scholarly journals Integrin αvβ3-targeted polydopamine-coated gold nanostars for photothermal ablation therapy of hepatocellular carcinoma

2021 ◽  
Author(s):  
Yang Li ◽  
Ping Hu ◽  
Xiali Wang ◽  
Xu Hou ◽  
Fengzhen Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Αvβ3 Integrin ◽  
Ablation Therapy ◽  
Gold Nanostars ◽  
In Vivo Experiments ◽  
Human Liver Cancer Cells

Abstract Photothermal therapy (PTT) has emerged as a promising cancer therapeutic method. In this study, Arg-Gly-Asp (RGD) peptide-conjugated polydopamine-coated gold nanostars (Au@PDA-RGD NPs) were prepared for targeting PTT of hepatocellular carcinoma (HCC). A polydopamine (PDA) shell was coated on the surface of gold nanostars by the oxidative self-polymerization of dopamine (termed as Au@PDA NPs). Au@PDA NPs were further functionalized with polyethylene glycol (PEG) and RGD peptide to improve biocompatibility as well as selectivity toward the HCC cells. Au@PDA-RGD NPs showed an intense absorption at 822 nm, which makes them suitable for NIR-excited PTT. Our results indicated that the Au@PDA-RGD NPs were effective for the PTT therapy of the αVβ3 integrin receptor-overexpressed HepG2 cells in vitro. Further antitumor mechanism studies showed that the Au@PDA-RGD NPs-based PTT induced human liver cancer cells death via the mitochondrial-lysosomal and autophagy pathways. In vivo experiments showed that Au@PDA-RGD NPs had excellent tumor treatment efficiency and negligible side effects. Thus, our study showed that Au@PDA-RGD NPs could offer an excellent nanoplatform for PTT of HCC.

scholarly journals HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6

2018 ◽  
Vol 46 (2) ◽  
pp. 461-470 ◽  
Author(s):  
Xiaotang Zhou ◽  
Fan Yang ◽  
Ying Yang ◽  
Ying Hu ◽  
Weixia Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Nuclear Transfer ◽  
Nuclear Translocation ◽  
Neutralizing Antibody ◽  
Rrna Synthesis ◽  
In Vivo Experiments ◽  
B Virus

Background/Aims: Patients with hepatitis B virus (HBV) infection are at a high risk of developing hepatocellular carcinoma (HCC). In this study, we aim to investigate the roles of HBV on angiogenin (ANG), as well as the effects on cell proliferation in presence of ANG down-regulation. Methods: Serum ANG was determined by ELISA. The expression of ANG mRNA and protein in HCC cell lines with or without HBV/HBx were determined. Western blot and ELISA were conducted to determine the effects of HBV/HBx on IL-6 expression. The role of IL-6 on ANG was evaluated by IL-6 recombinant protein or IL-6 neutralizing antibody. Immunofluorescence staining was used to detect the nuclear translocation of ANG. MTT was performed to evaluate the relative inhibition ratio. Result: In vivo experiments showed elevation of serum ANG in patients infected with HBV. In vitro experiments showed HBV and HBx contributed to the transcription and translation of ANG. ANG expression showed increase after IL-6 stimulation, and ANG protein decreased in the presence of IL-6 blocking with its antibody. HBV promoted nuclear translocation of ANG. Inhibiting ANG expression or blocking of nuclear transfer of ANG attenuated the 45S rRNA synthesis and cell proliferation. Conclusion: HBV and HBx protein can increase the level of ANG through IL-6. HBV and HBx contributed to the nuclear translocation of ANG. Cell proliferation was inhibited after inhibiting the expression or nuclear transfer of ANG.

scholarly journals Silencing of KNTC1 inhibits hepatocellular carcinoma cells progression via suppressing PI3K/Akt pathway

