scholarly journals Plasmodium infection prevents recurrence and metastasis of hepatocellular carcinoma potentially via inhibiting EMT

2020 ◽  
Author(s):  
Yun Liang ◽  
Xiao Chen ◽  
Zhu Tao ◽  
Meng Ma ◽  
Dickson Adah ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Recurrence ◽  
Treated Group ◽  
Control Group ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Tumor Bearing ◽  
Tumor Tissues ◽  
Gsk 3Β

Abstract Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide and is characterized by a high rate of recurrence. We have previously reported Plasmodium infection inhibits tumor development and metastasis in a murine Lewis lung cancer model. In the current study, we aimed to examine the effects of Plasmodium infection on HCC metastasis and recurrence.Methods: Antitumor effects of Plasmodium infection were determined using two murine orthotopic HCC models, the non-resection model for investigating the effect of Plasmodium infection on liver tumor progression and metastasis, the resection model for investigating the effect of Plasmodium infection on the tumor recurrence after tumor was removed. Tumor tissues derived from tumor-bearing mice treated with or without Plasmodium infection were harvested after 15 days of tumor inoculation. The biomarkers related to epithelial-mesenchymal transition (EMT) and molecules associated with CCR10-mediated PI3K/Akt/GSK-3β/Snail pathway signaling were identified by qRT-PCR and western blot. Results: We found that Plasmodium infection significantly suppressed progression, recurrence and metastasis of HCC and prolonged the survival of tumor-bearing mice in both models. The expression levels of E-cadherin were significantly higher in Plasmodium treated group compared with those in control group, whereas the expression levels of Snail were significantly lower in the treated group than those in control group. Furthermore, Plasmodium infection inhibited the activation of Akt and GSK-3β in the tumor tissues by downregulating the expression of CCR10, thereby suppressing the accumulation of Snail and potentially contributed to the suppression of EMT and the prevention of tumor recurrence and metastasis.Conclusion: This study suggested that Plasmodium infection inhibited recurrence and metastasis, improved the prognosis of HCC potentially via suppression of CCR10‑mediated PI3K/Akt/GSK‑3β/Snail signaling, and prevention of EMT. These findings may be important in the development of novel therapy for HCC recurrence and metastasis especially for patients during the perioperative period.

scholarly journals Jianpi-Huayu Formula Inhibits Development of Hepatocellular Carcinoma by Regulating Expression of miR-602, Which Targets the RASSF1A Gene

2020 ◽  
Vol 19 ◽  
pp. 153473541990080 ◽  
Author(s):  
Yajing Huang ◽  
Cheng Zhou ◽  
Huihong Wen ◽  
Yongxu Chen ◽  
Yingjie Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
Tumor Cell ◽  
Liver Tumor ◽  
Cell Apoptosis ◽  
Control Group ◽  
Tumor Cell Apoptosis ◽  
Expression Levels ◽  
Rassf1a Gene ◽  
Tumor Tissues

The traditional Chinese medicine formula Jianpi-Huayu (JPHY) has been reported to be effective in the treatment of hepatocellular carcinoma (HCC). However, its underlying mechanism remains unclear. In this article, we employed an orthotopic transplantation model in nude mice to explore whether JPHY could inhibit the development of HCC by regulating miR-602, which targets the Ras association domain-containing protein 1A (RASSF1A) pathway. HCC SMMC-7721 cells were treated with JPHY to test whether the RASSF1A gene as mediated by miR-602 affected the proliferation and apoptosis of tumor cells. We subsequently detected miR-602, RASSF1A, and tumor cell apoptosis–related markers in cells and liver tumor tissues. We observed that mice treated with JPHY had smaller tumors and higher survival rates than untreated ones. Similarly, JPHY-treated SMMC-7721 cells exhibited alterations in morphology and higher cytotoxicity compared with the control group. Furthermore, we found that JPHY decreased overexpression of miR-602 and increased protein expression levels of the RASS1A gene, which in turn altered protein expression levels of tumor cell apoptosis–related genes in the cells and liver tumor tissues of drug-treated mice. These results indicated that JPHY could potentially be used to treat HCC by targeting miR-602, which targets the RASSF1A gene, which in turn plays a major role in HCC pathogenesis.

