Objective To investigate effects of glucose excursion on the oxidative/antioxidative system in subjects with different types of glucose regulation. Methods A total of 30 individuals with normal glucose regulation (NGR...Objective To investigate effects of glucose excursion on the oxidative/antioxidative system in subjects with different types of glucose regulation. Methods A total of 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR) and 27 subjects with newly diagnosed type 2 diabetes mellitus (T2DM) were selected and recruited for 3 days’ continuous glucose monitor system (CGMS) assessment. The data from CGMS was used to calculate the mean amplitude of glycemic excursion (MAGE), mean blood glucose (MBG) and its standard deviation (SDBG), area under the ROC curve when the blood glucose 5.6 mmol/L within 24 h (AUC 5.6), mean of daily differences (MODD), and mean postprandial glucose excursion (MPPGE). In all groups, the content or activity of malondialdehyde (MDA), total antioxidation capacity (TAOC) and glutathione peroxidase (GSH‐Px) were detected. Results Glucose excursion parameters of subjects with T2DM or IGR were higher than those of NGR subjects (P0.05 or 0.01). Moreover, Glucose excursion parameters of T2DM subjects were higher than those of IGR subjects (P0.05 or 0.01). Subjects with T2DM or IGR had significant higher MDA levels and lower GSH‐Px/MDA and TAOC/MDA levels compared to NGR subjects (P0.01). T2DM subjects had even higher MDA levels and lower GSH‐Px/MDA levels than IGR (P0.05 or 0.01). According to the median of normal population for MAGE, T2DM and IGR subjects were divided into MAGE2.6mmol/L Group and MAGE≤2.6mmol/L Group. MAGE2.6mmol/L Group had higher levels of MDA and lower levels of GSH‐Px/MDA than MAGE≤2.6mmol/L Group (P0.05). There was no significant difference between the two groups (P0.05) in terms of the levels of TAOC/MDA. Pearson correlation analysis showed that MDA was positively correlated with FPG, 2hPG, MAGE, and SBP. GSH‐Px/MDA was negatively correlated with MAGE and TC. TAOC/MDA was negatively correlated with FPG. Partial correlation analysis showed that the relationship between MDA and MAGE, GSH‐Px/MDA, and MAGE remained significant after adjustments for the other differences among groups. Conclusion Glucose excursion contributed significantly to promoting lipid peroxidation and decreasing antioxidation capacity than chronic sustained hyperglycemia did in the subjects with different types of glucose regulation.展开更多
Gastric cancer is one of the most common malignancies and a leading cause of cancer mortality worldwide.The pathogenesis mechanisms of gastric cancer are still not fully clear.Inactivation of tumor suppressor genes an...Gastric cancer is one of the most common malignancies and a leading cause of cancer mortality worldwide.The pathogenesis mechanisms of gastric cancer are still not fully clear.Inactivation of tumor suppressor genes and activation of oncogenes caused by genetic and epigenetic alterations are known to play significant roles in carcinogenesis.Accumulating evidence has shown that epigenetic silencing of the tumor suppressor genes,particularly caused by hypermethylation of CpG islands in promoters,is critical to carcinogenesis and metastasis.Here,we review the recent progress in the study of methylations of tumor suppressor genes involved in the pathogenesis of gastric cancer.We also briefly describe the mechanisms that induce tumor suppressor gene methylation and the status of translating these molecular mechanisms into clinical applications.展开更多
Colorectal cancer(CRC)causes approximately 600000deaths annually and is the third leading cause of cancer mortality worldwide.Despite significant advancements in treatment options,CRC patient survival is still poor ow...Colorectal cancer(CRC)causes approximately 600000deaths annually and is the third leading cause of cancer mortality worldwide.Despite significant advancements in treatment options,CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making.Since there exists a need to find new biomarkers to improve diagnosis of CRC,the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice.Epigenetic alterations are thought to hold great promise as tumor biomarkers.In this review,we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers,including DNA methylation,microRNA expression and histone modification,in cancer tissue,stool,plasma,serum,cell lines and xenografts.These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening,early diagnosis,prognosis,therapy choice and recurrence surveillance for CRC patients.However,these studies have typically been small in size,and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.展开更多
Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical rol...Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical role in lung development and lung cancer differentiation and morphogenesis, molecular mechanisms mediating Nkx2-1 cell- and tissue-specific expression in normal and cancerous lungs have yet to be fully elucidated. The recent identification of prognostic biomarkers in lung cancer, particularly in lung adenocarcinoma (ADC), and the different reactivity of patients to chemotherapeutic drugs have opened new avenues for evaluating patient survival and the development of novel effective therapeutic strategies. The function of Nkx2-1 as a proto-oncogene was recently characterized and the gene is implicated as a contributory factor in lung cancer development. In this review, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of Nkx2-1 as a novel biomarker of lung cancer.展开更多
Objective: The novel estrogen receptor-α (ER-α) variant ER-α36 is reported to be functional in the es-trogen signaling pathway and is related to tamoxifen resistance in breast cancer. However, ER-α36 tends to be a...Objective: The novel estrogen receptor-α (ER-α) variant ER-α36 is reported to be functional in the es-trogen signaling pathway and is related to tamoxifen resistance in breast cancer. However, ER-α36 tends to be a favorable factor for survival in patients without tamoxifen therapy. To investigate the mechanisms behind this paradox, we determined the differences between the transcriptional profiles of ER-α36 and full-length ER-α (ER-α66) in breast cancers and matched normal tissues. Methods: We analyzed ER-α36 and ER-α66 messenger RNA ( mRNA) levels in 74 pairs of breast cancers and matched normal tissues using a real-time quantitative polymerase chain reaction (PCR) assay, and correlated the results with their clinicopathological characteristics. Results: Breast cancers expressed lower ER-α36 mRNA levels than matched normal tissues regardless of their ER-α66 expression status. Down-regulation of ER-α36 mRNA was correlated with local progression, lymph node metastasis, and advanced cancer stage. The level of ER-α66 mRNA was lower in ER-α negative breast cancers compared with matched normal tissues. No differences in ER-α66 mRNA levels were observed during cancer progression. Conclusion: Down-regulation of ER-α36 is associated with carcinogenesis and progression of breast cancer.展开更多
Background Estrogen is involved in suppression of colon cancer development and exerts its function via estrogen receptors α and β （ERa, ERβ）. The recently identified ERα46 resulted from exon 1-deletion from the ...Background Estrogen is involved in suppression of colon cancer development and exerts its function via estrogen receptors α and β （ERa, ERβ）. The recently identified ERα46 resulted from exon 1-deletion from the 66-kDa full length form of ERa66 is devoid of the transactivation domain AF-1, whose function remains largely unknown. Methods In this study, we compared the expression of ERa46 mRNA in 32 normal colorectal tissues and their matched colorectal cancer tissues by real-time quantitative polymerase chain reaction （PCR）. Human colon adenocarcinoma cell HT-29, that has low endogenous expression of ERα46, was transfected with ERα46-expression vector; methyl thiazolyl tetrazolium （MTT） assay, flow cytometry, DNA fragmentation and TUNEL staining were used to evaluate the proliferation and apoptosis status of the cells in the presence of 17β-oestradiol. Results Higher ERα46 mRNA levels were observed in normal colorectal tissues than in the corresponding cancer tissues. ERα46-transfected cells showed a significantly decreased growth rate than control cells and an accumulation of cells in the G0/1 phase and a reduced proportion of cells in G2/M phase after exposed to 10^-8 mol/L 17β-oestradiol. There were also more positive TUNEL stained cells in ERα46-transfected cells than the control cells in the presence of 17β-oestradiol （P 〈0.05）. Conclusions These data suggest that ERα46 may be involved in the development and/or progression of colorectal cancer via mediating growth inhibition and apoptosis of cancer cells in the presence of 17β-oestradiol.展开更多
Plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA (lncRNA) gene identified as a recurrent breakpoint of Burkitt’s lymphomas. Human PVT1 gene is located on region 8q24.21, a well-known cancer risk r...Plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA (lncRNA) gene identified as a recurrent breakpoint of Burkitt’s lymphomas. Human PVT1 gene is located on region 8q24.21, a well-known cancer risk region, and encodes at least 26 linear ncRNA isoforms and 26 circular RNA isoforms, as well as 6 microRNAs. Several PVT1 functioning models have been reported recently such as competing endogenous RNA (ceRNA) activity and regulating protein stability of oncogenes, especially MYC oncogene. The promoter of PVT1 gene is a boundary element of tumor-suppressor DNA. CircPVT1 derived from PVT1 gene is also a critical non-coding oncogenic RNA. Although substantial advancements have been made in understanding the roles of PVT1 in cancer recently, the detailed mechanisms underlying its functions remain unclear. Herein, we summarize the recent progressions on the mechanisms underlying PVT1 regulated gene expression at different levels. We also discuss the interaction between lncRNA and protein, RNA and DNA, as well as the potential cancer therapy strategy by targeting these networks.展开更多
Even though insulin-like growth factor 2(IGF2)has been reported to be overexpressed in nonalcoholic fatty liver disease(NAFLD),its role in the progression of NAFLD and the potential mechanism remain largely unclear.Us...Even though insulin-like growth factor 2(IGF2)has been reported to be overexpressed in nonalcoholic fatty liver disease(NAFLD),its role in the progression of NAFLD and the potential mechanism remain largely unclear.Using in vitro models,we found that IGF2 was the key overexpressed gene in steatosis,suggesting a possible association between IGF2 and NAFLD.Interestingly,loss-of-function experiments revealed that inhibition of IGF2 protein impaired mitochondrial biogenesis and respiration.It additionally disrupted the expression changes of mitochondrial fusion and fission-related proteins necessary in maintaining mitochondrial homeostasis.Consistently,IGF2 knockdown reduced the mitochondrial membrane potential and increased the production of reactive oxygen species.Mechanistically,IGF2 regulates mitochondrial functions by modulating the expression of SIRT1 and its downstream gene PGCla.This research opens a new frontier on the role of IGF2 in energy metabolism,which potentially participates in the development of NAFLD.As such,IGF2 is a potential therapeutic target against NAFLD.展开更多
Golgi protein 73(GP73),a resident protein of the Golgi apparatus,is notably elevated in hepatocellular carcinoma(HCC).While its critical role in remodeling the tumor microenvironment(TME)is recognized,the intricate me...Golgi protein 73(GP73),a resident protein of the Golgi apparatus,is notably elevated in hepatocellular carcinoma(HCC).While its critical role in remodeling the tumor microenvironment(TME)is recognized,the intricate mechanisms are not fully understood.This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2(PHD-2)in a competitive manner,thereby impeding the hydroxylation of hypoxia-induced factor-1α(HIF-1α).The effect above promotes the production and secretion of vascular endothelial growth factor A(VEGFA).Moreover,exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells(HUVECs)and competitively interact with HECTD1,an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2(GRB2).This interaction stabilizes GRB2,thereby activating the Ras-mitogen-activated protein kinase(MAPK)signaling pathway.Consequently,escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells,fostering angiogenesis in the TME.Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.展开更多
The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironmen...The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.展开更多
