scholarly journals Galangin Inhibits Cholangiocarcinoma Cell Growth and Metastasis through Downregulation of MicroRNA-21 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yang Zou ◽  
Rong Li ◽  
Dabin Kuang ◽  
Meiling Zuo ◽  
Wenqun Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Cholangiocarcinoma Cell ◽  
Proliferation And Metastasis

Galangin, a natural flavonoid product derived from the root of galangal, is emerging as a promising anticancer agent against multiple cancers. Yet, whether it also has antitumor effects on cholangiocarcinoma (CCA) and the underlying mechanism is still unknown. Herein, we demonstrate that galangin exhibits multiple antitumor effects on CCA cells including decreases cell viability; inhibits proliferation, migration, and invasion; and induces apoptosis. Moreover, those phenotypic changes are associated with downregulated microRNA-21 (miR-21) expression. To support, overexpression of miR-21 blocks galangin-mediated antisurvival and metastasis effects on CCA cells. Mechanically, galangin increases the expression of phosphatase and tensin homolog (PTEN), a direct target of miR-21, resulting in decreased phosphorylation of AKT, a protein kinase which plays a critical role in controlling survival and apoptosis. In contrast, overexpression of miR-21 abrogates galangin-regulated PTEN expression and AKT phosphorylation. Taken together, these findings indicate that galangin inhibits CCA cell proliferation and metastasis and induces cell apoptosis through a miR-21-dependent manner, and galangin may provide a novel potential therapeutic adjuvant to treat CCA.

scholarly journals Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyang Li ◽  
Shuangqing Yang ◽  
Huaqing Ma ◽  
Mengjia Ruan ◽  
Luyan Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Underlying Mechanism ◽  
Tissue Growth ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

scholarly journals Local Regeneration of Cortisol by 11β-HSD1 Contributes to Insulin Resistance of the Granulosa Cells in PCOS

2016 ◽  
Vol 101 (5) ◽  
pp. 2168-2177 ◽  
Author(s):  
Qinling Zhu ◽  
Rujuan Zuo ◽  
Yaqiong He ◽  
Yuan Wang ◽  
Zi-jiang Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Reductase Activity ◽  
Underlying Mechanism ◽  
Cortisol Concentration ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog

Abstract Context: Insulin resistance (IR) of the granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome (PCOS). The underlying mechanism remains largely unresolved. Objective: The objective of the study was to investigate the relationship of IR of the granulosa cells with cortisol in the follicular fluid and 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and -2) in the granulosa cells in PCOS. Design: Follicular fluid and granulosa cells were collected from non-PCOS and PCOS patients with and without IR to measure cortisol concentration and the amounts of 11β-HSD1 and -2, which were then correlated with IR status. The effects of cortisol on the expression of genes pertinent to IR were studied in cultured human granulosa cells. Results: Cortisol concentration in the follicular fluid, 11β-HSD1 but not 11β-HSD2 mRNA in the granulosa cells were significantly elevated in PCOS with IR. Increased reductase and decreased oxidase activities of 11β-HSD were observed in granulosa cells in PCOS with IR. In cultured granulosa cells, insulin-induced Akt phosphorylation was significantly attenuated by cortisol. Cortisol not only increased phosphatase and tensin homolog deleted on chromosome 10, an inhibitor of Akt phosphorylation, but also 11β-HSD1 in the cells. Conclusions: Increased 11β-HSD1 expression and its reductase activity in granulosa cells are the major causes of increased cortisol concentration in the follicular fluid of PCOS with IR. The consequent excessive cortisol might contribute to IR of the granulosa cells in PCOS patients by attenuating Akt phosphorylation via induction of phosphatase and tensin homolog deleted on chromosome 10 expression, which might be further exacerbated by the induction of 11β-HSD1.

scholarly journals Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Hanyue Chang ◽  
Qiaoshi Xu ◽  
Jiayi Li ◽  
Mingyu Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Critical Role ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Histone Deacetylase 3 ◽  
Proliferation And Metastasis ◽  
Immunosuppressive Microenvironment ◽  
Transcriptional Complex

AbstractPyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

11-O-Galloyl Bergenin from Corylopsis coreanas Leaves Induces Autophagy and Apoptosis in Human Osteosarcoma

2021 ◽  
Vol 49 (08) ◽  
pp. 2017-2031
Author(s):  
Kyung-Ran Park ◽  
Yoon-Ju Kwon ◽  
Myounglae Cho ◽  
Il Keun Kwon ◽  
Jin Tae Hong ◽  
...  
Keyword(s):  
Annexin V ◽  
Mg63 Cell ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Antitumor Effects ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Induced Apoptosis

Osteosarcoma is the most common malignant bone-forming tumor, wherein most patients with high grade osteosarcomas are treated with chemotherapy. Despite this, survival for metastatic or relapsed osteosarcoma patients has remained at an overall 5-year survival rate of 20%. In particular, the extracts of Corylopsis coreana (Korean winter hazel), a cultivated woody plant in South Korea, have shown beneficial anti-inflammatory, anti-oxidative, anti-osteoclastic, and antihyperuricemic properties. Therefore, this study aimed to demonstrate the antitumor activities and underlying mechanism of 11-O-Galloyl bergenin (OGAL) isolated from Corylopsis coreanas leaves in human osteosarcoma cells. Herein, we found that OGAL inhibited MG63 cell proliferation and induced cellular apoptosis as evidenced by cleaved-PARP, cleaved-caspase 3, TUNEL-positive cells, and Annexin V-positive cells. Specifically, OGAL-induced apoptosis was accompanied by p53 and p21 upregulation, BAX expression, and decreased Bcl-2 and cdk2. Moreover, OGAL induced autophagy via AKT inactivation, LC3II upregulation, and MG63 cell autophagosome formation. OGAL-induced autophagy was also accompanied by increased p38 phosphorylation, whereas JNK and ERK1/2 activities were found to be unaffected upon examining the MAPK signaling pathway. Furthermore, wound healing and Boyden chamber assays showed that OGAL suppressed MG63 cell migration and invasion. Given these findings, this study provided evidence that OGAL has antitumor effects by apoptosis and autophagy enhancement through increased p53, AKT, and p38 signaling, suggesting that OGAL may be a potential therapeutic strategy for osteosarcoma treatment.