scholarly journals A plant-based medicinal food inhibits the growth of human gastric carcinoma by reversing epithelial–mesenchymal transition via the canonical Wnt/β-catenin signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuxi Chen ◽  
Wuyang Yue ◽  
Lin Tian ◽  
Na Li ◽  
Yiyi Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Serum Levels ◽  
Ki 67 ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Tumor Tissues ◽  
Gsk 3Β ◽  
E Cadherin

Abstract Background Natural products, especially those with high contents of phytochemicals, are promising alternative medicines owing to their antitumor properties and few side effects. In this study, the effects of a plant-based medicinal food (PBMF) composed of six medicinal and edible plants, namely, Coix seed, Lentinula edodes, Asparagus officinalis L., Houttuynia cordata, Dandelion, and Grifola frondosa, on gastric cancer and the underlying molecular mechanisms were investigated in vivo. Methods A subcutaneous xenograft model of gastric cancer was successfully established in nude mice inoculated with SGC-7901 cells. The tumor-bearing mice were separately underwent with particular diets supplemented with three doses of PBMF (43.22, 86.44, and 172.88 g/kg diet) for 30 days. Tumor volumes were recorded. Histopathological changes in and apoptosis of the xenografts were evaluated by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, respectively. Serum levels of TNF-α, MMP-2, and MMP-9 were detected by enzyme-linked immunosorbent assay. The mRNA expression levels of β-catenin, GSK-3β, E-cadherin, N-cadherin, MMP-2/9, Snail, Bax, Bcl-2, Caspase-3/9, and Cyclin D1 were evaluated via real-time quantitative polymerase chain reaction. The protein expression levels of GSK-3β, E-cadherin, N-cadherin, and Ki-67 were determined by immunohistochemistry staining. Results PBMF treatment efficiently suppressed neoplastic growth, induced apoptosis, and aggravated necrosis in the xenografts of SGC-7901 cells. PBMF treatment significantly decreased the serum levels of MMP-2 and MMP-9 and significantly increased that of TNF-α. Furthermore, PBMF treatment notably upregulated the mRNA expression levels of GSK-3β, E-cadherin, Bax, Caspase-3, and Caspase-9 but substantially downregulated those of β-catenin, N-cadherin, MMP-2, MMP-9, Snail, and Cyclin D1 in tumor tissues. The Bax/Bcl-2 ratio was upregulated at the mRNA level. Moreover, PBMF treatment remarkably increased the protein expression levels of GSK-3β and E-cadherin but notably reduced those of Ki-67 and N-cadherin in tumor tissues. Conclusions The PBMF concocted herein exerts anti-gastric cancer activities via epithelial–mesenchymal transition reversal, apoptosis induction, and proliferation inhibition. The underlying molecular mechanisms likely rely on suppressing the Wnt/β-catenin signaling pathway.

Cleavage and polyadenylation-specific factor 3 induces cell cycle arrest via PI3K/Akt/GSK-3β signaling pathways and predicts a negative prognosis in hepatocellular carcinoma

2021 ◽  
Vol 15 (5) ◽  
pp. 347-358
Author(s):  
Ning Li ◽  
Shaotao Jiang ◽  
Rongdang Fu ◽  
Jin Lv ◽  
Jiyou Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Lines ◽  
Potential Role ◽  
Control Group ◽  
Specific Factor ◽  
Protein Levels ◽  
Cycle Arrest ◽  
Cleavage And Polyadenylation ◽  
Gsk 3Β