Objective: To understand the function of nicotinamide N-methyltransferase (NNMT) protein as tumor biomarker in renal carcinoma. Methods: Recombinant NNMT protein was used to prepare monoclonal antibodies by hybridoma ...Objective: To understand the function of nicotinamide N-methyltransferase (NNMT) protein as tumor biomarker in renal carcinoma. Methods: Recombinant NNMT protein was used to prepare monoclonal antibodies by hybridoma technique. The diagnostic and prognostic function of NNMT protein in renal carcinoma was evaluated by analyzing 74 renal cancer tissues through immunohistochemical staining for NNMT by using the prepared antibodies. Results: Two hybridomas named 2F8 and 1E7 stably secreting the monoclonal antibodies were isolated successfully, and characters such as isotypes and specificity were determined. NNMT protein was significantly up-regulated in renal cancer and significantly associated with tumor histology and ages. The univariate survival analysis demonstrated that the pT-status, high levels of NNMT, and distant metastasis were significant prognosticators. Conclusion: NNMT is over-expressed in a large proportion in renal cell cancers. High NNMT expression is significantly associated with unfavorable prognosis. However, the prognostic value of NNMT needs further verification in larger sample sizes.展开更多
Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer(PC).Both the long non-coding RNA(lncRNA)plasmacytoma variant translocation 1(PVT1)and hypoxic inducible factor-1α(HIF-1α)are highl...Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer(PC).Both the long non-coding RNA(lncRNA)plasmacytoma variant translocation 1(PVT1)and hypoxic inducible factor-1α(HIF-1α)are highly expressed in PC patients and play a crucial role in disease progression.Reciprocal regulation involving PVT1 and HIF-1αin PC,however,is poorly understood.Here,we report that PVT1 binds to the HIF-1αpromoter and activates its transcription.In addition,we found that PVT1 could bind to HIF-1αand increases HIF-1αpost-translationally.Our findings suggest that the PVTl-HIF-1αpositive feedback loop is a potential therapeutic target in the treatment of PC.展开更多
基金supported by the Shanghai United Developing Technology Project of Municipal Hospitals (SHDC12006101)the Health Bureau of Zhejiang Province (2009B091)
文摘Objective To investigate effects of glucose excursion on the oxidative/antioxidative system in subjects with different types of glucose regulation. Methods A total of 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR) and 27 subjects with newly diagnosed type 2 diabetes mellitus (T2DM) were selected and recruited for 3 days’ continuous glucose monitor system (CGMS) assessment. The data from CGMS was used to calculate the mean amplitude of glycemic excursion (MAGE), mean blood glucose (MBG) and its standard deviation (SDBG), area under the ROC curve when the blood glucose 5.6 mmol/L within 24 h (AUC 5.6), mean of daily differences (MODD), and mean postprandial glucose excursion (MPPGE). In all groups, the content or activity of malondialdehyde (MDA), total antioxidation capacity (TAOC) and glutathione peroxidase (GSH‐Px) were detected. Results Glucose excursion parameters of subjects with T2DM or IGR were higher than those of NGR subjects (P0.05 or 0.01). Moreover, Glucose excursion parameters of T2DM subjects were higher than those of IGR subjects (P0.05 or 0.01). Subjects with T2DM or IGR had significant higher MDA levels and lower GSH‐Px/MDA and TAOC/MDA levels compared to NGR subjects (P0.01). T2DM subjects had even higher MDA levels and lower GSH‐Px/MDA levels than IGR (P0.05 or 0.01). According to the median of normal population for MAGE, T2DM and IGR subjects were divided into MAGE2.6mmol/L Group and MAGE≤2.6mmol/L Group. MAGE2.6mmol/L Group had higher levels of MDA and lower levels of GSH‐Px/MDA than MAGE≤2.6mmol/L Group (P0.05). There was no significant difference between the two groups (P0.05) in terms of the levels of TAOC/MDA. Pearson correlation analysis showed that MDA was positively correlated with FPG, 2hPG, MAGE, and SBP. GSH‐Px/MDA was negatively correlated with MAGE and TC. TAOC/MDA was negatively correlated with FPG. Partial correlation analysis showed that the relationship between MDA and MAGE, GSH‐Px/MDA, and MAGE remained significant after adjustments for the other differences among groups. Conclusion Glucose excursion contributed significantly to promoting lipid peroxidation and decreasing antioxidation capacity than chronic sustained hyperglycemia did in the subjects with different types of glucose regulation.
