Lung cancer is featured with high mortality,with a 15%five-year survival rate worldwide.Genetic alterations,such as loss of function of tumor suppressor genes,frequently contribute to lung cancer initiation,progressio...Lung cancer is featured with high mortality,with a 15%five-year survival rate worldwide.Genetic alterations,such as loss of function of tumor suppressor genes,frequently contribute to lung cancer initiation,progression and metastasis.Liver kinase B1(LKB1),as a serine/threonine kinase and tumor suppressor,is frequently mutated and inactivated in non-small cell lung cancer(NSCLC).Recent studies have provided strong evidences that LKB1 loss promotes lung cancerigenesis process,especially lung cancer progression and metastasis.This review will summarize recent progress on how LKB1 modulates the process of lung cancerigenesis,emphasizing on LKB1 downstream signaling pathways and biological functions.We will further discuss the potential development of prognostic biomarkers or therapeutic targets in lung cancer clinic based on the molecular alteration associated with deregulated LKB1 signaling.展开更多
Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monito...Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.展开更多
Cancer cell metabolism reprogramming is one of the hallmarks of cancer.Cancer cells preferentially utilize aerobic glycolysis,which is regulated by activated oncogenes and the tumor microenvironment.Extracellular matr...Cancer cell metabolism reprogramming is one of the hallmarks of cancer.Cancer cells preferentially utilize aerobic glycolysis,which is regulated by activated oncogenes and the tumor microenvironment.Extracellular matrix(ECM)in the tumor microenvironment,including the basement membranes(BMs),is dynamically remodeled.However,whether and how ECM regulates tumor glycolysis is largely unknown.We show that type IV collagens,components of BMs essential for the tissue integrity and proper function,are differentially expressed in breast cancer subtypes thatα5 chain(α5(IV))is preferentially expressed in the luminal-type breast cancer and is regulated by estrogen receptor-α.α5(IV)is indispensable for luminal breast cancer development.Ablation ofα5(IV)significantly reduces the growth of luminal-type breast cancer cells and impedes the development of luminal-type breast cancer.Impaired cell growth and tumor development capability ofα5(IV)-ablated luminal breast cancer cells is attributed to the reduced expression of glucose transporter and glycolytic enzymes and impaired glycolysis in luminal breast cancer cells.Non-integrin collagen receptor discoidin domain receptor-1(DDR1)expression and p38 mitogen-activated protein kinase activation are attenuated inα5(IV)-ablated luminal breast cancer cells,resulting in reduced c-Myc oncogene expression and phosphorylation.Ectopic expression of constitutively active DDR1 or c-Myc restores the expression of glucose transporter and glycolytic enzymes,and thereafter restores aerobic glycolysis,cell proliferation,and tumor growth of luminal breast cancer.Thus,type IV collagenα5 chain is a luminal-type breast cancer-specific microenvironmental regulator modulating cancer cell metabolism.展开更多
Breast cancer is the second most common type of cancer and the leading cause of cancer death in women worldwide. Adjuvant tamoxifen therapy significantly slows down estrogen receptor （ER）-positive breast cancer prog...Breast cancer is the second most common type of cancer and the leading cause of cancer death in women worldwide. Adjuvant tamoxifen therapy significantly slows down estrogen receptor （ER）-positive breast cancer progression, prolongs diseasefree survival, and contributes to the decrease in breast cancer mortality （Musgrove and Sutherland, 2009）. However, majority of the death from breast cancer is due to metastasis that is resistant to therapy （Musgrove and Sutherland, 2009）.展开更多
Enzymes involved in collagen biosynthesis, including lysyl oxidase （LOX）, have been proposed as potential therapeutic targets for idio- pathic pulmonary fibrosis. LOX expression is significantly upregulated in bleom...Enzymes involved in collagen biosynthesis, including lysyl oxidase （LOX）, have been proposed as potential therapeutic targets for idio- pathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin （BLM）-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory ceU infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expres- sion of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subse- quent fibrosis process after lung injury.展开更多
Dear Editor,T-cell infection by SARS-CoV-2 and associated immune responses are correlated with disease severity and prognosis of COVID-19.Lymphopenia is associated with increased disease severity in COVID-19.Significa...Dear Editor,T-cell infection by SARS-CoV-2 and associated immune responses are correlated with disease severity and prognosis of COVID-19.Lymphopenia is associated with increased disease severity in COVID-19.Significantly lower circulating T and B cell counts were observed in patients who died from COVID-19 compared with survivors.Moreover,SARS-CoV-2 infection causes aberrant lymphocyte activation and dysfunction.展开更多