Background: Recent studies have shown that cleavage and polyadenylation-specific factor 3 (CPSF3) is a promising antitumor therapeutic target, but its potential role in hepatocellular carcinoma (HCC) has not been reported. Materials & methods: We explored the expression pattern of CPSF3 in HCC through bioinformatics analysis, quantitative polymerase chain reaction (qPCR) and western blot. The potential role of CPSF3 as a biomarker for HCC was evaluated by Kaplan–Meier analysis. Next, changes in HCC cell lines in the CPSF3 knockdown model group and the control group were assessed by Cell Counting Kit-8, clonal formation, flow cytometry and EdU staining. Western blot detected changes in protein levels of the PI3K/Akt/GSK-3β axis of two HCC cell lines in the knockdown group and the control group. Results: The results showed that the transcription and protein levels of CPSF3 were significantly higher in HCC tissues than in adjacent normal tissues (p < 0.05). The HCC cohort with increased expression of CPSF3 is associated with advanced stage and differentiation and predicts poorer prognosis (p < 0.05). CPSF3 knockdown significantly inhibited proliferation and clone formation of HepG2 and SMMC-7721 cell lines. Flow cytometry analysis showed G1–S cell cycle arrest in the CPSF3 knockdown group, and the results of EdU staining were consistent with this. Compared with the control group, p-Akt and cyclin D1 were decreased, and GSK-3β was increased in the knockdown group. Conclusion: CPSF3 may be a potential diagnostic biomarker and candidate therapeutic target for HCC.

scholarly journals Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells

2019 ◽  
Vol 47 (3) ◽  
pp. 1319-1329 ◽  
Author(s):  
Jian Zhang ◽  
Hai Ma ◽  
Liu Yang ◽  
Hongchun Yang ◽  
Zhenxing He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Trophoblast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Proliferation And Invasion

Objectives Overexpression of human trophoblast cell surface antigen 2 (Trop2) has been observed in many cancers; however, its roles in proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) remain unclear. Thus, this study aimed to characterize the function of Trop2 in HCC. Methods Trop2 protein expression was detected by immunohistochemistry in HCC tissues. Cell proliferation, apoptosis, and invasion were respectively measured by CCK-8, flow cytometry, Transwell, and wound healing assays. Expression levels of epithelial–mesenchymal transition-related proteins and Trop2 protein in HCC cell lines were detected by western blotting after silencing of the TROP2 gene. Results Trop2 protein was highly expressed in HCC tissues and HCC cell lines. Trop2 mRNA and protein expression levels decreased in HepG2 and HCCLM3 cells after transfection with Trop2 siRNA. Silencing of the TROP2 gene in HepG2 and HCCLM3 cells strongly inhibited cell proliferation and migration, while enhancing cell apoptosis. Investigation of the molecular mechanism revealed that silencing of the TROP2 gene suppressed epithelial–mesenchymal transition of HepG2 and HCCLM3 cells. Conclusions The results of the present study may improve understanding of the role of Trop2 in regulation of cell proliferation and invasion, and may aid in development of novel therapy for HCC.

scholarly journals Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Shixia Bu ◽  
Qian Wang ◽  
Junyan Sun ◽  
Xiao Li ◽  
Tingting Gu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Restraint Stress ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Chronic Restraint Stress ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Tumor Tissues

Abstract Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial–mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.

scholarly journals Change and significance of the expression of c-kit and SCF following recovery from unilateral testicular torsion in rats

2008 ◽  
Vol 31 (3) ◽  
pp. 98 ◽  
Author(s):  
Yi Guan ◽  
XinMin Zheng ◽  
ZhiWei Yang ◽  
ShiWen Li
Keyword(s):  
Germ Cells ◽  
Testicular Torsion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Torsion Group ◽  
Treated Group ◽  
Pcr Analysis ◽  
Control Group ◽  
Sham Operation ◽  
Expression Levels

Purpose: To investigate the change in expression levels of c-kit and SCF, and the protective effects of FSH on ischemia-reperfusion injury due to testicular torsion-detorsion. Methods: 24 adult male SD rats were divided into three groups of 8: control group, testicular torsion group and FSH-treated group. The control group was treated with sham-operation. Animals in the testicular torsion and FSH-treated groups were subjected to unilateral 720°counterclockwise testicular torsion for 2 hours and then reperfusion was allowed after detorsion. The FSH-treated group received intraperitoneal injection of FSH 15min before detorsion. Then, the rats were sacrificed and the testes were harvested. Histopathological changes were observed by light microscope, and the expression levels of c-kit, SCF in testicular tissue in the different groups were detected by Immunohistochemical assay and Quantitative Real-time RT-PCR analysis. Finally, the relative proportions of germ cells were measured by FCM. Results: c-kit and SCF were positive expressed in 52.58% and 61.16% of testicular cells of control tissues, respectively. Decreases of c-kit and SCF positive cells (15.01% and 9.18%) were found in the testicular torsion group. After being treated by FSH, the number of positive cells increased (31.25% and 20.01%). Moreover, the c-kit and SCF mRNA expression was increased dramatically (P < 0.01) in response to FSH stimulation. Furthermore, the number of haploid, diploid and tetraploid cells has also increased significantly in drug-treated testes (P < 0.01). Conclusion: The mechanism of tissue damage in the testicular torsion model, includes changes in the expression of c-kit and SCF following torsion. Also, FSH has a protective effect on germ cells after unilateral testicular torsion, which was reflected by increased c-kit and SCF levels.

