Xanthohumol regulates miR-4749-5p-inhibited RFC2 signaling in enhancing temozolomide cytotoxicity to glioblastoma

Ho, Kuo Hao; Kuo, Tai Chih; Lee, Yi Ting; Chen, Peng Hsu; Shih, Chwen Ming; Cheng, Chia Hsiung; Liu, Ann Jeng; Lee, Chin Cheng; Chen, Ku Chung

doi:10.1016/j.lfs.2020.117807

Cited by 27 publications

(24 citation statements)

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“…demonstrated that patients with higher grade of glioblastoma tend to express higher RFC2 and result in the resistance to temozolomide, which could be suppressed by miR-4749-5p (27). Peng et al reported that overexpression of RFC5 could lead to a temozolomide resistance in human glioma cells (47).…”

Section: Discussionmentioning

confidence: 99%

“…There were many studies about RFC2 and certain cancers, most of which stated that RFC2 was obviously upregulated in cancer tissues (19,28,52,53,54). Ho et al (27). demonstrated that impaired the activation of RFC2 signaling could enhance the temozolomide cytotoxicity to glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…Many previous researches have reported the subunits of RFCs to be remarkable differentially expressed genes when comparing tumor tissue and normal tissues in many cancer types, such as breast cancer, nasopharyngeal carcinoma, ovarian tumor, acute myeloid leukemia and so on (18,19,20,21,22,23,24,25). Some of the RFCs subunits including RFC2, RFC4 and RFC5, have been reported in glioma and glioblastoma, however, the studies are not su cient (26,27,28,29,30). The studies of RFC1 and RFC3 in brain and central nervous system cancer can rarely be found.…”

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confidence: 99%

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A Comprehensive Bioinformatic Analysis of RFC1/2/3/4/5 As Significant Clinical Indicators in The Diagnosis and Prognosis of Low-Grade Glioma

Wang

Huo

2021

Preprint

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Background: Replication factor C (RFC) proteins play a very important role in nuclear DNA replication, mismatch repair and cell cycle checkpoint pathways. However, the relationship between RFCs and brain tumors is still unclear, especially the diagnostic and prognostic significance of RFCs in low-grade glioma. Methods: In our study, we applied the Oncomine, GEPIA, Human Protein Atlas, cBioPortal, STRING, LinkedOmics and Tumor Immune Estimation Resource (TIMER) databases to analyze the transcriptional and survival data of RFCs in brain and central nervous system (CNS) cancer, especially in low-grade glioma.Results: We found that RFCs were highly expressed in brain and CNS cancer, including low-grade glioma. The transcriptional levels of RFCs were also associated with the tumor stages. Moreover, the survival analysis of RFCs in low-grade glioma patients revealed that enhanced expression of RFCs led to poorer prognosis. RFCs and their 50 frequently altered neighbor genes were found enriched in certain pathways. We also discovered the kinase targets, transcription factor targets and miRNA targets of RFCs in low-grade glioma. RFCs also showed positive correlation with certain infiltrated immune cells in low-grade glioma.Conclusions: These implied that RFCs are the possible biomarkers of the diagnosis and prognosis of low-grade glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A Comprehensive Bioinformatic Analysis of RFC1/2/3/4/5 As Significant Clinical Indicators in The Diagnosis and Prognosis of Low-Grade Glioma

Wang

Huo

2021

Preprint

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“…Previous studies have found that the inhibition of RFC2 can enhance the cytotoxicity of temozolomide to glioblastoma (Ho et al 2020). This article analyzed the functions and pathways of 50 similar genes of RFC2 in HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Up-regulated RFC2 Predicts Unfavorably Progression in Hepatocellular Carcinoma

Wang

2020

Preprint

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Background: Replication factor C (RFC) is closely related to tumor progression and metastasis. However, the functional significance of RFC2 in hepatocellular carcinoma remains unclear.Materials and methods: In order to solve this problem, the expression of RFC2 in liver cancer patients was analyzed through ONCOMINE, UALCAN, human protein atlas. Survival analysis was conducted using Kaplan-Meier plotter and GEPIA. GO and KEGG enrichment analyses were carried out. The protein-protein interaction (PPI) network was performed through Metascape.Result: The transcription and protein level of RFC2 in HCC were overexpressed, which was significantly related to the clinical individual cancer stage and pathological tumor grade of HCC patients. In addition, in patients with liver cancer, higher RFC2 expression was found to be significantly correlated with shorter OS and DFS. Furthermore, the function of RFC2 in liver cancer was DNA replication, and its main mechanism was the phase transition of the cell cycle.Conclusion: RFC2 might promote the development of liver cancer. It could also be used as a novel biomarker for the prognosis of liver cancer.