基金supported by grants from National Natural Science Foundation of China(No.30770920 and 81071651)Zhejiang Provincial Natural Science Foundation of China(No.R2100213,2009C33142,Z2090056 and WKJ2009-2-028)973 Project(No.2010CB834300)
文摘Gastric cancer is one of the most common malignancies and a leading cause of cancer mortality worldwide.The pathogenesis mechanisms of gastric cancer are still not fully clear.Inactivation of tumor suppressor genes and activation of oncogenes caused by genetic and epigenetic alterations are known to play significant roles in carcinogenesis.Accumulating evidence has shown that epigenetic silencing of the tumor suppressor genes,particularly caused by hypermethylation of CpG islands in promoters,is critical to carcinogenesis and metastasis.Here,we review the recent progress in the study of methylations of tumor suppressor genes involved in the pathogenesis of gastric cancer.We also briefly describe the mechanisms that induce tumor suppressor gene methylation and the status of translating these molecular mechanisms into clinical applications.
基金Supported by National Natural Science Foundation of China,No.81071651 and No.81372622the Program for Zhejiang Leading Team of ST innovation,No.2012R10046-03+3 种基金Major State Basic Research Development Program,No.2010CB834303National High Technology Research and Development Program of China,No.2012AA02A601Major Projects in Zhejiang Province,No.2012C13014-1the Fundamental Research Funds for the Central Universities,No.2012FZA7020
文摘Colorectal cancer(CRC)causes approximately 600000deaths annually and is the third leading cause of cancer mortality worldwide.Despite significant advancements in treatment options,CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making.Since there exists a need to find new biomarkers to improve diagnosis of CRC,the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice.Epigenetic alterations are thought to hold great promise as tumor biomarkers.In this review,we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers,including DNA methylation,microRNA expression and histone modification,in cancer tissue,stool,plasma,serum,cell lines and xenografts.These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening,early diagnosis,prognosis,therapy choice and recurrence surveillance for CRC patients.However,these studies have typically been small in size,and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.
基金supported by the Zhejiang Provincial Natural Science Foundation of China (No. LQ12H01001)the Zhejiang Provincial Medicine & Health Scientific Foundation of China (No. 2012KYA143)
文摘Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical role in lung development and lung cancer differentiation and morphogenesis, molecular mechanisms mediating Nkx2-1 cell- and tissue-specific expression in normal and cancerous lungs have yet to be fully elucidated. The recent identification of prognostic biomarkers in lung cancer, particularly in lung adenocarcinoma (ADC), and the different reactivity of patients to chemotherapeutic drugs have opened new avenues for evaluating patient survival and the development of novel effective therapeutic strategies. The function of Nkx2-1 as a proto-oncogene was recently characterized and the gene is implicated as a contributory factor in lung cancer development. In this review, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of Nkx2-1 as a novel biomarker of lung cancer.
基金Project supported by the National Basic Research Program (973) of China (No. 2009CB521704)the National Natural Science Foundation of China (No. 30772510)+2 种基金the Ministry of Health of China (No. WKJ2006-2-008)the Department of Science and Technology of Zhejiang Province (No. 2007C24011)the Natural Science Foundation of Zhejiang Province (No. R206060), China
文摘Objective: The novel estrogen receptor-α (ER-α) variant ER-α36 is reported to be functional in the es-trogen signaling pathway and is related to tamoxifen resistance in breast cancer. However, ER-α36 tends to be a favorable factor for survival in patients without tamoxifen therapy. To investigate the mechanisms behind this paradox, we determined the differences between the transcriptional profiles of ER-α36 and full-length ER-α (ER-α66) in breast cancers and matched normal tissues. Methods: We analyzed ER-α36 and ER-α66 messenger RNA ( mRNA) levels in 74 pairs of breast cancers and matched normal tissues using a real-time quantitative polymerase chain reaction (PCR) assay, and correlated the results with their clinicopathological characteristics. Results: Breast cancers expressed lower ER-α36 mRNA levels than matched normal tissues regardless of their ER-α66 expression status. Down-regulation of ER-α36 mRNA was correlated with local progression, lymph node metastasis, and advanced cancer stage. The level of ER-α66 mRNA was lower in ER-α negative breast cancers compared with matched normal tissues. No differences in ER-α66 mRNA levels were observed during cancer progression. Conclusion: Down-regulation of ER-α36 is associated with carcinogenesis and progression of breast cancer.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 30772510）, Ministry Health of the People＇s Republic of China （No. WKJ2006-2-008）, and Department of Science and Technology of Zhejiang Province （No. 2007C24011）.
