Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the...Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the tumor microenvironment.Beyond acting as a physical barrier,it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance.With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation,we discovered that fibronectin extra domain A(FN-EDA)derived from cancer-associated fibroblasts played a critical role in sorafenib resistance.Mechanistically,FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway,thereby countering the oxidative stress induced by sorafenib.Moreover,we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model,which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues,and through the analysis of HCC samples obtained from The Cancer Genome Atlas(TCGA)database.Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.展开更多
Oral squamous cell carcinoma(OSCC)is the most common type of oral malignancy,and metastasis accounts for the poor prognosis of OSCC.Autophagy is considered to facilitate OSCC development by mitigating various cellular...Oral squamous cell carcinoma(OSCC)is the most common type of oral malignancy,and metastasis accounts for the poor prognosis of OSCC.Autophagy is considered to facilitate OSCC development by mitigating various cellular stresses;nevertheless,the mechanisms of autophagy in OSCC cell proliferation and metastasis remain unknown.In our study,high-sensitivity label-free quantitative proteomics analysis revealed nuclear protein 1(NUPR1)as the most significantly upregulated protein in formalin-fixed paraffin-embedded tumour samples derived from OSCC patients with or without lymphatic metastasis.展开更多
In the process of checking the raw data1,the authors noticed several inadvertent mistakes occurring in Fig.5a,b,c,d,f that need to be corrected after online publication of the article.During the preparation of Fig.5,t...In the process of checking the raw data1,the authors noticed several inadvertent mistakes occurring in Fig.5a,b,c,d,f that need to be corrected after online publication of the article.During the preparation of Fig.5,the representative image showing TFE3 overexpression antagonized the NUPR1 KD-induced inhibition of OSCC cell proliferation and metastasis,were pasted and placed by mistake.The correct results should be as shown below.The authors apologize for these oversights and declare that these corrections do not affect the description,interpretation,or conclusions detailed in the original manuscript.展开更多
基金supported in part by the National Natural Science Foundation of China (No.81672856,82203669,81803028)the General Program of Chongqing Natural Science Foundation (China) (No.cstc2021jcyj-msxmX0687).
文摘Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the tumor microenvironment.Beyond acting as a physical barrier,it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance.With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation,we discovered that fibronectin extra domain A(FN-EDA)derived from cancer-associated fibroblasts played a critical role in sorafenib resistance.Mechanistically,FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway,thereby countering the oxidative stress induced by sorafenib.Moreover,we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model,which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues,and through the analysis of HCC samples obtained from The Cancer Genome Atlas(TCGA)database.Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.
基金This work was supported by the National Natural Science Foundation of China(81802716,32000552)the Natural Science Fund of Hunan Province of China(2020JJ5804)+3 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-5-037)Shanghai Clinical Research Center for Oral Diseases(19MC1910600)Shanghai Municipal Key Clinical Specialty(shslczdzk01601)Emerging Frontier Technology Joint Research Project(SHDC12018104),the project from Hainan Province Clinical Medical Center.
文摘Oral squamous cell carcinoma(OSCC)is the most common type of oral malignancy,and metastasis accounts for the poor prognosis of OSCC.Autophagy is considered to facilitate OSCC development by mitigating various cellular stresses;nevertheless,the mechanisms of autophagy in OSCC cell proliferation and metastasis remain unknown.In our study,high-sensitivity label-free quantitative proteomics analysis revealed nuclear protein 1(NUPR1)as the most significantly upregulated protein in formalin-fixed paraffin-embedded tumour samples derived from OSCC patients with or without lymphatic metastasis.
文摘In the process of checking the raw data1,the authors noticed several inadvertent mistakes occurring in Fig.5a,b,c,d,f that need to be corrected after online publication of the article.During the preparation of Fig.5,the representative image showing TFE3 overexpression antagonized the NUPR1 KD-induced inhibition of OSCC cell proliferation and metastasis,were pasted and placed by mistake.The correct results should be as shown below.The authors apologize for these oversights and declare that these corrections do not affect the description,interpretation,or conclusions detailed in the original manuscript.
