Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells...Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. In this study, we investigated the effects of hMSCs on two human hepatoma cell lines （H7402 and HepG2） using an animal transplantation model, a co-culture system and conditioned media from hMSCs. Animal transplantation studies showed that the latent time for tumor formation was prolonged and that the tumor size was smaller when SCID mice were injected with H7402 cells and an equal number of Z3 hMSCs. When co-cultured with Z3 cells, H7402 cell proliferation decreased, apoptosis increased, and the expression of Bcl-2, c-Myc, proliferating cell nuclear antigen （PCNA） and survivin was downregulated. After treatment with conditioned media derived from Z3 hMSC cultures, H4702 cells showed decreased colony-forming ability and decreased proliferation. Immunoblot analysis showed that β-catenin, Bcl-2, c-Myc, PCNA and survivin expression was downregulated in H7402 and HepG2 cells. Taken together, our findings demonstrate that hMSCs inhibit the malignant phenotypes of the H7402 and HepG2 human liver cancer cell lines, which include proliferation, colony-forming ability and oncogene expression both in vitro and in vivo. Furthermore, our studies provide evidence that the Wnt signaling pathway may have a role in hMSC-mediated targeting and tumor cell inhibition.展开更多
BACKGROUND Upper arm lymphedema is a common complication one year after breast cancer surgery,which profoundly impacts patients'quality of life.CASE SUMMARY We reported a case of lymphedema induced by prolonged su...BACKGROUND Upper arm lymphedema is a common complication one year after breast cancer surgery,which profoundly impacts patients'quality of life.CASE SUMMARY We reported a case of lymphedema induced by prolonged sun exposure 11 years after breast cancer surgery.CONCLUSION Breast screening,patient education and follow-up after hospital discharge could help to prevent upper-arm lymphedema.展开更多
Objective:We assessed the longitudinal risk of developing cervical intraepithelial neoplasia(CINs)with self-sampling human papillomavirus(HPV)tests,based on polymerase chain reaction(PCR)and signal amplification(care ...Objective:We assessed the longitudinal risk of developing cervical intraepithelial neoplasia(CINs)with self-sampling human papillomavirus(HPV)tests,based on polymerase chain reaction(PCR)and signal amplification(care HPV),to explore the appropriate intervals for cervical cancer screening.Methods:A prospective study was conducted in China during 2017-2020.Participants were invited for PCR and care HPV tests with self-samples at baseline.Women positive in either HPV test underwent colposcopy and biopsy if necessary.Women with baseline CIN grade one(CIN1)or less were followed up over 3 years.The absolute risk was assessed by the immediate risk(IR)and cumulative risk(CR),and the relative risk was assessed by the hazard ratio(HR)with a 95%confidence interval(CI).Results:A total of 8,126 women were included in the final analysis.Women positive for the PCR HPV test had comparable IRs of CIN2+and CIN3+to those positive on the care HPV test.With triage by HPV genotyping,women with HPV 16/18 infection had the highest IRs of CIN2+(21.15%)and CIN3+(9.67%).For CR,women negative for PCR HPV test had a lower risk of CIN2+than that reported in women negative on care HPV test(0.57%versus 0.98%,HR=0.58,95%CI:0.38,0.87),but no significant difference was found in the CRs of CIN3+between them(0.25%versus 0.39%,HR=0.64,95%CI:0.34,1.20).Among women with CIN1 or less at baseline,women who were persistent or recurrent positive on care HPV or PCR HPV test had a higher risk of developing CIN3+(11.36%-14.59%),compared with women remained HPV negative from baseline throughout follow-up(≤0.28%).Conclusions:Routine screening with 3-year intervals is acceptable for self-sampling HPV tests based on PCR or care HPV test.Women positive on HPV16/18 triaging at baseline or with CIN1 or less at baseline while being per-sistent or recurrent positive on care HPV or PCR HPV test during 3-year follow-up require immediate colposcopy or treatment.展开更多
