人核仁磷酸化蛋白1(Nucleolar and coiledbody phosphoprotein 1,NOLC1)在癌症的发生发展过程中起着至关重要的调控作用,为探讨NOLC1对肺癌细胞的作用,本研究通过Gateway系统构建重组NOLC1腺病毒载体,成功包装NOLC1腺病毒后,分别感染正...人核仁磷酸化蛋白1(Nucleolar and coiledbody phosphoprotein 1,NOLC1)在癌症的发生发展过程中起着至关重要的调控作用,为探讨NOLC1对肺癌细胞的作用,本研究通过Gateway系统构建重组NOLC1腺病毒载体,成功包装NOLC1腺病毒后,分别感染正常人类胚胎肺细胞(HEL)和非小细胞肺癌细胞(A549细胞),过表达NOLC1。通过MTT实验、AnnexinV-APC/PI双染法和线粒体膜电位实验,证明与HEL细胞相比,NOLC1的过表达对A549细胞的活性降低、凋亡增加、线粒体膜电位下降影响较为显著;通过Real-time PCR检测Caspase家族、TNF与受体家族和BCL2家族基因的表达,发现过表达NOLC1明显上调了A549细胞中促凋亡基因的表达,下调了抗凋亡基因的表达,其中两种重要的促凋亡蛋白CASP8和BAX均显著上调,但是在HEL细胞中这种影响不明显。研究结果表明过表达NOLC1蛋白通过对线粒体通路和死亡受体通路的共同作用,对非小细胞癌具有显著的抗肿瘤活性。展开更多
Although many tumor markers have been identified and studied in epithelial ovarian cancer,a potential and useful screening marker for ovarian cancer has not been yet clearly established. Ovarian cancer is considered a...Although many tumor markers have been identified and studied in epithelial ovarian cancer,a potential and useful screening marker for ovarian cancer has not been yet clearly established. Ovarian cancer is considered as a "silent killer"because of the absence of specific symptoms until late stage. Several validated biomarkers are currently used to diagnose and monitor the progression of the cancer,but very few of them show adequate specificity and sensitivity for different population screening. There is therefore an urge need to find biomarkers with high diagnostic accuracy and set up screening programs which can help detect ovarian cancer early,predict the response of the patient to anticancer therapy and guide physicians in choosing the best treatment for the patient. CA125,HE4 and STIP1 have been proven to play an important role as biomarkers in detecting and monitoring ovarian cancer. In this paper,we review evaluate,and highlight the role of CA125,HE4 and STIP1 in the detection of ovarian cancer.Potential biomarkers can help us distinguish malignancy from benign pelvic mass.展开更多
Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still...Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still an urgent need for reliable biomarkers that could overcome the lack of cancer-specifcity of prostate-specifc antigen, as well as alternative therapeutic targets for advanced metastatic cases. Reversible phosphorylation of proteins is a post-translational modifcation critical to the regulation of numerous cellular processes. Phosphoprotein phosphatase 1 （PPP1） is a major serine/threonine phos-phatase, whose specifcity is determined by its interacting proteins. These interactors can be PPP1 substrates, regulators, or even both. Deregulation of this protein-protein interaction network alters cell dynamics and underlies the development of several cancer hallmarks. Therefore, the identification of PPP1 interactome in specific cellular context is of crucial importance. The knowledge on PPP1 complexes in prostate cancer remains scarce, with only 4 holoenzymes characterized in human prostate cancer models. However, an increasing number of PPP1 interactors have been identifed as expressed in human prostate tissue, including the tumor suppressors TP53 and RB1. Efforts should be made in order to identify the role of such proteins in prostate carcinogenesis, since only 26 have yet well-recognized roles. Here, we revise literature and human protein databases to provide an in-depth knowledge on the biological significance of PPP1 complexes in human prostate carcinogenesis and their potential use as therapeutic targets for the development of new therapies for prostate cancer.展开更多
Reversible protein phosphorylation is a central regulatory mechanism of cell function. Deregulation of the balanced actions of protein kinases and phosphatases has been frequently associated with several pathological ...Reversible protein phosphorylation is a central regulatory mechanism of cell function. Deregulation of the balanced actions of protein kinases and phosphatases has been frequently associated with several pathological conditions, including cancer. Many studies have already addressed the role of protein kinases misregulation in cancer. However, much less is known about protein phosphatases influence. Phosphoprotein Phosphatase 1 (PPP1) is one of the major serine/threonine protein phosphatases who has three catalytic isoforms: PPP1CA, PPP1CB, and PPP1CC. Its function is achieved by binding to regulatory subunits, known as PPP1-interacting proteins (PIPs), which may prefer a catalytic isoform. Also, some inhibitors/enhancers may exhibit isoform specificity. Here we show that, prodigiosin (PG), a molecule with anticancer properties, promotes the formation of PPP1CA-AKT complex and not of PPP1CC-MAPK complex. Both, AKT and MAPK, are well-known PIPs from two pathways that crosstalk and regulate melanoma cells survival. In addition, the analysis performed using surface plasmon resonance (SPR) technology indicates that PPP1 interacts with obatoclax (OBX), a drug that belongs to the same family of PG. Overall, these results suggest that PG might, at least in part, act through PPP1C/PIPs. Also, this study is pioneer in demonstrating PPP1 isoform-specific modulation by small molecules.展开更多
Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(...Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.展开更多