2020 ◽  
Author(s):  
Hui Tong ◽  
Junjie Xie ◽  
Xiaohui Liu ◽  
Chenghong Peng ◽  
Baiyong Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Regression ◽  
Annexin V ◽  
Tumor Formation ◽  
Migration Ability ◽  
Migration Assay ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background: Kinetochore associated 1 (KNTC1) encodes a kinetochore component in Rod-Zwilch-ZW10 (RZZ) complex which is essential for the segregation of sister chromatids during mitosis and participates in the spindle checkpoint. Recent research demonstrated that kinetochore proteins may be potential biomarkers and may contribute to the development of human malignancies. Here, we sought to identify the biological significances of KNTC1 in hepatocellular carcinoma (HCC).Methods: KNTC1 expression was studied in HCC tissues by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was performed to generate KNTC1 knockdown HCC cell lines. The effects of KNTC1 on HCC cells proliferation, migration, apoptosis and tumor formation was analyzed by MTT assay, colony formation assay, wound-healing assay, transwell migration assay, annexin V assay in vitro and in nude mouse models in vivo.Results: Our immunohistochemistry experiment showed that KNTC1 was highly expressed in HCC tissues and correlated with terrible prognosis, indicating that KNTC1 acts a pivotal role in HCC development. Furthermore, shRNA KNTC1 (Lv‑shKNTC1) was applied to infect BEL-7404 and SK-HEP-1 to identify roles of KNTC1 on HCC. Lv‑shKNTC1 cells showed reduced proliferation ability, increased apoptosis and decreased migration ability. In vivo experiments suggested that xenografts grow significantly slower upon the silencing of KNTC1. Mechanistically, the protein levels of PIK3CA, p-Akt, CCND1, CDK6 are all down-regulated in Lv-KNTC1 SK-HEP-1 cells. Therefore, KNTC1 may affect the biological activity of HCC cells through PI3K/Akt signaling pathway. Conclusions: In summary, the key finding of this report highlighted the significance of KNTC1 in tumor regression of HCC, demonstrating KNTC1 as an innovative target for adjuvant treatment of HCC.

scholarly journals IR783 Encapsulated in TR-conjugated Liposomes for Enhancing NIR Imaging-guided Photothermal and Photodynamic Therapy

2021 ◽  
Author(s):  
Jiajia Lv ◽  
Tianjiao Luan ◽  
Mingyan Yang ◽  
Mengmeng Wang ◽  
Jie Gao ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Integrin Αvβ3 ◽  
Reticuloendothelial System ◽  
In Vivo Experiments ◽  
Nir Imaging ◽  
Diagnostic Agents ◽  
Tumor Selectivity ◽  
Physical And Chemical

Abstract We developed an integrin αvβ3-specific liposomes, TR-conjugated liposomes (TR-LPs), loading IR783 for NIR imaging-guided both PTT and PDT. The TR-LPs was composed of soyabeanphosphatidylcholine, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N- [methoxy(polyethylene glycol)-2000] (DSPE-PEG) and TR-functionalized DSPE-PEG. IR783, NIR PTT/PDT diagnostic agents, were encapsulated in the hydrophilic core of the TR-LPs. DSPE-PEG had ability of reducing the absorption of TR-LPs by the reticuloendothelial system and increase the cycle time in body. RGD fragment on the TR peptide (TR = c(RGD)-AGYLLGHINLHHLAHL(Aib)HHIL-cys) enhanced the tumor selectivity of liposomes by specifically targeting integrin αvβ3-overexpressing cancer cells. Simultaneously, the rest of fragment on the TR peptide can be changed to the positive charge in the tumor microenvironment (pH 6.5), improving cellular uptake of photoagents at tumor site. We executed a set of in vitro and in vivo experiments to verify if, by functionalizing liposomes with an integrin αvβ3-specific and pH responding peptide, it is possible to achieve NIR imaging guided PTT/PDT for tumor treatment. TR-conjugated liposomes exhibited favorable physical and chemical stability, loading capacity, biocompatibility and tumor targeting. TR-LPs can safely and efficiently delivery IR783 to tumor sites to achieve their therapeutic function. IR783-TR-LPs is promising as a potentially safe and effective phototherapeutic agents for NIR fluorescence-guided tumor therapy applications.

SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma

2019 ◽  
Vol 133 (20) ◽  
pp. 2085-2105 ◽  
Author(s):  
Liangliang Xu ◽  
Peng Wang ◽  
Xinfu Feng ◽  
Jianwei Tang ◽  
Lian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mrna Expression ◽  
Protein Level ◽  
Downstream Target ◽  
In Vivo Experiments ◽  
Pathological Differentiation ◽  
Important Pathway ◽  
Proliferation And Metastasis

Abstract A previous study reported that histone methyltransferase SETD3 is up-regulated in tumor tissues of hepatocellular carcinoma (HCC) and is associated with the growth of HCC. However, the clinical significance and the effect of SETD3 on HCC metastasis remain unclear. In the present study, both the protein and mRNA expression levels of SETD3 were measured in a larger cohort of HCC patients. The results showed that the protein level of SETD3 in HCC tissues was significantly higher than that in non-tumorous tissues, which was inconsistent with the mRNA expression level of SETD3. The high protein level of SETD3 in HCC tissues was significantly associated with male gender, poor pathological differentiation, liver cirrhosis and unfavorable prognosis of HCC patients. Subsequently, we demonstrated that SETD3 could be regulated at post-transcriptional step by a couple of miRNAs (miR-16, miR-195 and miR-497). Additionally, in vitro and in vivo experiments revealed that SETD3 played opposing roles in proliferation and metastasis of HCC: promoting proliferation but inhibiting metastasis. Mechanistic experiments revealed that doublecortin-like kinase 1 (DCLK1) was a downstream target of SETD3. SETD3 could increase the DNA methylation level of DCLK1 promoter to inhibit the transcription of DCLK1. Further study revealed that DCLK1/PI3K/matrix metalloproteinase (MMP) 2 (MMP-2) was an important pathway that mediated the effect of SETD3 on HCC metastasis. In conclusion, the present study revealed that SETD3 is associated with tumorigenesis and is a promising biomarker for predicting the prognosis of HCC patients after surgical resection. In addition, SETD3 plays inhibitory role in HCC metastasis partly through DCLK1/PI3K/MMP-2 pathway.

Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis

2020 ◽  
Author(s):  
Yan Zhang ◽  
Jintao He ◽  
Teng Yang ◽  
Wenhui He ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cyclin D1 ◽  
Gene Promoter ◽  
Liver X Receptor ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA (lncRNA) in human hepatocellular carcinoma (HCC), can promote the growth and metastasis of HCC cells. Therefore, it will be benefit to HCC treatment by effectively downregulating HULC. Liver X receptor (LXR), a member of nuclear receptor superfamily, exerts anti-tumor effects on various human malignancies including HCC. However, it is unclear whether the anti-HCC function of LXR is involved in the regulation of HULC. Methods Quantitative real-time PCR and Western blot were used to separately examine RNA and protein levels in HCC cells. Cell counting kit-8 assay was used to detect the growth of HCC cells in vitro . Dual-luciferase reporter assays were performed to analyze the regulation of forkhead box M1 (FOXM1) by miR-134-5p and the regulation of miR-134-5p by HULC. Xenograft models were engaged to evaluate the growth of HCC cells in vivo . Results In this study, we found that activation of LXR could inhibit the growth of HCC cells by downregulating HULC. Mechanistically, LXR decreased HULC via suppressing its gene promoter activity. Moreover, HULC and FOXM1 were highly expressed while miR-134-5p was lowly expressed in HCC tissues, and the level of HULC was positively correlated with that of FOXM1 while negatively correlated with that of miR-134-5p. Additionally, miR-134-5p downregulated FOXM1 by targeting 3′-untranslated region (UTR) of its mRNA, and HULC upregulated FOXM1 and its downstream target molecule cyclin D1 through sequestrating miR-134-5p. Furthermore, activation of LXR increased miR-134-5p while decreased FOXM1 by reducing HULC in HCC cells. The in vivo experiments showed that activation of LXR repressed the growth of HCC xenografts, and decreased HULC, FOXM1 and cyclin D1 while increased miR-134-5p in the xenografts. Conclusions Our results for the first time reveal that LXR can inhibit the growth of HCC cells by regulating HULC/miR-134-5p/FOXM1 axis. The novel pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a promising target in HCC treatment.