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“…And Festa et al reported that XN induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species (ROS) and activating MAPK pathways [ 9 ]. However, most of these studies investigated the mitochondria as the key node in the process of apoptosis but did not reveal the status of the mitochondria [ 8 , 9 , 10 ]. Therefore, in this study, we used an in vitro cultured rat glioma C6 cells to investigated the effects of XN on the cell survival and the mitochondrial response mechanism.…”

Section: Introductionmentioning

confidence: 99%

Xanthohumol-Induced Rat Glioma C6 Cells Death by Triggering Mitochondrial Stress

Hou

Song

Sun

et al. 2021

IJMS

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AIM: To investigate the underlying mechanisms of xanthohumol (XN) on the proliferation inhibition and death of C6 glioma cells. METHODS: To determine the effects of XN on C6 cells, cell proliferation and mortality after XN treatment were assessed by SRB assay and trypan blue assay respectively. Apoptotic rates were evaluated by flowcytometry after Annexin V-FITC/PI double staining. The influence of XN on the activity of caspase-3 was determined by Western blot (WB); and nuclear transposition of apoptosis-inducing factor (AIF) was tested by immunocytochemistry and WB. By MitoSOXTM staining, the mitochondrial ROS were detected. Mitochondrial function was also tested by MTT assay (content of succinic dehydrogenase), flow cytometry (mitochondrial membrane potential (MMP)—JC-1 staining; mitochondrial abundance—mito-Tracker green), immunofluorescence (MMP—JC-1 staining; mitochondrial morphology—mito-Tracker green), WB (mitochondrial fusion-fission protein—OPA1, mfn2, and DRP1; mitophagy-related proteins—Pink1, Parkin, LC3B, and P62), and high-performance liquid chromatography (HPLC) (energy charge). Finally, mitochondrial protein homeostasis of C6 cells after XN treatment with and without LONP1 inhibitor bortezomib was investigated by trypan blue assay (proliferative activity and mortality) and WB (mitochondrial protease LONP1). All cell morphology images were taken by a Leica Microsystems microscope. RESULTS: XN could lead to proliferation inhibition and death of C6 cells in a time- and dose-dependent manner and induce apoptosis of C6 cells through the AIF pathway. After long incubation of XN, mitochondria of C6 cells were seriously impaired, and mitochondria had a diffuse morphology and mitochondrial ROS were increased. The content of succinic dehydrogenase per cell was significantly decreased after XN insults of 24, 48, and 72 h. The energy charge was weakened after XN insult of 24 h. Furthermore, the MMP and mitochondrial abundance were significantly decreased; the protein expression levels of OPA1, mfn2, and DRP1 were down-regulated; and the protein expression levels of Pink1, Parkin, LC3B-II/LC3B-I, and p62 were up-regulated in long XN incubation times (24, 48, and 72 h). XN incubation with bortezomib for 48 h resulted in lower proliferative activity and higher mortality of C6 cells and caused the cell to have visible vacuoles. Moreover, the protein expression levels of LONP1 was up-regulated gradually as XN treatment time increased. CONCLUSION: These data supported that XN could induce AIF pathway apoptosis of the rat glioma C6 cells by affecting the mitochondria.

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Xanthohumol regulates miR-4749-5p-inhibited RFC2 signaling in enhancing temozolomide cytotoxicity to glioblastoma

Cited by 27 publications

References 27 publications

A Comprehensive Bioinformatic Analysis of RFC1/2/3/4/5 As Significant Clinical Indicators in The Diagnosis and Prognosis of Low-Grade Glioma

A Comprehensive Bioinformatic Analysis of RFC1/2/3/4/5 As Significant Clinical Indicators in The Diagnosis and Prognosis of Low-Grade Glioma

Up-regulated RFC2 Predicts Unfavorably Progression in Hepatocellular Carcinoma

Xanthohumol-Induced Rat Glioma C6 Cells Death by Triggering Mitochondrial Stress

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