Dear Editor,T cells recognize and eliminate cancer cells.Prolonged survival of cancer patients is associated with not only intratumoral T cell infiltration but also the functional status of infiltrated T cells(Galon a...Dear Editor,T cells recognize and eliminate cancer cells.Prolonged survival of cancer patients is associated with not only intratumoral T cell infiltration but also the functional status of infiltrated T cells(Galon and Bruni,2020).The immune contexture,including the number and functionality of T cells,is modulated by the tumor microenvironment(Joyce and Fearon,2015;Galon and Bruni,2020).展开更多
A non-radioisotopic method was developed for the assay of epidermal growth factor receptor (EGFR). A peptide with twenty amino acid residues around Tyr 1173, the major phosphorylation site of EGFR, was cloned as a GST...A non-radioisotopic method was developed for the assay of epidermal growth factor receptor (EGFR). A peptide with twenty amino acid residues around Tyr 1173, the major phosphorylation site of EGFR, was cloned as a GST fusion protein and used as substrate. Anti-phosphoty-rosine monoclonal antibody PY99 was used for the determination of the extent of phosphorylation. Both the specificity and the sensitivity were substantially higher than that of the existing method. Km value of the fusion protein is much lower (10 μmol/L) than that of the synthetic peptide (110 μmol/L). The method can be applied to the measurement of the tyrosine kinase activity of c-erb B2 (Neu/HER2).展开更多
基金the National Basic Research Program of China(Grant No.2010CB912102)the National Natural Science Foundation of China(Grant Nos.30871284,30971461 and 30971495)the Science and Technology Commission of Shanghai Municipality(No.09JC1416300)。
文摘Lung cancer is featured with high mortality,with a 15%five-year survival rate worldwide.Genetic alterations,such as loss of function of tumor suppressor genes,frequently contribute to lung cancer initiation,progression and metastasis.Liver kinase B1(LKB1),as a serine/threonine kinase and tumor suppressor,is frequently mutated and inactivated in non-small cell lung cancer(NSCLC).Recent studies have provided strong evidences that LKB1 loss promotes lung cancerigenesis process,especially lung cancer progression and metastasis.This review will summarize recent progress on how LKB1 modulates the process of lung cancerigenesis,emphasizing on LKB1 downstream signaling pathways and biological functions.We will further discuss the potential development of prognostic biomarkers or therapeutic targets in lung cancer clinic based on the molecular alteration associated with deregulated LKB1 signaling.
基金supported by the Lingang Laboratory (LG202103-02-03)National Natural Science Foundation of China (82173832,81973345 and 82104199)+2 种基金the State Key Laboratory of Drug Research (SIMM2205KF-05)Science and Technology Commission of Shanghai Municipality (22ZR1474400)“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”,Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020111).
文摘Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.
基金supported by grants from the Ministry of Science and Technology of China(2020YFA0803203)the National Natural Science Foundation of China(81430067,32070789,and 31900514).
文摘Cancer cell metabolism reprogramming is one of the hallmarks of cancer.Cancer cells preferentially utilize aerobic glycolysis,which is regulated by activated oncogenes and the tumor microenvironment.Extracellular matrix(ECM)in the tumor microenvironment,including the basement membranes(BMs),is dynamically remodeled.However,whether and how ECM regulates tumor glycolysis is largely unknown.We show that type IV collagens,components of BMs essential for the tissue integrity and proper function,are differentially expressed in breast cancer subtypes thatα5 chain(α5(IV))is preferentially expressed in the luminal-type breast cancer and is regulated by estrogen receptor-α.α5(IV)is indispensable for luminal breast cancer development.Ablation ofα5(IV)significantly reduces the growth of luminal-type breast cancer cells and impedes the development of luminal-type breast cancer.Impaired cell growth and tumor development capability ofα5(IV)-ablated luminal breast cancer cells is attributed to the reduced expression of glucose transporter and glycolytic enzymes and impaired glycolysis in luminal breast cancer cells.Non-integrin collagen receptor discoidin domain receptor-1(DDR1)expression and p38 mitogen-activated protein kinase activation are attenuated inα5(IV)-ablated luminal breast cancer cells,resulting in reduced c-Myc oncogene expression and phosphorylation.Ectopic expression of constitutively active DDR1 or c-Myc restores the expression of glucose transporter and glycolytic enzymes,and thereafter restores aerobic glycolysis,cell proliferation,and tumor growth of luminal breast cancer.Thus,type IV collagenα5 chain is a luminal-type breast cancer-specific microenvironmental regulator modulating cancer cell metabolism.