文摘Background Estrogen is involved in suppression of colon cancer development and exerts its function via estrogen receptors α and β （ERa, ERβ）. The recently identified ERα46 resulted from exon 1-deletion from the 66-kDa full length form of ERa66 is devoid of the transactivation domain AF-1, whose function remains largely unknown. Methods In this study, we compared the expression of ERa46 mRNA in 32 normal colorectal tissues and their matched colorectal cancer tissues by real-time quantitative polymerase chain reaction （PCR）. Human colon adenocarcinoma cell HT-29, that has low endogenous expression of ERα46, was transfected with ERα46-expression vector; methyl thiazolyl tetrazolium （MTT） assay, flow cytometry, DNA fragmentation and TUNEL staining were used to evaluate the proliferation and apoptosis status of the cells in the presence of 17β-oestradiol. Results Higher ERα46 mRNA levels were observed in normal colorectal tissues than in the corresponding cancer tissues. ERα46-transfected cells showed a significantly decreased growth rate than control cells and an accumulation of cells in the G0/1 phase and a reduced proportion of cells in G2/M phase after exposed to 10^-8 mol/L 17β-oestradiol. There were also more positive TUNEL stained cells in ERα46-transfected cells than the control cells in the presence of 17β-oestradiol （P 〈0.05）. Conclusions These data suggest that ERα46 may be involved in the development and/or progression of colorectal cancer via mediating growth inhibition and apoptosis of cancer cells in the presence of 17β-oestradiol.
文摘Plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA (lncRNA) gene identified as a recurrent breakpoint of Burkitt’s lymphomas. Human PVT1 gene is located on region 8q24.21, a well-known cancer risk region, and encodes at least 26 linear ncRNA isoforms and 26 circular RNA isoforms, as well as 6 microRNAs. Several PVT1 functioning models have been reported recently such as competing endogenous RNA (ceRNA) activity and regulating protein stability of oncogenes, especially MYC oncogene. The promoter of PVT1 gene is a boundary element of tumor-suppressor DNA. CircPVT1 derived from PVT1 gene is also a critical non-coding oncogenic RNA. Although substantial advancements have been made in understanding the roles of PVT1 in cancer recently, the detailed mechanisms underlying its functions remain unclear. Herein, we summarize the recent progressions on the mechanisms underlying PVT1 regulated gene expression at different levels. We also discuss the interaction between lncRNA and protein, RNA and DNA, as well as the potential cancer therapy strategy by targeting these networks.
基金This project was supported by grants from the Zhejiang Provincial Natural Science Foundation(LY20H070004)the Zhejiang Provincial Medical Science and Technology Program(2020KY166 and 2018KY484).
文摘Even though insulin-like growth factor 2(IGF2)has been reported to be overexpressed in nonalcoholic fatty liver disease(NAFLD),its role in the progression of NAFLD and the potential mechanism remain largely unclear.Using in vitro models,we found that IGF2 was the key overexpressed gene in steatosis,suggesting a possible association between IGF2 and NAFLD.Interestingly,loss-of-function experiments revealed that inhibition of IGF2 protein impaired mitochondrial biogenesis and respiration.It additionally disrupted the expression changes of mitochondrial fusion and fission-related proteins necessary in maintaining mitochondrial homeostasis.Consistently,IGF2 knockdown reduced the mitochondrial membrane potential and increased the production of reactive oxygen species.Mechanistically,IGF2 regulates mitochondrial functions by modulating the expression of SIRT1 and its downstream gene PGCla.This research opens a new frontier on the role of IGF2 in energy metabolism,which potentially participates in the development of NAFLD.As such,IGF2 is a potential therapeutic target against NAFLD.
