Dear Editor,Signet-ring cell carcinoma(SRCC)is a rare subtype of colorectal cancer(CRC)characterized histologically by the accumulation of mucins in the cytoplasm and displacement of nuclei to the cellular periphery,a...Dear Editor,Signet-ring cell carcinoma(SRCC)is a rare subtype of colorectal cancer(CRC)characterized histologically by the accumulation of mucins in the cytoplasm and displacement of nuclei to the cellular periphery,accounting for about 1%CRC(Fig.S1A)(Borger et al.,2007).Compare to common subtypes of CRC,such as adenocarcinoma(AC)and mucinous adenocarcinoma(MAC),SRCC is associated with aggressive behaviors and younger age at presentation(Kang et al.,2005;Sung et al.,2008;Nitsche et al.,2013;Hugen et al.,2014;Inamura et al.,2015).A retrospective analysis of CRC patient's data at Fudan University Shanghai Cancer Center(FUSCC)also indicated a worse overall and disease-free survival of SRCC patients(Fig.S1B and S1C,Table S1).展开更多
Systemic lupus erythematosus(SLE)is a systemic autoimmune disease,and the pathogenesis of SLE has not been fully elucidated.The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor tha...Systemic lupus erythematosus(SLE)is a systemic autoimmune disease,and the pathogenesis of SLE has not been fully elucidated.The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor that can promote the ubiquitination and subsequent degradation of various oncoproteins;however,the potential role of FBXW7 in autoimmune diseases is unclear.In the present study,we identified that FBXW7 is a crucial exacerbating factor for SLE development and progression in a mouse model induced by 2,6,10,14-tetramethylpentadecane(TMPD).Myeloid cell-specific FBXW7-deficient(Lysm+FBXW7f/f)C57BL/6 mice showed decreased immune complex accumulation,glomerulonephritis,glomerular mesangial cell proliferation,and basemembrane thickness in the kidney.Lysm+FBXW7f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells.In Lysm+FBXW7f/f mice,we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chi inflammatory monocytes were recruited to the peritoneal cavity.Consistently,diffuse pulmonary hemorrhage(DPH)was also decreased in Lysm+FBXW7f/f mice.Mechanistically,we clarified that FBXW7 promoted TMPD-induced cell apoptosis by catalyzing MCL1 degradation through K48-linked ubiquitination.Our work revealed that FBXW7 expression in myeloid cells played a crucial role in TMPD-induced SLE progression in mice,which may provide novel ideas and theoretical support for understanding the pathogenesis of SLE.展开更多
基金This study is supported by grants from the National Natural Science Foundation of China(81622038,31571479,and 81772965 to F.X.Y.,31470826 and 31670858 to G.H.)the National key R&D program of China(2018YFA0800304)to F.X.Y.,Science and Technology Commission of Shanghai Municipality(19JC1411100 to F.X.Y.,16411966300 to G.H.,16411966300 and 18401933402 to J.R)Shanghai Municipal Commission of Health and Family Planning(2017BR018 to F.X.Y.)and Shanghai Sailing Program(19YF1409500 to Y.L.).We would like to thank Dr.Kang Chen for proofreading of this manuscript.
文摘Dear Editor,Signet-ring cell carcinoma(SRCC)is a rare subtype of colorectal cancer(CRC)characterized histologically by the accumulation of mucins in the cytoplasm and displacement of nuclei to the cellular periphery,accounting for about 1%CRC(Fig.S1A)(Borger et al.,2007).Compare to common subtypes of CRC,such as adenocarcinoma(AC)and mucinous adenocarcinoma(MAC),SRCC is associated with aggressive behaviors and younger age at presentation(Kang et al.,2005;Sung et al.,2008;Nitsche et al.,2013;Hugen et al.,2014;Inamura et al.,2015).A retrospective analysis of CRC patient's data at Fudan University Shanghai Cancer Center(FUSCC)also indicated a worse overall and disease-free survival of SRCC patients(Fig.S1B and S1C,Table S1).
基金This work was supported by the National Natural Science Foundation of China(81771699,31870907,and 81571524)Natural Science Foundation of Zhejiang Province(Z19H100001)National Key Basic Research Program of China(2014CB542101).
文摘Systemic lupus erythematosus(SLE)is a systemic autoimmune disease,and the pathogenesis of SLE has not been fully elucidated.The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor that can promote the ubiquitination and subsequent degradation of various oncoproteins;however,the potential role of FBXW7 in autoimmune diseases is unclear.In the present study,we identified that FBXW7 is a crucial exacerbating factor for SLE development and progression in a mouse model induced by 2,6,10,14-tetramethylpentadecane(TMPD).Myeloid cell-specific FBXW7-deficient(Lysm+FBXW7f/f)C57BL/6 mice showed decreased immune complex accumulation,glomerulonephritis,glomerular mesangial cell proliferation,and basemembrane thickness in the kidney.Lysm+FBXW7f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells.In Lysm+FBXW7f/f mice,we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chi inflammatory monocytes were recruited to the peritoneal cavity.Consistently,diffuse pulmonary hemorrhage(DPH)was also decreased in Lysm+FBXW7f/f mice.Mechanistically,we clarified that FBXW7 promoted TMPD-induced cell apoptosis by catalyzing MCL1 degradation through K48-linked ubiquitination.Our work revealed that FBXW7 expression in myeloid cells played a crucial role in TMPD-induced SLE progression in mice,which may provide novel ideas and theoretical support for understanding the pathogenesis of SLE.