LncRNA PCAT18/miR-301a/TP53INP1 axis is involved in gastric cancer cell viability, migration and invasion

2020 ◽  
Vol 168 (5) ◽  
pp. 547-555
Author(s):  
Jin Dou ◽  
Daoyuan Tu ◽  
Haijian Zhao ◽  
Xiaoyu Zhang
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cell Lines ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Invasion And Migration ◽  
Proliferation And Metastasis ◽  
And Migration ◽  
Cell Proliferation And Metastasis

Abstract MiR-301a is as an oncogene involved in the regulation of gastric cancer (GC) progression, but the underlying mechanism is unclear. This study was to explore the lncRNA PCAT18/miR-301a/TP53INP1 axis in regulating the GC cell proliferation and metastasis. In the present study, GC tissues and cell lines were collected for the detection of PCAT18 expression. Herein, we found that PCAT18 is significantly decreases in human GC tissues and five GC cell lines. Overexpression of PCAT18 inhibits cell viability, invasion and migration of GC cells and tumour growth of GC xenograft tumours. PCAT18 negatively regulates the expression level of miR-301a. The interaction between PCAT18 and miR-301a is confirmed by RIP and RNA pull down. MiR-301a mimic increases cell viability and promotes cell migration and invasion and reverses the inhibitory action of PCAT18. TP53INP1 expression is negatively regulated by miR-301a and TP53INP1/miR-301a is involved in GC viability, migration and invasion. The promoting of PCAT18 on TP53INP1 expression is abolished by miR-301a overexpression. In conclusion, lncRNA PCAT18 acts as a tumour suppressor for GC and lncRNA PCAT18, miR-301a and TP53INP1 comprise a signal axis in regulating GC cell proliferation, migration and invasion.

scholarly journals Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052097145
Author(s):  
Jie Pan ◽  
Zongbin Xu ◽  
Meifang Xu ◽  
Xiaoyan Lin ◽  
Bingqiang Lin ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Human Colon ◽  
Migration And Invasion ◽  
Human Colon Cancer ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Forkhead Box ◽  
Mrna And Protein Expression ◽  
Cancer Tissues ◽  
Foxa1 Expression

Background This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. Methods We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. Results FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial–mesenchymal transition. Conclusion FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.

scholarly journals Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4560-4568 ◽  
Author(s):  
Bao Hoang ◽  
Patrick Frost ◽  
Yijiang Shi ◽  
Eileen Belanger ◽  
Angelica Benavides ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Complex Protein ◽  
Preclinical Work

Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin complex (TORC)1. To assess if the mammalian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM.

scholarly journals Extracellular HSP90α-LRP1 Signaling Promote Pancreatic Cancer Metastasis and Chemoresistance Via Regulating Epithelial-To-Mesenchymal Transition

2021 ◽  
Author(s):  
Nina Xue ◽  
Tingting Du ◽  
Fangfang Lai ◽  
Jing Jin ◽  
Ming Ji ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Extracellular heat shock protein 90α (HSP90α) has been reported to promote cancer cell invasion and migration. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α and its underlying mechanism for PC progression were still unclear. Our study pointed out that highly invasive Capan2 cells has a higher level of secreted HSP90α, rather than membrane HSP90α, compared with those of less invasive PL45 cells. The conditioned medium of Capan2 cells or recombinant HSP90α protein was able to stimulate the migration and invasion of PL45 or capan2 cells, which could be prevented by a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition (EMT) in PL45 cells, including increases in vimentin and snail expressions, decreases in E-cadherin expression and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by anti-HSP90α antibody in Capan2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) mRNA were associated with worsened patient survival in pancreatic adenocarcinoma. LRP1 as a receptor of eHSP90α for its stimulatory role of PC cells EMT and metastasis by activating AKT signaling. Down-regulation of LRP1 could promote chemosensitivity to gemcitabine and doxorubicin, but not to topotecan and paclitaxel in Capan2 cells. Therefore, our study reveals a critical role of secreted HSP90α on EMT events and suggests blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance.

scholarly journals LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Fei Chen ◽  
Meijun Li ◽  
Liang Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Cancer Susceptibility ◽  
Underlying Mechanism ◽  
Epigenetic Mechanism ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the third leading cause of cancer-related deaths worldwide. Besides, it has been revealed that long non-coding RNA (LncRNA) cancer susceptibility candidate 11 (CASC11) is involved in cancer progression. However, the functional role and underlying mechanism of CASC11 in HCC remains largely unknown. In this context, here, it was found that CASC11 was upregulated in HCC tissues and associated with tumor grades, metastasis, and prognosis of HCC patients. Functionally, CASC11 facilitated HCC cell proliferation, migration, and invasion in vitro, and enhanced tumor growth and metastasis in vivo. Mechanistically, CASC11 associated with and stabilized Ubiquitin-conjugating enzyme E2T (UBE2T) mRNA. To be specific, it decreased UBE2T N6-methyladenosine (m6A) level via recruiting ALKBH5. Moreover, CASC11 inhibited the association between UBE2T mRNA and m6A reader protein YTHDF2. Taken together, our findings demonstrate the epigenetic mechanism of CASC11 in the regulation of UBE2T expression and possibly provide a novel therapeutic target for HCC treatment.

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