker for the treatment of HCC.

scholarly journals Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3041
Author(s):  
Sonia Simón Serrano ◽  
Michele Tavecchio ◽  
Alvar Grönberg ◽  
Wondossen Sime ◽  
Mohamed Jemaà ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Primary Liver Cancer ◽  
Xenograft Model ◽  
Therapy Resistance ◽  
The Body ◽  
Cyclophilin Inhibitor

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient’s life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G2/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.

scholarly journals Evaluation of anticancer effects of Juniperus communis extract on hepatocellular carcinoma cells in vitro and in vivo

2021 ◽  
Author(s):  
Nan-Chieh Huang ◽  
Ru-Lai Huang ◽  
Xiao-Fan Huang ◽  
Kai-Fu Chang ◽  
Chien-Ju Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Primary Liver Cancer ◽  
Scientific Evidence ◽  
Autocrine Signaling ◽  
Juniperus Communis ◽  
Anticancer Properties ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for the fourth leading cause of all cancer deaths. Scientific evidence has found that plant extracts seem to be a reliable choice due to their multitarget effects against HCC. Juniperus communis has been used for centuries in traditional medicine and has reported its anticancer properties. As a result, the purpose of the study was to investigate the anticancer effect and mechanism of JCo extract on HCC in vitro and in vivo. In this study, we found that J. communis extract (JCo extract) inhibited the growth of human HCC cells by inducing cell cycle arrest at the G0/G1 phase, extensive apoptosis and suppressing metastatic protein expressions in HCC cells. Moreover, the combinational treatment of JCo and VP-16 was found to enhance the anti-cancer effect, revealing that JCo extract might have the potential to be utilized as an adjuvant to promote HCC treatment. Furthermore, in vivo study, JCo extract significantly suppressed HCC tumor growth and extended the lifespan with no or low systemic and pathological toxicity. JCo extract significantly upregulated the expression of pro-apoptotic proteins and tumor suppressor p53, suppressed VEGF/VEGFR autocrine signaling, downregulated cell cycle regulatory proteins and MMP2/MMP9 proteins. Overall, our results provide a basis for exploiting JCo extract as a potential anticancer agent against hepatocellular carcinoma.

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