Three superoxide dismutase genes from Tetranychus cinnabarinus (Boisduval) involved in the responses to temperature and acaricide stresses

2019 ◽  
Vol 24 (1) ◽  
pp. 16 ◽  
Author(s):  
Tianrong Xin ◽  
Xiaoyue Li ◽  
Jiadong Yin ◽  
Xianyan Ye ◽  
Ji Wang ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Metal Binding ◽  
Expression Profiles ◽  
Treated Group ◽  
The Other ◽  
Control Group ◽  
Tetranychus Cinnabarinus ◽  
Expression Levels ◽  
Relative Expression ◽  
Significant Difference

In almost all aerobic organisms, the superoxide dismutase (SOD) is considered as an important antioxidant enzyme regulating oxidative stress. Tetranychus cinnabarinus is an economically important polyphagous pest mite, which harms a variety of economic crops and ornamental plants. In the present study, the full-length cDNA sequences of cytoplasmic Cu/ZnSOD (TcSOD1), extracellular Cu/ZnSOD (TcSOD2) and mitochondrial MnSOD (TcSOD3) from T. cinnabarinus were cloned by combining RT-PCR and rapid amplification of cDNA ends (RACE). The corresponding open reading frames (ORFs) encode three putative polypeptides of 152, 232, 225 amino acid residues, respectively. These sequences share the conserved SOD functional domains, signature motifs and metal binding sites. Multiple alignment analysis revealed that cytosolic Cu/ZnSOD and mitochondrial MnSOD sequences are relatively conserved, while extracellular Cu/ZnSODs are more diverse. Phylogenetic analysis showed that SODs are organized into two major clades, corresponding to Cu/ZnSODs, and MnSODs. Cu/ZnSODs are subdivided into two branches, one being composed of cytoplasmic Cu/ZnSODs, and the other corresponding to extracellular Cu/ZnSODs. Expression profiles of the three genes were determined at different temperatures (4°C, 25°C, and 40°C) for 2 hours. The relative expression of TcSOD1, TcSOD2, and TcSOD3 were significantly down-regulated (0.344-, 0.287-, and 0.358-fold, respectively) at 4°C compared to 25°C (P<0.05). The relative expression levels of TcSOD1 and TcSOD2 genes were significantly down-regulated at 40°C (0.481- and 0.291-fold less than in the control group, respectively) (P<0.05), while there was no significant difference in the relative expression level of TcSOD3(P>0.05). Moreover, expression levels were altered after exposition to different acaricides. TcSOD1, TcSOD2, and TcSOD3 were significantly down-regulated (0.450-, 0.147- and 0.663-fold decreases, respectively) in the abamectin-treated group (P<0.05). TcSOD1 and TcSOD2 were down-regulated, in the fenpropathrin-treated group with 0.794- and 0.201-fold decreases, respectively. On the other hand, the expression of TcSOD3 was significantly increased (P<0.05), being 2.774-fold higher than in the control group. The expression of TcSOD2 was significantly down-regulated both the propargite- and cyflumetofen-treated groups (0.655- and 0.397-fold, respectively) (P<0.05). The data reported here indicate that SODs from T. cinnabarinus may play different and vital roles in anticipating the effects of oxidative damage at extreme temperatures and under different acaricides stress.

scholarly journals RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 167-174
Author(s):  
Ninzi Tian ◽  
Dong Wu ◽  
Ming Tang ◽  
Huichuan Sun ◽  
Yuan Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Response ◽  
Therapeutic Effects ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Expression Levels ◽  
Portal Vein Flow ◽  
Tumor Tissues ◽  
Resistant Group

