IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling

Lu, Jinchang; Song, Guohui; Tang, Qinglian; Zou, Changye; Hong, Feng; Zhao, Zhiqiang; Yong, Bicheng; Yin, Junqiang; Xu, Huaiyuan; Xie, Xianbiao; Kang, Tiebang; Lam, Yuk-Fai; Yang, Huiling; Shen, Jingnan; Wang, Jin

doi:10.1172/jci78437

Cited by 111 publications

(80 citation statements)

References 71 publications

(89 reference statements)

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“…Although osteosarcoma is the most common malignant primary musculoskeletal tumor, it is still a relatively rare disease with an incidence of about four per million individuals (18). Numerous efforts have been made to clarify the mechanism of osteosarcoma tumorigenesis and metastases, as well as to find out novel treatment for refractory cases (19)(20)(21). However, its rarity severely restricts clinical sample-based studies and clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Zhan

et al. 2018

Cancer Research

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The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here, we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and to impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8 T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma. Epigenetic regulation of CXCL12 controls metastasis and immune response in osteosarcoma, suggesting epigenetic therapies or therapies targeting CXCL12 have potential for therapeutic intervention in osteosarcoma. .

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Zhan

et al. 2018

Cancer Research

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“…Importantly, suppression of cell migration and invasion was not due to reduced overall cell number, as equal numbers of cells were reseeded into the wells after the pretreatment period, and migration or invasion was assessed within 24 hours. To investigate the ability of DGT to prevent osteosarcoma lung metastasis in vivo, we injected 143B cells into the tail vein of nude mice as described previously (26). In addition, the mice were randomly separated into two groups after 2 weeks; the control group received vehicle every day, and the treatment group received 300 mg/kg of DGT every day.…”

Section: Dgt Suppresses Osteosarcoma Cell Metastatic Potential Both Imentioning

confidence: 99%

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Zhao

Jia

et al. 2018

Clinical Cancer Research

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Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3b. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3b inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3b inactivation-mediated repression of the Hedgehog/Gli1 pathway.

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“…77 In addition, Iroquois homeobox 1 (IRX1) hypomethylation is a potential molecular marker for lung metastasis. 78 On the other hand, hypermethylation and correlated inactivation of genes also play important roles in human cancer metastasis. Semaphorin-3F (SEMA3F), a candidate tumor suppressor in human cancers, was hypermethylated in colorectal cancer, consequently leading to cancer migration and invasion.…”

Section: Dna Methylation Dysregulation In Cancer Metastasismentioning

confidence: 99%

Mutual regulation of microRNAs and DNA methylation in human cancers

Wang¹,

Wu²,

Claret

2017

Epigenetics

128

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microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper-and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.

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IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling

Cited by 111 publications

References 71 publications

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Mutual regulation of microRNAs and DNA methylation in human cancers

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