Endogenous peptides,bioactive agents with a small molecular weight and outstanding absorbability,regulate various cellular processes and diseases.However,their role in the occurrence of Hirschsprung’s disease(HSCR)re...Endogenous peptides,bioactive agents with a small molecular weight and outstanding absorbability,regulate various cellular processes and diseases.However,their role in the occurrence of Hirschsprung’s disease(HSCR)remains unclear.Here,we found that the expression of an endogenous peptide derived from YBX1(termed PDYBX1 in this study)was upregulated in the aganglionic colonic tissue of HSCR patients,whereas its precursor protein YBX1 was downregulated.As shown by Transwell and cytoskeleton staining assays,silencing YBX1 inhibited the migration of enteric neural cells,and this effect was partially reversed after treatment with PDYBX1.Moreover,immunoprecipitation and immunofluorescence revealed that ERK2 bound to YBX1 and PDYBX1.Downregulation of YBX1 blocked the ERK1/2 pathway,but upregulation of PDYBX1 counteracted this effect by binding to ERK2,thereby promoting cell migration and proliferation.Taken together,the endogenous peptide PDYBX1 may partially alleviate the inhibition of the ERK1/2 pathway caused by the downregulation of its precursor protein YBX1 to antagonize the impairment of enteric neural cells.PDYBX1 may be exploited to design a novel potential therapeutic agent for HSCR.展开更多
Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive e...Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype(GAPEP),a unique subtype with a poor prognosis and frequent liver metastases.New substituted molecular(SM)classifications based on immunohistochemistry(IHC)are needed.Methods:According to the IHC staining results,we divided 582 cases into six types:mismatch repair deficient(dMMR),Epstein-Barr virus associated(EBVa),the primitive enterocyte phenotype(PEP),the epithelial mes-enchymal transition(EMT)phenotype,not otherwise specified/P53 mutated(NOS/P53m)and not otherwise specified/P53 wild-type(NOS/P53w).We analyzed the clinicopathological features,the immune microenviron-ment(PD-L1,CD8)and expression of HER2 and VEGFR2 of those types.Results:There were 31(5.3%)cases of the dMMR type,13(2.2%)cases of the EBVa type,44(7.6%)cases of the PEP type,122(21.0%)cases of the EMT type,127(21.8%)cases of the NOS/P53m type and 245(42.1%)cases of the NOS/P53w type.Patients with the dMMR type had the best survival(P<0.001).Patients with the EBVa type were younger(P<0.001)and had higher PD-L1 and CD8 expression(P<0.001)than other patients.Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis.Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients(P<0.001).Conclusion:Different SM classifications have different clinicopathological features and expression patterns,which indicate the probable clinical treatment strategies for these subtypes.展开更多
基金supported by the National Natural Science Foundation of China(82001590,81801496,and 82270540).
文摘Endogenous peptides,bioactive agents with a small molecular weight and outstanding absorbability,regulate various cellular processes and diseases.However,their role in the occurrence of Hirschsprung’s disease(HSCR)remains unclear.Here,we found that the expression of an endogenous peptide derived from YBX1(termed PDYBX1 in this study)was upregulated in the aganglionic colonic tissue of HSCR patients,whereas its precursor protein YBX1 was downregulated.As shown by Transwell and cytoskeleton staining assays,silencing YBX1 inhibited the migration of enteric neural cells,and this effect was partially reversed after treatment with PDYBX1.Moreover,immunoprecipitation and immunofluorescence revealed that ERK2 bound to YBX1 and PDYBX1.Downregulation of YBX1 blocked the ERK1/2 pathway,but upregulation of PDYBX1 counteracted this effect by binding to ERK2,thereby promoting cell migration and proliferation.Taken together,the endogenous peptide PDYBX1 may partially alleviate the inhibition of the ERK1/2 pathway caused by the downregulation of its precursor protein YBX1 to antagonize the impairment of enteric neural cells.PDYBX1 may be exploited to design a novel potential therapeutic agent for HSCR.
基金supported by the Peking Union Medical College Youth Fund(2017320030)the Beijing Hope Run Special Fund(No.LC2018A12),the CAMS Initiative for Innovative Medicine(CIFMS)(No.2016-I2M-3-005)+1 种基金the Medical and Health Science and Tech-nology Innovation Project of the Chinese Academy of Medical Sci-ences(2016-12M-1-007)the China International Medical Exchange Foundation Xiansheng Anti-Tumor Therapy Special Research Fund(cimf-f-h001-314).
文摘Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype(GAPEP),a unique subtype with a poor prognosis and frequent liver metastases.New substituted molecular(SM)classifications based on immunohistochemistry(IHC)are needed.Methods:According to the IHC staining results,we divided 582 cases into six types:mismatch repair deficient(dMMR),Epstein-Barr virus associated(EBVa),the primitive enterocyte phenotype(PEP),the epithelial mes-enchymal transition(EMT)phenotype,not otherwise specified/P53 mutated(NOS/P53m)and not otherwise specified/P53 wild-type(NOS/P53w).We analyzed the clinicopathological features,the immune microenviron-ment(PD-L1,CD8)and expression of HER2 and VEGFR2 of those types.Results:There were 31(5.3%)cases of the dMMR type,13(2.2%)cases of the EBVa type,44(7.6%)cases of the PEP type,122(21.0%)cases of the EMT type,127(21.8%)cases of the NOS/P53m type and 245(42.1%)cases of the NOS/P53w type.Patients with the dMMR type had the best survival(P<0.001).Patients with the EBVa type were younger(P<0.001)and had higher PD-L1 and CD8 expression(P<0.001)than other patients.Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis.Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients(P<0.001).Conclusion:Different SM classifications have different clinicopathological features and expression patterns,which indicate the probable clinical treatment strategies for these subtypes.
