AIM To determine the potential roles of CD4 and micro RNA(mi R)-145 in gastric cancer.METHODS The levels of CD44 and mi R-145 were determined in gastric cancer cells. Quantitative real-time polymerase chain reaction w...AIM To determine the potential roles of CD4 and micro RNA(mi R)-145 in gastric cancer.METHODS The levels of CD44 and mi R-145 were determined in gastric cancer cells. Quantitative real-time polymerase chain reaction was used to measure to the level of CD44 m RNA. A luciferase reporter assay and western blotting were performed to examine the effect of mi R-145 on CD44 expression. Tumor sphere and MTT assays were carried out to evaluate the self-renewal and chemo-resistance properties of gastric cancer cells.RESULTS The expression of CD44 was greatly increased and mi R-145 was decreased in gastric cancer cells that were highly enriched in cancer stem cells(CSCs). The results demonstrated that mi R-145 regulated CD44 by targeting directly the CD44 3'-untranslated region(3'-UTR). In gastric cancer cells, overexpression of mi R-145 repressed the activity of the CD44 3'-UTR, and disruption of mi R-145/CD44 3'-UTR interactions abrogated the silencing effects. In addition, mi R-145 inhibition stimulated CD44 3'-UTR activity and disruption of mi R-145/CD44 3'-UTR interactions abrogated this stimulatory effect. Enforced CD44 expression greatly increased tumor sphere formation and chemoresistance in gastric cancer cells. Furthermore, the inhibition of CSCs and the chemo-sensitivity of gastric cancer cells treated with mi R-145 were significantly abrogated by overexpression of CD44. CONCLUSION mi R-145 targeting of CD44 plays critical roles in the regulation of tumor growth and chemo-resistance in gastric cancer.展开更多
Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transp...Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability(pharmacokinetics,or PK)and therapeutic efficacy(pharmacodynamics,or PD)of drugs.Recent studies have suggested that the long non-coding RNAs(IncRNAs)are highly relevant to drug metabolism and drug resistance,including chemoresistance in cancers,through the regulation of drug metabolism and disposition related genes.This review summarizes the regulation of enzymes,transporters,or regulatory proteins involved in drug metabolism by IncRNAs,with a particular emphasis on drug metabolism and chemo-resistance in cancer patients.The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related IncRNAs are also proposed.Understanding the role of IncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms,but also enable the discovery of IncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients,including cancer patients.展开更多
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early ...Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.展开更多
Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract.These dynamic communities,the environment and their metabolites constitute the microbiota.Growing data suggests a...Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract.These dynamic communities,the environment and their metabolites constitute the microbiota.Growing data suggests a causal role of a dysbiotic microbiota in several pathologies,such as metabolic and neurological disorders,immunity dysregulations and cancer,especially the well-studied colorectal cancer development.However,many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent.The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis.For example,Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins.However,dysbiosis may also cause a proinflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity,as demonstrated for Fusobacterium nucleatum.Microbiota has a crucial role in several stages of postoperative course;dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis(and other collagenase-producers microbes)are suggested as a cause of anastomotic leak.Consequently,unbalanced presence of some species,together with altered immune response may also have a prognostic role.Microbiota has also a substantial role in effectiveness of chemotherapy,chemoresistance and in the related side effects.In other words,a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.展开更多
Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the...Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.展开更多
Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of dr... Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.展开更多
Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK compl...Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas(TCGA) dataset was used to evaluate the breast cancer patients’ response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SKBR-3, were subsequently adopted for in vitro work.Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival(OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio(HR)=2.04, 95% confidence interval(95% CI), 1.36-3.07] and disease-free survival(DFS)(P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. A展开更多
基金Supported by Quanzhou excellent personnel training,No.10A16Natural Science Foundation of Fujian Province,No.JA08084Fujian Medical University,No.092D014
