Aberrant expression of circular RNAs(circ RNAs)is frequently linked to colorectal cancer(CRC).Here,we identified circ ZFR as a promising biomarker for CRC diagnosis and prognosis.Circ ZFR was upregulated in CRC tissue...Aberrant expression of circular RNAs(circ RNAs)is frequently linked to colorectal cancer(CRC).Here,we identified circ ZFR as a promising biomarker for CRC diagnosis and prognosis.Circ ZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence,advanced-stages,and metastasis.In both in vitro and in vivo settings,circ ZFR promoted the growth and spread while suppressing apoptosis of CRC.Exosomes with circ ZFR overexpression promoted the proliferation and migration of cocultured CRC cells.Mechanistically,epithelial splicing regulatory protein 1(ESRP1)in CRC cells may enhance the production of circ ZFR.BCL2-associated transcription factor 1(BCLAF1)bound to circ ZFR,which prevented its ubiquitinated degradation.Additionally,circ ZFR sponged mi R-3127-5p to boost rhotekin 2(RTKN2)expression.Our TCP1-CD-QDs nanocarrier was able to carry and deliver circ ZFR si RNA(si-circ ZFR)to the vasculature of CRC tissues and cells,which inhibited the growth of tumors in patient-derived xenograft(PDX)models.Taken together,our results show that circ ZFR is an oncogenic circ RNA,which promotes the development and spread of CRC in a BCLAF1 and mi R-3127-5p-dependent manner.Circ ZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.展开更多
Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters.PA28γis known to be highly upregulated in cancers,but its specific role in the microenvironment remains unclear...Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters.PA28γis known to be highly upregulated in cancers,but its specific role in the microenvironment remains unclear.Here,we demonstrated that PA28γis loaded in exosomes released from head and neck squamous cell carcinoma(HNSCC)cells.Exosomal PA28γis internalized by T cells,subsequently weakening their cytotoxic functions and increasing the expression of CD25 and LAG-3.Using a tumor orthotopic transplant model constructed with PA28γ^(-/-)mice,we found that T cells could take up PA28γfrom tumor cells.Mass cytometry(CyTOF)analysis indicated that knockdown of PA28γreduced the infiltration of CD25+and LAG-3+T cells.Importantly,high-PA28γ-expressing tumors are more responsive to CD25 and LAG-3 immune checkpoint therapy than low-PA28γ-expressing tumors in vivo.Mechanically,exosomal PA28γenhanced T-cell exhaustion by degrading BCLAF1 after it was internalized.HNSCC cohort analysis revealed that the expression of PA28γwas positively correlated with the infiltration of CD25+and LAG-3+T cells and that high levels of these markers could predict a poor prognosis.In summary,exosomal PA28γinduces a T-cell exhaustion phenotype by inhibiting their tumor-killing ability,promoting malignant progression via the PA28γ/BCLAF1/CD25&LAG-3 pathway.These findings reveal a novel cell‒cell interaction between tumors and T cells in the HNSCC microenvironment.展开更多
基金supported by the National Natural Science Foundation of China(81771502,82302899,32071349,81701820)the Natural Science Foundation of Zhejiang Province(LH19H160001,LY20H180014)the Department of Health of Zhejiang Province(2018KY473,2018PY025)。
文摘Aberrant expression of circular RNAs(circ RNAs)is frequently linked to colorectal cancer(CRC).Here,we identified circ ZFR as a promising biomarker for CRC diagnosis and prognosis.Circ ZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence,advanced-stages,and metastasis.In both in vitro and in vivo settings,circ ZFR promoted the growth and spread while suppressing apoptosis of CRC.Exosomes with circ ZFR overexpression promoted the proliferation and migration of cocultured CRC cells.Mechanistically,epithelial splicing regulatory protein 1(ESRP1)in CRC cells may enhance the production of circ ZFR.BCL2-associated transcription factor 1(BCLAF1)bound to circ ZFR,which prevented its ubiquitinated degradation.Additionally,circ ZFR sponged mi R-3127-5p to boost rhotekin 2(RTKN2)expression.Our TCP1-CD-QDs nanocarrier was able to carry and deliver circ ZFR si RNA(si-circ ZFR)to the vasculature of CRC tissues and cells,which inhibited the growth of tumors in patient-derived xenograft(PDX)models.Taken together,our results show that circ ZFR is an oncogenic circ RNA,which promotes the development and spread of CRC in a BCLAF1 and mi R-3127-5p-dependent manner.Circ ZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.
基金supported by grants from the National Natural Science Foundation of China(82273320,82472686,82072999)the CAMS Innovation Fund for Medical Sciences(2019-I2 M-5-004).
文摘Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters.PA28γis known to be highly upregulated in cancers,but its specific role in the microenvironment remains unclear.Here,we demonstrated that PA28γis loaded in exosomes released from head and neck squamous cell carcinoma(HNSCC)cells.Exosomal PA28γis internalized by T cells,subsequently weakening their cytotoxic functions and increasing the expression of CD25 and LAG-3.Using a tumor orthotopic transplant model constructed with PA28γ^(-/-)mice,we found that T cells could take up PA28γfrom tumor cells.Mass cytometry(CyTOF)analysis indicated that knockdown of PA28γreduced the infiltration of CD25+and LAG-3+T cells.Importantly,high-PA28γ-expressing tumors are more responsive to CD25 and LAG-3 immune checkpoint therapy than low-PA28γ-expressing tumors in vivo.Mechanically,exosomal PA28γenhanced T-cell exhaustion by degrading BCLAF1 after it was internalized.HNSCC cohort analysis revealed that the expression of PA28γwas positively correlated with the infiltration of CD25+and LAG-3+T cells and that high levels of these markers could predict a poor prognosis.In summary,exosomal PA28γinduces a T-cell exhaustion phenotype by inhibiting their tumor-killing ability,promoting malignant progression via the PA28γ/BCLAF1/CD25&LAG-3 pathway.These findings reveal a novel cell‒cell interaction between tumors and T cells in the HNSCC microenvironment.