基金Supplementary material is available at Journal of Molecular Cell Biology online. We thank Drs Mien-Chie Hung （M. D. Anderson Cancer Center）, Kou-Juey Wu （National Yang-Ming University）, and Jeong Hoon Kim （Sungkyunkwan University） for sharing reagents. This work was supported by National Basic Research Program of China （2010CB912102 and 2010CB529703） and National Natural Science Foundation of China （31190061 and 31371408）. G.G. is SA-SIBS scholar.
文摘Breast cancer is the second most common type of cancer and the leading cause of cancer death in women worldwide. Adjuvant tamoxifen therapy significantly slows down estrogen receptor （ER）-positive breast cancer progression, prolongs diseasefree survival, and contributes to the decrease in breast cancer mortality （Musgrove and Sutherland, 2009）. However, majority of the death from breast cancer is due to metastasis that is resistant to therapy （Musgrove and Sutherland, 2009）.
基金This work was supported by the National Basic Research Program of China （2010CB912102 and 2010CB529703） and the National Natural Science Foundation of China （31190061, 31371408, and 81430067）. G.G. is a scholar of the SA-SIBS Scholarship Program.
文摘Enzymes involved in collagen biosynthesis, including lysyl oxidase （LOX）, have been proposed as potential therapeutic targets for idio- pathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin （BLM）-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory ceU infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expres- sion of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subse- quent fibrosis process after lung injury.
基金This research was supported by the National Key R&D Program of China(2020YFA0509000 to J.C.)the National Natural Science Foundation of China(32030024,31830112,and 31525016 to J.C.,92169112 and 82161138002 to S.J.)+2 种基金Program of Shanghai Academic Research Leader(19XD1404200)Shanghai Municipal Science and Technology Major Project(ZD2021CY001 to S.J)National Ten Thousand Talents Program.The authors gratefully acknowledge the support of the SA-SIBS scholarship program.
文摘Dear Editor,T-cell infection by SARS-CoV-2 and associated immune responses are correlated with disease severity and prognosis of COVID-19.Lymphopenia is associated with increased disease severity in COVID-19.Significantly lower circulating T and B cell counts were observed in patients who died from COVID-19 compared with survivors.Moreover,SARS-CoV-2 infection causes aberrant lymphocyte activation and dysfunction.
基金supported by grants from the Ministry of Science and Technology of China(2020YFA0803203)the National Natural Science Foundation of China(32070789 and 81430067).
文摘Dear Editor,T cells recognize and eliminate cancer cells.Prolonged survival of cancer patients is associated with not only intratumoral T cell infiltration but also the functional status of infiltrated T cells(Galon and Bruni,2020).The immune contexture,including the number and functionality of T cells,is modulated by the tumor microenvironment(Joyce and Fearon,2015;Galon and Bruni,2020).
基金the fund of Chinese Academy of Sciences (Grant No. KJ952-S1-15).
文摘A non-radioisotopic method was developed for the assay of epidermal growth factor receptor (EGFR). A peptide with twenty amino acid residues around Tyr 1173, the major phosphorylation site of EGFR, was cloned as a GST fusion protein and used as substrate. Anti-phosphoty-rosine monoclonal antibody PY99 was used for the determination of the extent of phosphorylation. Both the specificity and the sensitivity were substantially higher than that of the existing method. Km value of the fusion protein is much lower (10 μmol/L) than that of the synthetic peptide (110 μmol/L). The method can be applied to the measurement of the tyrosine kinase activity of c-erb B2 (Neu/HER2).
