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.

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 LncRNA-SNHG6 promotes the progression of hepatocellular carcinoma by targeting miR-6509-5p and HIF1A

2020 ◽  
Author(s):  
Xiaoxi Fan ◽  
Zhongwei Zhao ◽  
Jingjing Song ◽  
Dengke Zhang ◽  
Fazong Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Bioinformatics Analysis ◽  
Carcinoma Cell ◽  
Noncoding Rnas ◽  
Migration And Invasion ◽  
Carcinoma Cell Lines ◽  
Huh7 Cells

Abstract Background: Accumulating evidences has been reported that long noncoding RNAs play crucial roles in the progression of hepatocellular carcinoma (HCC). SnoRNA host gene 6 (SNHG6) is believed to be involved in several human cancers, but the specific molecular mechanism of SNHG6 in HCC is not well studied. Methods: In this study, we experimentally down-regulated the SNHG6 in two hepatocellular carcinoma cell lines, and measured the proliferation, migration and invasion abilities and the apoptotic levels in vitro. Also, we performed the xenograft assay to investigate the function of SNHG6 during the tumor growth. Results: We found SNHG6 was highly expressed in HCC tissues. Next, using Hep3B and Huh7 cells, we confirmed knockdown of SNHG6 could reduce the proliferation, migration and invasion abilities in vitro. Also, by bioinformatics analysis, further molecular and cellular experiments, we found miR-6509-5p bound to SNHG6 directly, and the expression level of HIF1A was regulated through SNHG6/miR-6509-5p axis. Finally, we found that down-regulation of SNHG6 could dramatically reduce the tumor growth ability of Huh7 cells in vivo . Conclusions: We concluded that SNHG6/miR-6509-5p/ HIF1A axis functioned in the progression of hepatocellular carcinoma, and could be the promising therapeutic targets in hepatocellular carcinoma.

Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach

2019 ◽  
Vol 19 (5) ◽  
pp. 342-354 ◽  
Author(s):  
Zeinab Salah ◽  
Eman M. Abd El Azeem ◽  
Hanan F. Youssef ◽  
Amira M. Gamal-Eldeen ◽  
Abdel R. Farrag ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Hepg2 Cells ◽  
Cloning And Expression ◽  
Great Promise ◽  
Control Group ◽  
Qrt Pcr ◽  
Nano Formulation

Background: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. Objective: We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. Methods: In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. Results: ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. Conclusion: Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.

scholarly journals HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 119
Author(s):  
Vasiliki Papatheofani ◽  
Georgia Levidou ◽  
Panagiotis Sarantis ◽  
Evangelos Koustas ◽  
Michalis V. Karamouzis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Tumors ◽  
Normal Liver ◽  
Primary Liver Tumors ◽  
The Stability ◽  
Hu Antigen R ◽  
Post Transcriptional Regulation

Hu-antigen R (HuR) is a post-transcriptional regulator that belongs to the embryonic lethal abnormal vision Drosophila-like family (ELAV). HuR regulates the stability, translation, subcellular localization, and degradation of several target mRNAs, which are implicated in carcinogenesis and could affect therapeutic options. HuR protein is consistently highly expressed in hepatocellular carcinoma (HCC) compared to the adjacent normal liver tissue and is involved in the post-transcriptional regulation of various genes implicated in liver malignant transformation. Additionally, HuR protein seems to be a putative prognosticator in HCC, predicting worse survival. This review summarizes the recent evidence regarding the role of HuR in primary liver tumors, as presented in clinical studies, in vitro experiments and in vivo animal models. In conclusion, our review supports the consistent role of HuR protein in the development, prognosis, and treatment of HCC. Additional studies are expected to expand current information and exploit its putative employment as a future candidate for more personalized treatment in these tumors.

scholarly journals Huxie Huaji Ointment Induced Apoptosis of Liver Cancer Cells In Vivo and In Vitro by Activating the Mitochondrial Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yuan Cai ◽  
Qing Du ◽  
Tian-Hao Deng ◽  
Bing-Bing Shen ◽  
Yan-Mei Peng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Hepg2 Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Cell Counting ◽  
Cyt C

