Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements
Abstract Background Epigenetic alteration is an important indicator of crosstalk between cancer cells and surrounding microenvironment components including mesenchymal stem cells (MSC). Human menstrual blood-derived stem cells (MenSCs) are novel source of MSCs which exert suppressive effects on canc...
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-019-1243-8 |
| _version_ | 1818144046036549632 |
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| author | Yichen Wu Xin Chen Yongjia Zhao Yanling Wang Yifei Li Charlie Xiang |
| author_facet | Yichen Wu Xin Chen Yongjia Zhao Yanling Wang Yifei Li Charlie Xiang |
| author_sort | Yichen Wu |
| collection | DOAJ |
| description | Abstract Background Epigenetic alteration is an important indicator of crosstalk between cancer cells and surrounding microenvironment components including mesenchymal stem cells (MSC). Human menstrual blood-derived stem cells (MenSCs) are novel source of MSCs which exert suppressive effects on cancers via multiple components of microenvironmental paracrine signaling. However, whether MenSCs play a crucial role in the epigenetic regulation of cancer cells remains unknown. Methods Epigenetic alterations of hepatocellular carcinoma (HCC) mediated by MenSCs were examined by immunofluorescence, ELISA, and RT-PCR assays. The suppressive impact of MenSCs on HCC was investigated in vitro using CCK8, apoptosis, wound healing, and invasion assays and in vivo using a xenograft mice model. MeDIP-seq, hMeDIP-seq, and RNA-seq were used to identify the genome-wide pattern of DNA methylation and hydroxymethylation in HCC cells after MenSC therapy. Results We show that HCC cells display distinct genome-wide alterations in DNA hydroxymethylation and methylation after MenSC therapy. MenSCs exert an inhibitory effect on HCC growth via regulating 5-hmC and 5-mC abundance in the regulatory regions of oncogenic pathways including PI3K/AKT and MAPK signaling, especially in enhancers and promoters. FOXO3 expression is rescued via reversal of 5-hmC and 5-mC levels in its enhancers and contributes to the activation of downstream apoptosis. Inactivation of the MAPK pathway further disrupts c-myc-mediated epithelial-mesenchymal transitions (EMT). Additionally, chemotherapy resistance-associated genes including ID4 and HMGA1 are suppressed via amending 5-hmC and 5-mC abundance at their regulatory regions. HMGA1 and BYSL might be potential targets for gene-modified MSC therapy. Conclusions Our results confirm that MSCs could regulate the epigenetic mechanism of HCC cells and provide a novel concept for a modified MSC strategy or combination therapy with chemotherapeutics based on epigenetics. |
| first_indexed | 2024-12-11T11:41:20Z |
| format | Article |
| id | doaj.art-777fafe92c2e44b0b9e7900a02cd5028 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-11T11:41:20Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-777fafe92c2e44b0b9e7900a02cd50282022-12-22T01:08:36ZengBMCStem Cell Research & Therapy1757-65122019-05-0110111510.1186/s13287-019-1243-8Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elementsYichen Wu0Xin Chen1Yongjia Zhao2Yanling Wang3Yifei Li4Charlie Xiang5State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang UniversityAbstract Background Epigenetic alteration is an important indicator of crosstalk between cancer cells and surrounding microenvironment components including mesenchymal stem cells (MSC). Human menstrual blood-derived stem cells (MenSCs) are novel source of MSCs which exert suppressive effects on cancers via multiple components of microenvironmental paracrine signaling. However, whether MenSCs play a crucial role in the epigenetic regulation of cancer cells remains unknown. Methods Epigenetic alterations of hepatocellular carcinoma (HCC) mediated by MenSCs were examined by immunofluorescence, ELISA, and RT-PCR assays. The suppressive impact of MenSCs on HCC was investigated in vitro using CCK8, apoptosis, wound healing, and invasion assays and in vivo using a xenograft mice model. MeDIP-seq, hMeDIP-seq, and RNA-seq were used to identify the genome-wide pattern of DNA methylation and hydroxymethylation in HCC cells after MenSC therapy. Results We show that HCC cells display distinct genome-wide alterations in DNA hydroxymethylation and methylation after MenSC therapy. MenSCs exert an inhibitory effect on HCC growth via regulating 5-hmC and 5-mC abundance in the regulatory regions of oncogenic pathways including PI3K/AKT and MAPK signaling, especially in enhancers and promoters. FOXO3 expression is rescued via reversal of 5-hmC and 5-mC levels in its enhancers and contributes to the activation of downstream apoptosis. Inactivation of the MAPK pathway further disrupts c-myc-mediated epithelial-mesenchymal transitions (EMT). Additionally, chemotherapy resistance-associated genes including ID4 and HMGA1 are suppressed via amending 5-hmC and 5-mC abundance at their regulatory regions. HMGA1 and BYSL might be potential targets for gene-modified MSC therapy. Conclusions Our results confirm that MSCs could regulate the epigenetic mechanism of HCC cells and provide a novel concept for a modified MSC strategy or combination therapy with chemotherapeutics based on epigenetics.http://link.springer.com/article/10.1186/s13287-019-1243-8Mesenchymal stem cellHCCEpigenetics5-HydroxymethylcytosineEnhancer |
| spellingShingle | Yichen Wu Xin Chen Yongjia Zhao Yanling Wang Yifei Li Charlie Xiang Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements Stem Cell Research & Therapy Mesenchymal stem cell HCC Epigenetics 5-Hydroxymethylcytosine Enhancer |
| title | Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements |
| title_full | Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements |
| title_fullStr | Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements |
| title_full_unstemmed | Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements |
| title_short | Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements |
| title_sort | genome wide dna methylation and hydroxymethylation analysis reveal human menstrual blood derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5 hmc in enhancer elements |
| topic | Mesenchymal stem cell HCC Epigenetics 5-Hydroxymethylcytosine Enhancer |
| url | http://link.springer.com/article/10.1186/s13287-019-1243-8 |
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