Background and aims:Secreted phosphoprotein 1(SPP1)functions in several physiological processes.The role of SPP1 expression in the prognosis and tumor immunity of hepatocellular carcinoma(HCC)is unknown.The aim of thi...Background and aims:Secreted phosphoprotein 1(SPP1)functions in several physiological processes.The role of SPP1 expression in the prognosis and tumor immunity of hepatocellular carcinoma(HCC)is unknown.The aim of this study was to investigate the expression pattern of SPP1 in HCC and its correlation with prognosis and tumor immunity.Methods:Clinical and gene expression data of The Cancer Genome Atlas-liver hepatocellular carcinoma(LIHC)cohort and 11 other HCC datasets were collected.The Kaplan–Meier method and Cox regression analysis were used to analyze the prognostic value of SPP1.The DESeq2 package in R was used to analyze SPP1-related genes.Gene Ontology analysis and gene set enrichment analysis were used to determine the biological function of SPP1 in HCC.The single sample Gene Set Enrichment Analysis(ssGSEA)method was used to analyze the immune infiltrates of HCC.Illumina human methylation 450 data and level 3 HTSeq-FPKM data from The Cancer Genome Atlas-LIHC were used to analyze the effects of DNA methylation level on SPP1 expression.Results:SPP1 was overexpressed in HCC and correlated with T stage,histological grade,adjacent hepatic tissue inflammation,and vascular invasion in HCC.The analysis of survival rates indicated that high SPP1 levels were associated with poor overall survival in HCC.Functional analysis showed that SPP1 is related to tumor immunity,especially macrophage infiltration.Aberrant demethylation of the promoter region is one of the mechanisms underlying the increase of SPP1 in HCC.Conclusion:Our results indicate that SPP1 is an independent prognostic factor for HCC and is correlated with the clinical features and macrophage infiltration in HCC.展开更多
The dialogue between the mammalian conceptus(embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy w...The dialogue between the mammalian conceptus(embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients,collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of adult onset of metabolic diseases. Histotroph includes numerous amino acids, but arginine plays a particularly important role as a source of nitric oxide and polyamines required for fetal-placental development in rodents, swine and humans through mechanisms that remain to be fully elucidated. Mechanisms whereby arginine regulates expression of genes via the mechanistic target of rapamycin cell signaling pathways critical to conceptus development, implantation and placentation are discussed in detail in this review.展开更多
文摘Although many tumor markers have been identified and studied in epithelial ovarian cancer,a potential and useful screening marker for ovarian cancer has not been yet clearly established. Ovarian cancer is considered as a "silent killer"because of the absence of specific symptoms until late stage. Several validated biomarkers are currently used to diagnose and monitor the progression of the cancer,but very few of them show adequate specificity and sensitivity for different population screening. There is therefore an urge need to find biomarkers with high diagnostic accuracy and set up screening programs which can help detect ovarian cancer early,predict the response of the patient to anticancer therapy and guide physicians in choosing the best treatment for the patient. CA125,HE4 and STIP1 have been proven to play an important role as biomarkers in detecting and monitoring ovarian cancer. In this paper,we review evaluate,and highlight the role of CA125,HE4 and STIP1 in the detection of ovarian cancer.Potential biomarkers can help us distinguish malignancy from benign pelvic mass.
基金Supported by Fundao para a Ciência e Tecnologia(FCT)(PTDC/QUI-BIQ/118492/2010)Fundo Europeu de Desenvolvimento Regional(FEDER)(FCOMP-01-0124-FEDER-020895),Portugal
文摘Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still an urgent need for reliable biomarkers that could overcome the lack of cancer-specifcity of prostate-specifc antigen, as well as alternative therapeutic targets for advanced metastatic cases. Reversible phosphorylation of proteins is a post-translational modifcation critical to the regulation of numerous cellular processes. Phosphoprotein phosphatase 1 （PPP1） is a major serine/threonine phos-phatase, whose specifcity is determined by its interacting proteins. These interactors can be PPP1 substrates, regulators, or even both. Deregulation of this protein-protein interaction network alters cell dynamics and underlies the development of several cancer hallmarks. Therefore, the identification of PPP1 interactome in specific cellular context is of crucial importance. The knowledge on PPP1 complexes in prostate cancer remains scarce, with only 4 holoenzymes characterized in human prostate cancer models. However, an increasing number of PPP1 interactors have been identifed as expressed in human prostate tissue, including the tumor suppressors TP53 and RB1. Efforts should be made in order to identify the role of such proteins in prostate carcinogenesis, since only 26 have yet well-recognized roles. Here, we revise literature and human protein databases to provide an in-depth knowledge on the biological significance of PPP1 complexes in human prostate carcinogenesis and their potential use as therapeutic targets for the development of new therapies for prostate cancer.