Objective:Death receptor 4(DR4;TRAIL-R1)critically mediates extrinsic apoptosis cascades via binding to TNF-related apoptosis-inducing ligand(TRAIL).However,intrinsic and/or acquired resistance are observed in the cli...Objective:Death receptor 4(DR4;TRAIL-R1)critically mediates extrinsic apoptosis cascades via binding to TNF-related apoptosis-inducing ligand(TRAIL).However,intrinsic and/or acquired resistance are observed in the clinical application of TRAIL.The aim of this study was to investigate the function and molecular mechanism of CD13 in the TRAIL/DR4 pathway against tumor cells,and provide a new strategy for improving therapeutic efficacy or overcoming TRAIL-resistance.Methods:TRAIL protein was expressed as a secretory protein in a Pichia pastoris expression system and was isolated and purified by affinity chromatography.The cell viability and apoptosis were evaluated with MTT(thiazolyl blue tetrazolium bromide)assays and annexin V-FITC/PI staining with flow cytometry analysis,respectively.Western blot analysis was used to detect the levels of the indicated proteins in tumor cells.DR4 degradation or stability was examined with cycloheximide chase assays,and cell surface DR4 was assessed with flow cytometric analysis after staining with a FITC-conjugated antibody.The effects of cell migration were determined with Transwell and gelatin zymography assays.A xenograft nude mouse model was used to detect the anti-tumor effect in vivo,and the proliferation in tumor tissues was examined with immunohistochemical staining.Results:CD13 inhibition potently sensitized tumor cells to TRAIL-induced killing,including proliferation inhibition,increased apoptosis,and migration suppression.In addition,the inhibition of CD13 elevated both total cellular expression and cell surface DR4 through stabilizing DR4 by suppressing its degradation.DR4 si RNA attenuated the enhanced anti-tumor effects of TRAIL plus CD13 inhibition.Interestingly,these phenomena were p-ERK1/2 independent,although p-ERK1/2 down-regulation was tightly correlated with the cooperation of TRAIL and CD13 inhibition.Moreover,a synergistic decrease in tumor growth was surprisingly achieved in the xenograft model by treatment of TRAIL with a CD13 inhibitor(**P<0.01,CDI=0.47).Conclusions:CD13 inhibition cooperates with TRAIL in enhancing DR4-mediated cell death,through the up-regulation and stabilization of DR4 in a p-ERK1/2-independent manner.Thus CD13 inhibition has emerged as an effective strategy for TRAIL/DR4-based therapy.展开更多
Multidrug resistance （MDR） is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein （LRP）, a non-ATP-binding cassette （ABC） transporter, is high in tumor cells, resulting...Multidrug resistance （MDR） is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein （LRP）, a non-ATP-binding cassette （ABC） transporter, is high in tumor cells, resulting in their resistance to a variety of cytotoxic drugs. However, the function of LRP in tumor drug resistance is not yet explicit. Our previous studies had shown that Kinesin KIF4A was overexpressed in cisplatin （DDP）-resistant human lung adenocarcinoma cells （A549/DDP cells） compared with A549 cells. The expression of KIF4A in A549 or A549/DDP cells significantly affects cisplatin resistance but the detailed mechanisms remain unclear. Here, we performed co-immunoprecipitation experiments to show that the tail domain of KIF4A interacted with the N-terminal of LRP. Immunofluorescence images showed that both the ability of binding to LRP and the motility of KIF4A were essential for the dispersed cytoplasm distribution of LRP. Altogether, our results shed light on a potential mechanism in that motor protein KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane. Thus KIF4A might be a cisplatin resistance-associated protein and serves as a potential target for chemotherapeutic drug resistance in lung cancer.展开更多
基金This work was supported by grants from the National Basic Research Program of China （973 Program, No. 2007CB914800 to Xiaodong Zhang）, National Natural Science Foundation of China （No. 30570698 to Xiaodong Zhang） and Tianjin Natural Scientific Foundation （No. 033801211 to Xiaodong Zhang）.