AbstractObjectivesMonitoring the early treatment effect of sorafenib in advanced hepatocellular carcinoma (HCC) patients is a diagnostic challenge. In a previous study, we reported the potential role of liver computed tomography perfusion (CTP) in the assessment of the response to sorafenib therapy in HCC. The present study aims to investigate whether sorafenib-targeted genes is correlated with CTP parameter, and investigate the potential of sorafenib-targeted genes in early prediction of therapeutic response to sorafenib in advanced HCC.MethodsA total of 21 HCC patients were enrolled. Sorafenib was administered orally at a dose of 400 mg twice daily continuously. Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) criteria. CTP scanning was performed before and after two weeks of sorafenib treatment using a 320-detector row CT scanner. The perfusion parameters of portal vein flow (PVF), hepatic artery flow (HAF), and perfusion index (PI) were acquired by CTP. The expression levels of several sorafenib-targeted genes were assayed using real-time quantitative PCR and western blot analysis. Logistic regression was performed to analyze the relationship between HAF values and RAF1 expression levels.ResultsAccording to mRECIST, the disease control rate (CR+PR+SD) of treatment group was 70.5% after two months of treatment. Compared to background controls, tumor tissues exhibited higher HAF. A sorafenib-targeted gene, RAF1 expression, was increased in tumor tissues especially in the sorafenib-resistant group. The sorafenib-resistant group exhibited a significantly higher RAF1 expression and HAF than the sensitive group. Moreover, the RAF1 expression is positively correlated with the HAF value.ConclusionRAF1 expression might predict therapeutic effects of sorafenib in advanced HCC, where RAF1 could potentially serve as a molecular marker for monitoring early therapeutic effects after sorafenib treatment.

scholarly journals Gan-Qing-Ning Formula Inhibits the Growth of Hepatocellular Carcinoma by Promoting Apoptosis and Inhibiting Angiogenesis in H22 Tumor-Bearing Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Fan-Yan Zeng ◽  
Kai-Li Zhao ◽  
Le-Zhen Lin ◽  
Ying Deng ◽  
Si Qin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antitumor Effect ◽  
Caspase 3 ◽  
Tumor Tissue ◽  
Mitochondrial Apoptosis ◽  
Apoptosis Pathway ◽  
Expression Levels ◽  
Mitochondrial Apoptosis Pathway ◽  
Tumor Bearing ◽  
Mrna Expression Levels

Objective. Gang-Qing-Ning (GQN) is a traditional Chinese medicine formula that has been used in the treatment of hepatocellular carcinoma (HCC) in the folk population for decades. However, scientific validation is still necessary to lend credibility to the traditional use of GQN against HCC. This study investigates the antitumor effect of GQN on H22 tumor-bearing mice and its possible mechanism. Methods. Fifty H22 tumor-bearing mice were randomly assigned to five groups. Three groups were treated with high, medium, and low dosages of GQN (27.68, 13.84, and 6.92 g/kg, respectively); the positive control group was treated with cytoxan (CTX) (20 mg/kg) and the model group was treated with normal saline. After 10 days’ treatment, the tumor inhibitory rates were calculated. Pathological changes in tumor tissue were observed, and the key proteins and genes of the mitochondrial apoptosis pathway were measured, as well as the mRNA expression levels of VEGF in tumor tissue. Results. The tumor inhibitory rates of high, medium, and low dosages of GQN groups were 47.39%, 38.26%, and 22.17%, respectively. The high dosage of the GQN group significantly increased the protein and mRNA expression levels of Bax, Cyt-C, and cleaved Caspase 3 (or Caspase 3) (P<0.01) but decreased the expression levels of Bcl-2, VEGF, and microvessel density (MVD) (P<0.01). Conclusions. The high dosage of GQN can significantly inhibit the tumor growth in H22 tumor-bearing mice. It exerts the antitumor effect by enhancing proapoptotic factors and inhibiting the antiapoptotic factor of the mitochondrial apoptosis pathway and inhibiting tumor angiogenesis.

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