Hippo/YAP signaling pathway is involved in osteosarcoma chemoresistance

Background:Osteosarcoma is the most common bone malignancy in children and adolescents,and 20%-30%of the patients suffer from poor prognosis because of individual chemoresistance.The Hippo/yes-associated protein(YAP) signaling pathway has been shown to play a role in tumor chemoresistance,but no previous report has focused on its involvement in osteosarcoma chemoresistance.This study aimed to investigate the role of the Hippo/YAP signaling pathway in osteosarcoma chemoresistance and to determine potential treatment targets.Methods:Using the Cell Titer-Glo Luminescent cell viability assay and flow cytometry analysis,we determined the proliferation and chemosensitivity of YAP-overexpressing and YAP-knockdown osteosarcoma cells.In addition,using western blotting and the real-time polymerase chain reaction technique,we investigated the alteration of the Hippo/YAP signaling pathway in osteosarcoma cells treated with chemotherapeutic agents.Results:Mammalian sterile 20-like kinase 1(MST1) degradation was increased,and large tumor suppressor kinase1/2(LAT51/2) total protein levels were decreased by methotrexate and doxorubicin,which increased activation and nuclear translocation of YAP.Moreover,YAP increased the proliferation and chemoresistance of MG63 cells.Conclusions:The Hippo/YAP signaling pathway plays a role in osteosarcoma chemoresistance,and YAP is a potential target for reducing chemoresistance.

Maternal Thyroid-Stimulating Hormone Level and Thyroid Peroxidase Antibody Status in the First and Second Trimester of Pregnancy and Their Relationship with the Risk of Gestational Diabetes Mellitus

Objective:To investigate thyroid-stimulating hormone(TSH)levels and thyroid peroxidase antibody(TPOAb)in early pregnancy and to estimate the risk of development of gestational diabetes mellitus(GDM).Methods:The levels of TSH,free thyroxine,free triiodothyronine,and TPOAb were retrospectively evaluated in 2333 pregnant women.All women recruited were divided into groups of TSH high(H),TSH low(L),TSH(H)TPOAb positive(+),TSH(H)TPOAb negative(-),TSH normal(N)TPOAb(+),TSH(L)TPOAb(+),TSH(L)TPOAb(-),and estimated the risk of GDM.Results:TSH level(X^(2)=13.0024,P=0.0015)and TSH combined TPOAb(X^(2)=20.0038,P=0.0012)were correlated to development of GDM.The level of TSH in 95 women was increased,and in 216 women were decreased.Of the 2333 pregnant women,546 patients were diagnosed with GDM,with a prevalence of 23.40%.The prevalence of GDM was 35.78%and 28.70%for the TSH high(H)and TSH low(L)pregnant women,respectively.The increased TSH(P=0.0013,odds ratio:2.09,confidence interval:1.34-3.28)was correlated to increase GDM incidence.TSH(H)TPOAb(+)(n=29),TSH(H)TPOAb(-)(n=58),TSH normal(N)TPOAb(+)(n=265),TSH(L)TPOAb(+)(n=30),TSH(L)TPOAb(-)(n=154)were in this study.The prevalence of GDM was 51.72%,29.31%,23.02%,26.67%,and 29.87%for the TSH(H)TPOAb(+),TSH(H)TPOAb(-),TSH(N)TPOAb(+),TSH(L)TPOAb(+),and TSH(L)TPOAb(-)pregnant women,respectively.Only the TSH(H)TPOAb(+)pregnant women had a significant higher incidence of GDM(P=0.0018,odds ratio:3.63,confidence interval:1.62-8.16).Trimester specific results showed that only second trimester had higher GDM risk either analyze TSH or the combination of TSH and TPOAb.Conclusion:Elevated TSH level and TPOAb positive in the second trimester of pregnancy were correlated to an increased risk of GDM.