基金supported by grants from Fundacao para a Ciencia e Tecnologia(FCT)of the Portuguese Ministry of Science and Higher Education(PTDC/DTP-PIC/0460/2012)by FEDER through Eixo I do Programa Operacional Fatores de Competitividade(POFC)(FCOMP-01-0124-FEDER-028692)co-funded by QREN
文摘Reversible protein phosphorylation is a central regulatory mechanism of cell function. Deregulation of the balanced actions of protein kinases and phosphatases has been frequently associated with several pathological conditions, including cancer. Many studies have already addressed the role of protein kinases misregulation in cancer. However, much less is known about protein phosphatases influence. Phosphoprotein Phosphatase 1 (PPP1) is one of the major serine/threonine protein phosphatases who has three catalytic isoforms: PPP1CA, PPP1CB, and PPP1CC. Its function is achieved by binding to regulatory subunits, known as PPP1-interacting proteins (PIPs), which may prefer a catalytic isoform. Also, some inhibitors/enhancers may exhibit isoform specificity. Here we show that, prodigiosin (PG), a molecule with anticancer properties, promotes the formation of PPP1CA-AKT complex and not of PPP1CC-MAPK complex. Both, AKT and MAPK, are well-known PIPs from two pathways that crosstalk and regulate melanoma cells survival. In addition, the analysis performed using surface plasmon resonance (SPR) technology indicates that PPP1 interacts with obatoclax (OBX), a drug that belongs to the same family of PG. Overall, these results suggest that PG might, at least in part, act through PPP1C/PIPs. Also, this study is pioneer in demonstrating PPP1 isoform-specific modulation by small molecules.
文摘Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
基金supported by Shandong Natural Science Foundation[grant number ZR2021MH339].
文摘Background and aims:Secreted phosphoprotein 1(SPP1)functions in several physiological processes.The role of SPP1 expression in the prognosis and tumor immunity of hepatocellular carcinoma(HCC)is unknown.The aim of this study was to investigate the expression pattern of SPP1 in HCC and its correlation with prognosis and tumor immunity.Methods:Clinical and gene expression data of The Cancer Genome Atlas-liver hepatocellular carcinoma(LIHC)cohort and 11 other HCC datasets were collected.The Kaplan–Meier method and Cox regression analysis were used to analyze the prognostic value of SPP1.The DESeq2 package in R was used to analyze SPP1-related genes.Gene Ontology analysis and gene set enrichment analysis were used to determine the biological function of SPP1 in HCC.The single sample Gene Set Enrichment Analysis(ssGSEA)method was used to analyze the immune infiltrates of HCC.Illumina human methylation 450 data and level 3 HTSeq-FPKM data from The Cancer Genome Atlas-LIHC were used to analyze the effects of DNA methylation level on SPP1 expression.Results:SPP1 was overexpressed in HCC and correlated with T stage,histological grade,adjacent hepatic tissue inflammation,and vascular invasion in HCC.The analysis of survival rates indicated that high SPP1 levels were associated with poor overall survival in HCC.Functional analysis showed that SPP1 is related to tumor immunity,especially macrophage infiltration.Aberrant demethylation of the promoter region is one of the mechanisms underlying the increase of SPP1 in HCC.Conclusion:Our results indicate that SPP1 is an independent prognostic factor for HCC and is correlated with the clinical features and macrophage infiltration in HCC.
基金supported by National Research Initiative Competitive Grants from the Animal Reproduction Program (2008-35203-19120, 2009-35206-05211, 201167015-20067, and 2011-67015-20028)Animal Growth & Nutrient Utilization Program (2008-35206-18764) of the USDA National Institute of Food and AgricultureTexas A&M Agri Life Research (H-8200)
文摘The dialogue between the mammalian conceptus(embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients,collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of adult onset of metabolic diseases. Histotroph includes numerous amino acids, but arginine plays a particularly important role as a source of nitric oxide and polyamines required for fetal-placental development in rodents, swine and humans through mechanisms that remain to be fully elucidated. Mechanisms whereby arginine regulates expression of genes via the mechanistic target of rapamycin cell signaling pathways critical to conceptus development, implantation and placentation are discussed in detail in this review.