文摘Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. In this study, we investigated the effects of hMSCs on two human hepatoma cell lines （H7402 and HepG2） using an animal transplantation model, a co-culture system and conditioned media from hMSCs. Animal transplantation studies showed that the latent time for tumor formation was prolonged and that the tumor size was smaller when SCID mice were injected with H7402 cells and an equal number of Z3 hMSCs. When co-cultured with Z3 cells, H7402 cell proliferation decreased, apoptosis increased, and the expression of Bcl-2, c-Myc, proliferating cell nuclear antigen （PCNA） and survivin was downregulated. After treatment with conditioned media derived from Z3 hMSC cultures, H4702 cells showed decreased colony-forming ability and decreased proliferation. Immunoblot analysis showed that β-catenin, Bcl-2, c-Myc, PCNA and survivin expression was downregulated in H7402 and HepG2 cells. Taken together, our findings demonstrate that hMSCs inhibit the malignant phenotypes of the H7402 and HepG2 human liver cancer cell lines, which include proliferation, colony-forming ability and oncogene expression both in vitro and in vivo. Furthermore, our studies provide evidence that the Wnt signaling pathway may have a role in hMSC-mediated targeting and tumor cell inhibition.
文摘BACKGROUND Upper arm lymphedema is a common complication one year after breast cancer surgery,which profoundly impacts patients'quality of life.CASE SUMMARY We reported a case of lymphedema induced by prolonged sun exposure 11 years after breast cancer surgery.CONCLUSION Breast screening,patient education and follow-up after hospital discharge could help to prevent upper-arm lymphedema.
基金supported by the China Med-ical Board(grant number:16-255)the National Key R&D Program of China(grant number:2018YFC1315504)the National Natural Sci-ence Foundation of China(grant number:81761128006).
文摘Objective:We assessed the longitudinal risk of developing cervical intraepithelial neoplasia(CINs)with self-sampling human papillomavirus(HPV)tests,based on polymerase chain reaction(PCR)and signal amplification(care HPV),to explore the appropriate intervals for cervical cancer screening.Methods:A prospective study was conducted in China during 2017-2020.Participants were invited for PCR and care HPV tests with self-samples at baseline.Women positive in either HPV test underwent colposcopy and biopsy if necessary.Women with baseline CIN grade one(CIN1)or less were followed up over 3 years.The absolute risk was assessed by the immediate risk(IR)and cumulative risk(CR),and the relative risk was assessed by the hazard ratio(HR)with a 95%confidence interval(CI).Results:A total of 8,126 women were included in the final analysis.Women positive for the PCR HPV test had comparable IRs of CIN2+and CIN3+to those positive on the care HPV test.With triage by HPV genotyping,women with HPV 16/18 infection had the highest IRs of CIN2+(21.15%)and CIN3+(9.67%).For CR,women negative for PCR HPV test had a lower risk of CIN2+than that reported in women negative on care HPV test(0.57%versus 0.98%,HR=0.58,95%CI:0.38,0.87),but no significant difference was found in the CRs of CIN3+between them(0.25%versus 0.39%,HR=0.64,95%CI:0.34,1.20).Among women with CIN1 or less at baseline,women who were persistent or recurrent positive on care HPV or PCR HPV test had a higher risk of developing CIN3+(11.36%-14.59%),compared with women remained HPV negative from baseline throughout follow-up(≤0.28%).Conclusions:Routine screening with 3-year intervals is acceptable for self-sampling HPV tests based on PCR or care HPV test.Women positive on HPV16/18 triaging at baseline or with CIN1 or less at baseline while being per-sistent or recurrent positive on care HPV or PCR HPV test during 3-year follow-up require immediate colposcopy or treatment.