文摘AIM To determine the potential roles of CD4 and micro RNA(mi R)-145 in gastric cancer.METHODS The levels of CD44 and mi R-145 were determined in gastric cancer cells. Quantitative real-time polymerase chain reaction was used to measure to the level of CD44 m RNA. A luciferase reporter assay and western blotting were performed to examine the effect of mi R-145 on CD44 expression. Tumor sphere and MTT assays were carried out to evaluate the self-renewal and chemo-resistance properties of gastric cancer cells.RESULTS The expression of CD44 was greatly increased and mi R-145 was decreased in gastric cancer cells that were highly enriched in cancer stem cells(CSCs). The results demonstrated that mi R-145 regulated CD44 by targeting directly the CD44 3'-untranslated region(3'-UTR). In gastric cancer cells, overexpression of mi R-145 repressed the activity of the CD44 3'-UTR, and disruption of mi R-145/CD44 3'-UTR interactions abrogated the silencing effects. In addition, mi R-145 inhibition stimulated CD44 3'-UTR activity and disruption of mi R-145/CD44 3'-UTR interactions abrogated this stimulatory effect. Enforced CD44 expression greatly increased tumor sphere formation and chemoresistance in gastric cancer cells. Furthermore, the inhibition of CSCs and the chemo-sensitivity of gastric cancer cells treated with mi R-145 were significantly abrogated by overexpression of CD44. CONCLUSION mi R-145 targeting of CD44 plays critical roles in the regulation of tumor growth and chemo-resistance in gastric cancer.
基金supported in part by NIH grant ES030429(to W.X.)and CA222274(to D.Y.)supported in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy.
文摘Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability(pharmacokinetics,or PK)and therapeutic efficacy(pharmacodynamics,or PD)of drugs.Recent studies have suggested that the long non-coding RNAs(IncRNAs)are highly relevant to drug metabolism and drug resistance,including chemoresistance in cancers,through the regulation of drug metabolism and disposition related genes.This review summarizes the regulation of enzymes,transporters,or regulatory proteins involved in drug metabolism by IncRNAs,with a particular emphasis on drug metabolism and chemo-resistance in cancer patients.The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related IncRNAs are also proposed.Understanding the role of IncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms,but also enable the discovery of IncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients,including cancer patients.
基金Pancare Foundation (https://www.pancare.org.au) for supporting the pancreatic cancer research program in the Department of Surgery, University of Melbournesupported by Melbourne International Fee Remission Scholarship (MIFRS)+1 种基金Melbourne International Research Scholarship (MIRS)the Moshe Sambor Scholarship (Pancare Foundation)
文摘Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
基金Supported by University of Florence,No.ex60%2018。
文摘Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract.These dynamic communities,the environment and their metabolites constitute the microbiota.Growing data suggests a causal role of a dysbiotic microbiota in several pathologies,such as metabolic and neurological disorders,immunity dysregulations and cancer,especially the well-studied colorectal cancer development.However,many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent.The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis.For example,Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins.However,dysbiosis may also cause a proinflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity,as demonstrated for Fusobacterium nucleatum.Microbiota has a crucial role in several stages of postoperative course;dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis(and other collagenase-producers microbes)are suggested as a cause of anastomotic leak.Consequently,unbalanced presence of some species,together with altered immune response may also have a prognostic role.Microbiota has also a substantial role in effectiveness of chemotherapy,chemoresistance and in the related side effects.In other words,a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.
基金the Japan Society for the Promotion of Science(JSPS),KAKENHI,Grant Number 26350974.
文摘Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.
基金Supported by The National Institutes of Health/National Institute on Aging, AG014343the Department of Veterans Affairs, to Adhip PN Majumdar
文摘 Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.
基金supported by the Cardiff University China Medical Scholarship。
文摘Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas(TCGA) dataset was used to evaluate the breast cancer patients’ response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SKBR-3, were subsequently adopted for in vitro work.Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival(OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio(HR)=2.04, 95% confidence interval(95% CI), 1.36-3.07] and disease-free survival(DFS)(P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. A
