Background Proteins containing the Jumonji C(JmjC)domain participated in tumorigenesis and cancer progression.However,the mechanisms underlying this effect are still poorly understood.Our objective was to investigate ...Background Proteins containing the Jumonji C(JmjC)domain participated in tumorigenesis and cancer progression.However,the mechanisms underlying this effect are still poorly understood.Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2(JARID2)—a JmjC family protein—in breast cancer,as well as its latent association with obesity.Methods Immunohistochemistry,The Cancer Genome Atlas,Gene Expression Omnibus,and other databases were used to analyze the expression of JARID2 in breast cancer cells.Growth curve,5-ethynyl-2-deoxyuridine(EdU),colony formation,and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion.Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness.RNA-sequencing,Kyoto Encyclopedia of Genes and Genomes,and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates.Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2.The results were further verified using co-immunoprecipitation and glutathione S-transferase(GST)pull-down experiments.Using chromatin immunoprecipitation(ChIP)sequencing,we sought the target genes that JARID2 and metastasis-associated protein 1(MTA1)jointly regulated;the results were validated by ChIP-PCR,quantitative ChIP(qChIP)and ChIP-reChIP assays.A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes.Results In this study,we found that JARID2 was highly expressed in multiple types of cancer including breast cancer.JARID2 promoted glycolysis,lipid metabolism,proliferation,invasion,and stemness of breast cancer cells.Furthermore,JARID2 physically interacted with the nucleosome remodeling and deacetylase(NuRD)complex,transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated(BRCA2),RB transcriptional corepressor 1(RB1),and inositol polyphosphate-4-phosphatase type II B(INPP4B).Additionally,JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in the breast cancer microenvironment.Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer.Conclusion Our data indicated that JARID2 promoted breast tumorigenesis and development,confirming JARID2 as a target for cancer treatment.展开更多
Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy ...Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206^(+) TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking “don’t eat me” recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:41931291,42125707,82273403,82203820,82002993Major State Basic Research Development Program of China,Grant/Award Number:2022YFA1103402+2 种基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Numbers:2019PT310027,2021-RC310-006Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-018China Postdoctoral Science Foundation,Grant/Award Number:2022M710454。
文摘Background Proteins containing the Jumonji C(JmjC)domain participated in tumorigenesis and cancer progression.However,the mechanisms underlying this effect are still poorly understood.Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2(JARID2)—a JmjC family protein—in breast cancer,as well as its latent association with obesity.Methods Immunohistochemistry,The Cancer Genome Atlas,Gene Expression Omnibus,and other databases were used to analyze the expression of JARID2 in breast cancer cells.Growth curve,5-ethynyl-2-deoxyuridine(EdU),colony formation,and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion.Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness.RNA-sequencing,Kyoto Encyclopedia of Genes and Genomes,and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates.Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2.The results were further verified using co-immunoprecipitation and glutathione S-transferase(GST)pull-down experiments.Using chromatin immunoprecipitation(ChIP)sequencing,we sought the target genes that JARID2 and metastasis-associated protein 1(MTA1)jointly regulated;the results were validated by ChIP-PCR,quantitative ChIP(qChIP)and ChIP-reChIP assays.A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes.Results In this study,we found that JARID2 was highly expressed in multiple types of cancer including breast cancer.JARID2 promoted glycolysis,lipid metabolism,proliferation,invasion,and stemness of breast cancer cells.Furthermore,JARID2 physically interacted with the nucleosome remodeling and deacetylase(NuRD)complex,transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated(BRCA2),RB transcriptional corepressor 1(RB1),and inositol polyphosphate-4-phosphatase type II B(INPP4B).Additionally,JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in the breast cancer microenvironment.Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer.Conclusion Our data indicated that JARID2 promoted breast tumorigenesis and development,confirming JARID2 as a target for cancer treatment.
基金This work was supported by the National Natural Science Foundation of China(81772638 and 81903025)CAMS Innovation Fund for Medical Sciences(2016-I2M-1-001).
文摘Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206^(+) TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking “don’t eat me” recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.