基金supported by grants from the Beijing Natural Science Foundation(Grant No.7202132)CAMS Innovation Fund for Medical Sciences(CIFMS+1 种基金Grant No.2016-I2M-02-002)“Significant New Drug Development”Major Science and Technology Development Projects of China(Grant No.2018ZX09711001-007-002)。
文摘Objective:Death receptor 4(DR4;TRAIL-R1)critically mediates extrinsic apoptosis cascades via binding to TNF-related apoptosis-inducing ligand(TRAIL).However,intrinsic and/or acquired resistance are observed in the clinical application of TRAIL.The aim of this study was to investigate the function and molecular mechanism of CD13 in the TRAIL/DR4 pathway against tumor cells,and provide a new strategy for improving therapeutic efficacy or overcoming TRAIL-resistance.Methods:TRAIL protein was expressed as a secretory protein in a Pichia pastoris expression system and was isolated and purified by affinity chromatography.The cell viability and apoptosis were evaluated with MTT(thiazolyl blue tetrazolium bromide)assays and annexin V-FITC/PI staining with flow cytometry analysis,respectively.Western blot analysis was used to detect the levels of the indicated proteins in tumor cells.DR4 degradation or stability was examined with cycloheximide chase assays,and cell surface DR4 was assessed with flow cytometric analysis after staining with a FITC-conjugated antibody.The effects of cell migration were determined with Transwell and gelatin zymography assays.A xenograft nude mouse model was used to detect the anti-tumor effect in vivo,and the proliferation in tumor tissues was examined with immunohistochemical staining.Results:CD13 inhibition potently sensitized tumor cells to TRAIL-induced killing,including proliferation inhibition,increased apoptosis,and migration suppression.In addition,the inhibition of CD13 elevated both total cellular expression and cell surface DR4 through stabilizing DR4 by suppressing its degradation.DR4 si RNA attenuated the enhanced anti-tumor effects of TRAIL plus CD13 inhibition.Interestingly,these phenomena were p-ERK1/2 independent,although p-ERK1/2 down-regulation was tightly correlated with the cooperation of TRAIL and CD13 inhibition.Moreover,a synergistic decrease in tumor growth was surprisingly achieved in the xenograft model by treatment of TRAIL with a CD13 inhibitor(**P<0.01,CDI=0.47).Conclusions:CD13 inhibition cooperates with TRAIL in enhancing DR4-mediated cell death,through the up-regulation and stabilization of DR4 in a p-ERK1/2-independent manner.Thus CD13 inhibition has emerged as an effective strategy for TRAIL/DR4-based therapy.
基金Project supported by the National Natural Science Foundation of China(Nos.31271485 and 31301138)the Tianjin Research Program of Application Foundation and Advanced Technology(No.12JC 2DJC21400)+3 种基金the Doctor Foundation of Tianjin Normal University(Nos.52XB1104 and 52XB1005)the Joint Funds of the Xinjiang Uygur Autonomous Region Natural Science Foundation(No.2016 D01C375)the Program for New Century Excellent Talents in University in China(No.NCET-11-1066)the State Key Laboratory of Molecular Oncology(No.SKL-KF-2017-18),China
文摘Multidrug resistance （MDR） is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein （LRP）, a non-ATP-binding cassette （ABC） transporter, is high in tumor cells, resulting in their resistance to a variety of cytotoxic drugs. However, the function of LRP in tumor drug resistance is not yet explicit. Our previous studies had shown that Kinesin KIF4A was overexpressed in cisplatin （DDP）-resistant human lung adenocarcinoma cells （A549/DDP cells） compared with A549 cells. The expression of KIF4A in A549 or A549/DDP cells significantly affects cisplatin resistance but the detailed mechanisms remain unclear. Here, we performed co-immunoprecipitation experiments to show that the tail domain of KIF4A interacted with the N-terminal of LRP. Immunofluorescence images showed that both the ability of binding to LRP and the motility of KIF4A were essential for the dispersed cytoplasm distribution of LRP. Altogether, our results shed light on a potential mechanism in that motor protein KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane. Thus KIF4A might be a cisplatin resistance-associated protein and serves as a potential target for chemotherapeutic drug resistance in lung cancer.
