Delta-tocotrienol enhances the antitumor effects of interferon alpha through ROS and Erk/MAPK signaling pathways in hepatocellular carcinoma cells

2021 ◽  
Author(s):  
Alvaro Lucci ◽  
Marina C Vera ◽  
Carla G Comanzo ◽  
Florencia Lorenzetti ◽  
Anabela C Ferretti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Interferon Alpha ◽  
Combined Treatment ◽  
Mapk Signaling ◽  
Nuclear Antigen ◽  
Migration And Invasion ◽  
Ros Generation ◽  
Antitumor Effects ◽  
Potential Strategy ◽  
Hcc Cells

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared to single therapies. Combining δ-tocotrienol and IFN α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases MMP-7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and ROS generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anticancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN α therapy showed promising results for HCC cells treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

scholarly journals mascRNA and its parent lncRNA MALAT1 promote proliferation and metastasis of hepatocellular carcinoma cells by activating ERK/MAPK signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shu-Juan Xie ◽  
Li-Ting Diao ◽  
Nan Cai ◽  
Li-Ting Zhang ◽  
Sha Xiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Mammalian Cells ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Erk Mapk ◽  
Lncrna Malat1 ◽  
Hcc Cells

AbstractMALAT1-associated small cytoplasmic RNA (mascRNA) is a cytoplasmic tRNA-like small RNA derived from nucleus-located long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). While MALAT1 was extensively studied and was found to function in multiple cellular processes, including tumorigenesis and tumor progression, the role of mascRNA was largely unknown. Here we show that mascRNA is upregulated in multiple cancer cell lines and hepatocellular carcinoma (HCC) clinical samples. Using HCC cells as model, we found that mascRNA and its parent lncRNA MALAT1 can both promote cell proliferation, migration, and invasion in vitro. Correspondingly, both of them can enhance the tumor growth in mice subcutaneous tumor model and can promote metastasis by tail intravenous injection of HCC cells. Furthermore, we revealed that mascRNA and MALAT1 can both activate ERK/MAPK signaling pathway, which regulates metastasis-related genes and may contribute to the aggressive phenotype of HCC cells. Our results indicate a coordination in function and mechanism of mascRNA and MALAT1 during development and progress of HCC, and provide a paradigm for deciphering tRNA-like structures and their parent transcripts in mammalian cells.

scholarly journals Cryptotanshinone Induces Apoptosis and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma Cells In Vitro

2020 ◽  
Vol 15 (1) ◽  
pp. 1934578X1989957
Author(s):  
Qianyu Zhang ◽  
Liqun Wang ◽  
Cailing Gan ◽  
Yan Yu ◽  
Yali Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Salvia Miltiorrhiza ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Western Blot Assay ◽  
Signal Transducers ◽  
Anticancer Effects ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
Hcc Cells

Cryptotanshinone (CPT), an active quinoid diterpene isolated from Salvia miltiorrhiza Bunge, was previously reported to have potential anticancer effects. However, the mechanisms of CPT on hepatocellular carcinoma (HCC) cells are not well understood. In this study, we investigated the anticancer effects of CPT on HCC cells. Thiazolyl blue tetrazolium bromide assay showed dose-dependent and time-dependent cytotoxicity of CPT on human HCC cells, especially in HCCLM3 and Huh-7 cells. Hoechst 33258 stain, flow cytometry assay, and Western blot assay all indicated that CPT could distinctly induce the apoptosis of human HCC cells and break intracellular homeostasis by triggering the imbalance of mitochondrial transmembrane potential ( Δψm) and reactive oxygen species. In addition, CPT could significantly inhibit HCCLM3 and Huh-7 cells’ migration and invasion via the signal transducers and activators of transcription 3/matrix metalloproteinases mediated signaling pathway. Our findings demonstrated that the antitumor effects of CPT on human HCC cells were by suppressing cell proliferation, inducing cell apoptosis and impairing cell migration and invasion.

scholarly journals Asparagus Polysaccharide Suppresses the Migration, Invasion, and Angiogenesis of Hepatocellular Carcinoma Cells Partly by Targeting the HIF-1α/VEGF Signalling Pathway In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Wei Cheng ◽  
Ziwei Cheng ◽  
Dongwei Xing ◽  
Minguang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptional Activation ◽  
Umbilical Vein ◽  
Signalling Pathway ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Vegf Signalling ◽  
Hcc Cells

