Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomer...Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 （BMP7） induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.展开更多
Transforming growth factor-beta(TGFβ)is a highly potent immunosuppressive cytokine.Although TGFβis a tumor suppressor in early/premalignant cancer lesions,the cytokine has several tumor-promoting effects in advanced...Transforming growth factor-beta(TGFβ)is a highly potent immunosuppressive cytokine.Although TGFβis a tumor suppressor in early/premalignant cancer lesions,the cytokine has several tumor-promoting effects in advanced cancer;abrogation of the antitumor immune response is one of the most important tumor-promoting effects.As several immunoregulatory mechanisms have recently been shown to be targets of specific T cells,we hypothesized that TGFβis targeted by naturally occurring specific T cells and thus could be a potential target for immunomodulatory cancer vaccination.Hence,we tested healthy donor and cancer patient T cells for spontaneous T-cell responses specifically targeting 3820-mer epitopes derived from TGFβ1.We identified numerous CD4^(+)and CD8^(+)T-cell responses against several epitopes in TGFβ.Additionally,several ex vivo responses were identified.By enriching specific T cells from different donors,we produced highly specific cultures specific to several TGFβ-derived epitopes.Cytotoxic CD8^(+)T-cell clones specific for both a 20-mer epitope and a 9-mer HLA-A2 restricted killed epitope peptide were pulsed in HLA-A2+target cells and killed the HLA-A2+cancer cell lines THP-1 and UKE-1.Additionally,stimulation of THP-1 cancer cells with cytokines that increased TGFβexpression increased the fraction of killed cells.In conclusion,we have shown that healthy donors and cancer patients harbor CD4^(+)and CD8^(+)T cells specific for TGFβ-derived epitopes and that cytotoxic T cells with specificity toward TGFβ-derived epitopes are able to recognize and kill cancer cell lines in a TGFβ-dependent manner.展开更多
基金We thank Claude Labrie for the plasmid construct encoding BMPRII truncation and Peter Lansdorp for the TFL-Telo 2.2 software program for telomere analysis. This work was supported by grants from the National Basic Research Program （973 Program） （No. 2012CB911204）, National Natural Science Foundation of China （Grant Nos. 81170313 and 81272889）, the National Health and Medical Research Council of Australia and Australia Research Council. Cancer Council of Victoria, Australia.
文摘Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 （BMP7） induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.
基金This project was supported by the Danish Health Authority grant“Empowering Cancer Immunotherapy in Denmark”,grant number 4-1612-236/8the Copenhagen University Hospital,Herlev,and Gentoftesupported through a research funding agreement between IO Biotech ApS and the National Center for Cancer Immune Therapy(CCIT-DK).
文摘Transforming growth factor-beta(TGFβ)is a highly potent immunosuppressive cytokine.Although TGFβis a tumor suppressor in early/premalignant cancer lesions,the cytokine has several tumor-promoting effects in advanced cancer;abrogation of the antitumor immune response is one of the most important tumor-promoting effects.As several immunoregulatory mechanisms have recently been shown to be targets of specific T cells,we hypothesized that TGFβis targeted by naturally occurring specific T cells and thus could be a potential target for immunomodulatory cancer vaccination.Hence,we tested healthy donor and cancer patient T cells for spontaneous T-cell responses specifically targeting 3820-mer epitopes derived from TGFβ1.We identified numerous CD4^(+)and CD8^(+)T-cell responses against several epitopes in TGFβ.Additionally,several ex vivo responses were identified.By enriching specific T cells from different donors,we produced highly specific cultures specific to several TGFβ-derived epitopes.Cytotoxic CD8^(+)T-cell clones specific for both a 20-mer epitope and a 9-mer HLA-A2 restricted killed epitope peptide were pulsed in HLA-A2+target cells and killed the HLA-A2+cancer cell lines THP-1 and UKE-1.Additionally,stimulation of THP-1 cancer cells with cytokines that increased TGFβexpression increased the fraction of killed cells.In conclusion,we have shown that healthy donors and cancer patients harbor CD4^(+)and CD8^(+)T cells specific for TGFβ-derived epitopes and that cytotoxic T cells with specificity toward TGFβ-derived epitopes are able to recognize and kill cancer cell lines in a TGFβ-dependent manner.