scholarly journals N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Junjie Xu ◽  
Zhe Wan ◽  
Minyue Tang ◽  
Zhongjie Lin ◽  
Shi Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Investigation ◽  
Acquired Resistance ◽  
Rna Stability ◽  
Circular Rna ◽  
Clinical Samples ◽  
In Vivo Experiments ◽  
Induced Apoptosis

Abstract Background and aims Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. Methods In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. Results In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. Conclusions This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.

scholarly journals Silencing of KNTC1 inhibits hepatocellular carcinoma cells progression via suppressing PI3K/Akt pathway

2020 ◽  
Author(s):  
Hui Tong ◽  
Junjie Xie ◽  
Xiaohui Liu ◽  
Chenghong Peng ◽  
Baiyong Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Regression ◽  
Annexin V ◽  
Tumor Formation ◽  
Migration Ability ◽  
Migration Assay ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background: Kinetochore associated 1 (KNTC1) encodes a kinetochore component in Rod-Zwilch-ZW10 (RZZ) complex which is essential for the segregation of sister chromatids during mitosis and participates in the spindle checkpoint. Recent research demonstrated that kinetochore proteins may be potential biomarkers and may contribute to the development of human malignancies. Here, we sought to identify the biological significances of KNTC1 in hepatocellular carcinoma (HCC).Methods: KNTC1 expression was studied in HCC tissues by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was performed to generate KNTC1 knockdown HCC cell lines. The effects of KNTC1 on HCC cells proliferation, migration, apoptosis and tumor formation was analyzed by MTT assay, colony formation assay, wound-healing assay, transwell migration assay, annexin V assay in vitro and in nude mouse models in vivo.Results: Our immunohistochemistry experiment showed that KNTC1 was highly expressed in HCC tissues and correlated with terrible prognosis, indicating that KNTC1 acts a pivotal role in HCC development. Furthermore, shRNA KNTC1 (Lv‑shKNTC1) was applied to infect BEL-7404 and SK-HEP-1 to identify roles of KNTC1 on HCC. Lv‑shKNTC1 cells showed reduced proliferation ability, increased apoptosis and decreased migration ability. In vivo experiments suggested that xenografts grow significantly slower upon the silencing of KNTC1. Mechanistically, the protein levels of PIK3CA, p-Akt, CCND1, CDK6 are all down-regulated in Lv-KNTC1 SK-HEP-1 cells. Therefore, KNTC1 may affect the biological activity of HCC cells through PI3K/Akt signaling pathway.Conclusions: In summary, the key finding of this report highlighted the significance of KNTC1 in tumor regression of HCC, demonstrating KNTC1 as an innovative target for adjuvant treatment of HCC.

scholarly journals Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 817 ◽  
Author(s):  
Jisi Zhao ◽  
Shuang Li ◽  
Yingying Jin ◽  
Jessica Wang ◽  
Wenjing Li ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Tumor Targeting ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Therapeutic Modality ◽  
In Vivo Experiments ◽  
Small Molecule Ligands ◽  
Pyropheophorbide A

Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment.

scholarly journals Anthocyanins Derived from Vitis coignetiae Pulliat Contributes Anti-Cancer Effects by Suppressing NF-κB Pathways in Hep3B Human Hepatocellular Carcinoma Cells and In Vivo