Hypoxia-inducible factor-1α (HIF-1α) plays a key role by triggering the transcriptional activation of a number of genes involved in migration, invasion, and angiogenesis in hepatocellular carcinoma (HCC). Thus, suppressing tumour growth by targeting the HIF-1α/VEGF signalling pathway represents a promising strategy for the treatment of HCC. In our previous studies, we found that asparagus polysaccharide (ASP) suppressed the proliferation and promoted the apoptosis of HCC cells both in vivo and in vitro. To further explore the potential mechanisms of the antitumor effects of ASP in HCC, we investigated effects of ASP on the migration, invasion, and angiogenesis of HCC cells (SK-Hep1 and Hep-3B) using an in vitro experimental model. First, we found that ASP effectively suppressed the proliferation of the SK-Hep1 and Hep-3B cells but did not cause significant cytotoxicity in normal liver cells (L-O2). Then, we found that ASP inhibited the migration and invasion of the SK-Hep1 and Hep-3B cells and HCC cells-induced angiogenesis of human umbilical vein endothelial cells in a concentration-dependent manner. Mechanistic studies revealed that the inhibition of migration, invasion, and angiogenesis by ASP in the SK-Hep1 and Hep-3B cells might occur via the downregulation of HIF-1α/VEGF signalling pathway. Finally, our results also showed that the inhibition of HIF-1α by ASP may be mediated through the downregulation of the phosphorylation levels of AKT, mTOR, and ERK. In conclusion, our results suggest that ASP suppresses the migration, invasion, and angiogenesis of HCC cells partly via inhibiting the HIF-1α/VEGF signalling pathway.

scholarly journals NT157 Inhibits Hepatocellular Carcinoma Growth and Sensitizes Cells to Sorafenib

2021 ◽  
Author(s):  
Yu Wang ◽  
Si-Zhe Yu ◽  
Shi-Rong Zhang ◽  
Jia Hou ◽  
Min Jiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Advanced Hepatocellular Carcinoma ◽  
Downstream Signaling ◽  
Potential Strategy ◽  
Induced Apoptosis ◽  
Hcc Cells

Abstract Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.

scholarly journals HIF-1α RNAi Combined with Asparagus Polysaccharide Exerts an Antiangiogenesis Effect on Hepatocellular Carcinoma In Vitro and In Vivo

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Tingting Zhu ◽  
Ziwei Cheng ◽  
Xiaolin Peng ◽  
Dongwei Xing ◽  
Minguang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Primary Liver Cancer ◽  
Combined Treatment ◽  
Mapk Signaling ◽  
Comprehensive Treatment ◽  
Mapk Signaling Pathways ◽  
Hcc Cells

Background. Hepatocellular carcinoma (HCC) is the main form of primary liver cancer and is one of the most prevalent and life-threatening malignancies globally. Hypoxia activates hypoxia-inducible factor-1α (HIF-1α), which is the key factor in promoting angiogenesis in HCC. Currently, there are few studies on the effects of HIF-1α-targeted gene therapy combined with traditional Chinese herbal extracts. Objective. We investigated the effects of HIF-1α RNA interference (RNAi) combined with asparagus polysaccharide (ASP) on HCC in vitro and in vivo. Methods. CCK-8, wound-healing, transwell, and human umbilical vein endothelial cell tube formation assays were performed to evaluate the proliferation, migration, invasion, and angiogenesis of HCC cells in vitro. In addition, western blotting, qPCR, and immunohistochemistry were performed to detect the expression of HIF-1α, vascular endothelial growth factor, AKT, p-AKT, ERK, p-ERK, and CD34 in HCC cells. Results. The combination of HIF-1α RNAi and ASP significantly inhibited the proliferation, migration, invasion, and angiogenesis of SK-Hep1 and Hep-3B cells compared with the use of HIF-1α RNAi or ASP alone. In addition, this combined treatment was shown to exert these effects by regulating the PI3K and MAPK signaling pathways. These results were observed both in vitro and in vivo. Conclusion. Our study indicates that HIF-1α RNAi combined with ASP inhibits angiogenesis in HCC via the PI3K and MAPK signaling pathways. Thus, we suggest that this combination may be an effective method for the comprehensive treatment of HCC, which may provide new ideas for the treatment of other malignant tumors.

scholarly journals The mRNA of TCTP functions as a sponge to maintain homeostasis of TCTP protein levels in hepatocellular carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Wei Liu ◽  
Qi Liu ◽  
Beilei Zhang ◽  
Zhibin Lin ◽  
Xia Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
Combined Treatment ◽  
Migration And Invasion ◽  
Protein Accumulation ◽  
Mrna Levels ◽  
Expression Levels ◽  
Protein Levels ◽  
Hcc Cells ◽  
In Cells

AbstractTranslationally controlled tumor protein (TCTP) is a highly conserved protein that accumulated in the tumorigenesis of various malignancies. Despite the important role of TCTP protein in tumor progression, the precise function and underlying mechanistic regulation of TCTP mRNA in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that TCTP protein was overexpressed in HCC patients but TCTP mRNA expression levels were reversed. TCTP knockout HCC cells exhibited attenuated abilities of proliferation, migration, and invasion. The knockdown of TCTP by siRNA effectively reduced TCTP mRNA levels but not protein levels in HCC cells. Moreover, although the constitutive knockdown of TCTP inhibited almost 80% of TCTP protein expression levels in tumors of wildtype transgenic mice (TCTP KD/WT), partial restoration of TCTP protein expression was observed in the tumors of heterozygous TCTP mice (TCTP KD/TCTP±). The blockage of mRNA synthesis with ActD stimulated TCTP protein expression in HCC cells. In contrast, combined treatment with ActD and CHX or MG132 treatment alone did not lead to the TCTP protein accumulation in cells. Furthermore, following the introduction of exogenous TCTP in cells and orthotopic HCC tumor models, the endogenous TCTP protein did not change with the recombinational TCTP expression and kept a rather stable level. Dual-luciferase assays revealed that the coding sequence of TCTP mRNA functions as a sponge to regulate the TCTP protein expression. Collectively, our results indicated that the TCTP mRNA and protein formed a closed regulatory circuit and works as a buffering system to keep the homeostasis of TCTP protein levels in HCC.