基金supported by the National Natural Science Foundation of China under grant 82103397 to Y.L.R&D Program of Zhejiang Province under grant 2024C03142 to L.Z.
文摘Golgi protein 73(GP73),a resident protein of the Golgi apparatus,is notably elevated in hepatocellular carcinoma(HCC).While its critical role in remodeling the tumor microenvironment(TME)is recognized,the intricate mechanisms are not fully understood.This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2(PHD-2)in a competitive manner,thereby impeding the hydroxylation of hypoxia-induced factor-1α(HIF-1α).The effect above promotes the production and secretion of vascular endothelial growth factor A(VEGFA).Moreover,exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells(HUVECs)and competitively interact with HECTD1,an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2(GRB2).This interaction stabilizes GRB2,thereby activating the Ras-mitogen-activated protein kinase(MAPK)signaling pathway.Consequently,escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells,fostering angiogenesis in the TME.Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.
基金National Natural Science Foundation of China,Grant/Award Numbers:81602471,81672729,81972453,81972597Natural Science Foundation of Zhejiang Province,Grant/Award Numbers:LY19H160055,LY19H160059,LR22H160011+2 种基金Natural Science Foundation of Ningbo,Grant/Award Number:2019A610315Cixi Agricultural and Social Development Science and Technology Project,Grant/Award Number:CN2020006Zheng Shu Medical Elite Scholarship Fund。
文摘The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.
基金Project supported by the Science Foundation of Health Bureau of Zhejiang Province (Nos. 2005A055 and 2008B114)the Science Foundation of Education Bureau of Zhejiang Province (No. 20061271), China
文摘Objective: To understand the function of nicotinamide N-methyltransferase (NNMT) protein as tumor biomarker in renal carcinoma. Methods: Recombinant NNMT protein was used to prepare monoclonal antibodies by hybridoma technique. The diagnostic and prognostic function of NNMT protein in renal carcinoma was evaluated by analyzing 74 renal cancer tissues through immunohistochemical staining for NNMT by using the prepared antibodies. Results: Two hybridomas named 2F8 and 1E7 stably secreting the monoclonal antibodies were isolated successfully, and characters such as isotypes and specificity were determined. NNMT protein was significantly up-regulated in renal cancer and significantly associated with tumor histology and ages. The univariate survival analysis demonstrated that the pT-status, high levels of NNMT, and distant metastasis were significant prognosticators. Conclusion: NNMT is over-expressed in a large proportion in renal cell cancers. High NNMT expression is significantly associated with unfavorable prognosis. However, the prognostic value of NNMT needs further verification in larger sample sizes.
基金supported by grants from the Public Welfare Project of Science and Technology Department of.Zhejiang Province,China(2017C33056)the Zhejiang Provincial Natural Science Foundation(LY15H030011 and LY16H070002)the Zhejiang Provincial Medical Science and Technology Program(2017KY403 and 2015RCA013).
文摘Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer(PC).Both the long non-coding RNA(lncRNA)plasmacytoma variant translocation 1(PVT1)and hypoxic inducible factor-1α(HIF-1α)are highly expressed in PC patients and play a crucial role in disease progression.Reciprocal regulation involving PVT1 and HIF-1αin PC,however,is poorly understood.Here,we report that PVT1 binds to the HIF-1αpromoter and activates its transcription.In addition,we found that PVT1 could bind to HIF-1αand increases HIF-1αpost-translationally.Our findings suggest that the PVTl-HIF-1αpositive feedback loop is a potential therapeutic target in the treatment of PC.