Huxie Huaji (HXHJ) Ointment is a famous traditional Chinese medicinal prescription and is commonly used for the clinical treatment of hepatocellular carcinoma by boosting immunity and detoxification. However, the scientific evidence for the effect of HXHJ Ointment on hepatocellular carcinoma and the underlying molecular mechanism are lacking. The present study aimed to identify the effects of HXHJ Ointment on hepatocellular carcinoma in vitro and in vivo as well as investigating the mechanistic basis for the anticancer effect of HXHJ ointment. First, liquid chromatography-mass spectrometry was used to verify the composition of HXHJ Ointment and quality control. Second, in vitro, Cell Counting Kit (CCK8) cell viability assay and Hoechst 33342 staining assay were performed to explain the cell apoptosis. The protein levels of tumor suppressor protein (p53), B-cell lymphoma 2 gene (Bcl-2), cytochrome C (Cyt-C), and aspartate proteolytic enzyme-3 (caspase-3) were examined by immunofluorescence. Finally, in vivo, hematoxylin and eosin (H&E) staining was used to observe the pathological changes in hepatocellular carcinoma samples. Western blots and immunohistochemistry were used to detect the anticancer properties of HXHJ ointment. The results in vitro showed that 20% HXHJ Ointment serum could significantly inhibit HepG2 cell proliferation, increased tumor suppressor gene p53, downregulated antiapoptotic protein Bcl-2, promoted the release of mitochondrial Cyt-C, activated caspase-3, and induced HepG2 cell apoptosis. Furthermore, in vivo experiments showed that HXHJ Ointment could effectively inhibit tumor growth in nude mice xenotransplanted with HepG2 cells, changed the morphology of tumor cells, and regulated the expression of apoptosis-related protein pathway p53/Bcl-2/Cyt-C/caspase-3. HXHJ Ointment can significantly inhibit the development of hepatocellular carcinoma, and its mechanism may be related to the regulation of p53/Bcl-2/Cyt-C/caspase-3 signaling pathway to induce cell mitochondrial apoptosis.

scholarly journals BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wen-Jing Yang ◽  
Yun-Fan Sun ◽  
An-Li Jin ◽  
Li-Hua Lv ◽  
Jie Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
P53 Mutation ◽  
Dependent Manner ◽  
Differentiation Potential ◽  
Self Renewal

Abstract Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.

scholarly journals LncRNA-SNHG6 promotes the progression of hepatocellular carcinoma by targeting miR-6509-5p and FKBP1A

2020 ◽  
Author(s):  
Zhongwei Zhao ◽  
Jingjing Song ◽  
Dengke Zhang ◽  
Fazong Wu ◽  
Jianfei Tu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Molecular Mechanism ◽  
Bioinformatics Analysis ◽  
Noncoding Rnas ◽  
Migration And Invasion ◽  
Huh7 Cells ◽  
Growth Ability

Abstract Accumulating evidences has been reported that long noncoding RNAs play crucial roles in the progression of hepatocellular carcinoma (HCC). snoRNA host gene 6 (SNHG6) is believed to be involved in several human cancers, but the specific molecular mechanism of SNHG6 in HCC is not well studied. Here, we found SNHG6 was highly expressed in HCC tissues. Next, using Hep3B and Huh7 cells, we confirmed knockdown of SNHG6 could reduce the proliferation, migration and invasion abilities in vitro. Also, by bioinformatics analysis, further molecular and cellular experiments, we found miR-6509-5p bound to SNHG6 directly, and the expression level of FKBP1A was regulated through SNHG6/ miR-6509-5p axis. Finally, we found that down-regulation of SNHG6 could dramatically reduce the tumor growth ability of Huh7 cells in vivo. Taking together, we concluded that SNHG6/miR-6509-5p/FKBP1A axis functioned in the progression of hepatocellular carcinoma, and could be the promising therapeutic targets in hepatocellular carcinoma.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

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