scholarly journals Apoptotic Effects of Xanthium strumarium via PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Juyoung Kim ◽  
Kyung Hee Jung ◽  
Hyung Won Ryu ◽  
Doo-Young Kim ◽  
Sei-Ryang Oh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Caspase 3 ◽  
Mtor Pathway ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Mechanistic Study ◽  
Migration And Invasion ◽  
Xanthium Strumarium ◽  
Apoptotic Effects ◽  
Hcc Cells

Xanthium strumarium (XS) has been traditionally used as a medicinal herb for treating inflammatory diseases, such as appendicitis, chronic bronchitis, rheumatism, and rhinitis. In this study, we yielded ethanol extracts from XS and investigated whether they could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. The XS-5 and XS-6 extracts dose-dependently inhibited the growth and proliferation in HCC cell lines. The apoptotic effects of them were observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling- (TUNEL-) positive apoptotic cells. They also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, they inhibited the invasion and migration of HCC cells. In an ex vivo model, the extracts significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of the cleaved caspase-3. A mechanistic study revealed that they effectively suppressed PI3K/AKT/mTOR signaling pathways in HCC cells. Taken together, our findings demonstrate that they could efficiently not only induce apoptosis but also inhibit cell growth, migration, and invasion of human HCC cells by blocking the PI3K/AKT/mTOR pathway. We suggest XS-5 and XS-6 as novel natural anti-HCC agents.

scholarly journals A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

2021 ◽  
Vol 11 (5) ◽  
pp. 332
Author(s):  
Szu-Jen Wang ◽  
Pei-Ming Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Cancer Genomics ◽  
Gene Signature ◽  
Migration And Invasion ◽  
Advanced Hcc ◽  
Telomerase Inhibitor ◽  
Cell Cycle Related Gene ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug–gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.

scholarly journals Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells

Reports ◽  
2021 ◽  
Vol 4 (2) ◽  
pp. 17
Author(s):  
Vikrant Rai ◽  
Devendra K. Agrawal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Vitamin D ◽  
Chronic Inflammation ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Mediators Of Inflammation ◽  
Tnf Α ◽  
Hcc Cells

Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.

scholarly journals Circular RNA hsa_circ_101555 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-145-5p and regulating CDCA3 expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Xiaoguang Gu ◽  
Jianan Zhang ◽  
Yajuan Ran ◽  
Hena Pan ◽  
JinHong Jia ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Biological Effects ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Casein Kinase 1 ◽  
Mouse Xenograft Model ◽  
Hcc Cells

AbstractCircular RNAs have been reported to play significant roles in regulating pathophysiological processes while also guiding clinical diagnosis and treatment of hepatocellular carcinoma (HCC). However, only a few circRNAs have been identified thus far. Herein, we investigated the role of a specific closed-loop structure of hsa_circ_101555 that was generated by back-splicing of the host gene casein kinase 1 gamma 1 (CSNK1G1) in the development and proliferation of HCC. We investigated the expression of Hsa_circ_101555 in HCC and normal tissues using bioinformatics. The expression level of hsa_circ_101555 was further detected by fluorescence in situ hybridization and qRT-PCR in ten HCC patients. Transwell, migration, WST-1 assays, and colony formation assays were used to evaluate the role of hsa_circ_101555 in HCC development and proliferation. The regulatory mechanisms of hsa_circ_101555 in miR-145-5p and CDCA3 were determined by dual luciferase reporter assay. A mouse xenograft model was also used to determine the effect of hsa_circ_101555 on HCC growth in vivo. hsa_circ_101555 showed greater stability than the linear RNA; while in vitro and in vivo results demonstrated that hsa_circ_101555 silencing significantly suppressed cell proliferation, migration, and invasion of HCC cells. Rescue experiments further demonstrated that suppression of miR-145-5p significantly attenuated the biological effects of hsa_circ_101555 knockdown in HCC cells. We also identified a putative oncogene CDCA3 as a potential miR-145-5p target. Thus, our results demonstrated that hsa_circ_101555 might function as a competing endogenous RNA of miR-145-5p to upregulate CDCA3 expression in HCC. These findings suggest that hsa_circ_101555 may be a potential therapeutic target for patients with HCC.

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