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5445
Author(s):  
Min Jeong Kim ◽  
Anjugam Paramanantham ◽  
Won Sup Lee ◽  
Jeong Won Yun ◽  
Seong Hwan Chang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carcinoma Cells ◽  
Human Hepatocellular Carcinoma ◽  
Hepatocellular Carcinoma Cells ◽  
In Vivo Experiments ◽  
Anti Cancer ◽  
Hep3b Cells ◽  
Human Hepatocellular Carcinoma Cells

We previously demonstrated that anthocyanins from the fruits of Vitis coignetiae Pulliat (AIMs) induced the apoptosis of hepatocellular carcinoma cells. However, many researchers argued that the concentrations of AIMs were too high for in vivo experiments. Therefore, we performed in vitro at lower concentrations and in vivo experiments for the anti-cancer effects of AIMs. AIMs inhibited the cell proliferation of Hep3B cells in a dose-dependent manner with a maximum concentration of 100 µg/mL. AIMs also inhibited the invasion and migration at 100 µg/mL concentration with or without the presence of TNF-α. To establish the relevance between the in vitro and in vivo results, we validated their effects in a Xenograft model of Hep3B human hepatocellular carcinoma cells. In the in vivo test, AIMs inhibited the tumorigenicity of Hep3B cells in the xenograft mouse model without showing any clinical signs of toxicity or any changes in the body weight of mice. AIMs inhibited the activation NF-κB and suppressed the NF-κB-regulated proteins, intra-tumoral microvessel density (IMVD) and the Ki67 activity of Hep3B xenograft tumors in athymic nude mice. In conclusion, this study indicates that AIMs have anti-cancer effects (inhibition of proliferation, invasion, and angiogenesis) on human hepatocellular carcinoma xenograft through the inhibition of NF-κB and its target protein.

scholarly journals Silencing of KNTC1 inhibits hepatocellular carcinoma cells progression via suppressing PI3K/Akt pathway

2020 ◽  
Author(s):  
Hui Tong ◽  
Junjie Xie ◽  
Xiaohui Liu ◽  
Chenghong Peng ◽  
Baiyong Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Regression ◽  
Annexin V ◽  
Tumor Formation ◽  
Migration Ability ◽  
Migration Assay ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background: Kinetochore associated 1 (KNTC1) encodes a kinetochore component in Rod‐Zwilch‐ZW10 (RZZ) complex which is essential for the segregation of sister chromatids during mitosis and participates in the spindle checkpoint. Recent research demonstrated that kinetochore proteins may be potential biomarkers and may contribute to the development of human malignancies. Here, we sought to identify the biological significances of KNTC1 in hepatocellular carcinoma (HCC).Methods: KNTC1 expression was studied in HCC tissues by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was performed to generate KNTC1 knockdown HCC cell lines. The effects of KNTC1 on HCC cells proliferation, migration, apoptosis and tumor formation was analyzed by MTT assay, colony formation assay, wound‐healing assay, transwell migration assay, annexin V assay in vitro and in nude mouse models in vivo.Results: Our immunohistochemistry experiment showed that KNTC1 was highly expressed in HCC tissues and correlated with terrible prognosis, indicating that KNTC1 acts a pivotal role in HCC development. Furthermore, shRNA KNTC1 (Lv‐shKNTC1) was applied to infect BEL‐7404 and SK‐HEP‐1 to identify roles of KNTC1 on HCC. Lv‐shKNTC1 cells showed reduced proliferation ability, increased apoptosis and decreased migration ability. In vivo experiments suggested that xenografts grow significantly slower upon the silencing of KNTC1. Mechanistically, the protein levels of PIK3CA, p‐Akt, CCND1, CDK6 are all down‐regulated in Lv‐KNTC1 SK‐HEP‐1 cells. Therefore, KNTC1 may affect the biological activity of HCC cells through PI3K/Akt signaling pathway.Conclusions: In summary, the key finding of this report highlighted the significance of KNTC1 in tumor regression of HCC, demonstrating KNTC1 as an innovative target for adjuvant treatment of HCC.

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