Naofumi Mukaida - Academia.edu (original) (raw)

Papers by Naofumi Mukaida

Research paper thumbnail of Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter

Molecular and Cellular Biology, 1997

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian ... more Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers. Although the primary target of paclitaxel is microtubules, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that it may have additional cellular effects. Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in subsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lipopolysaccharide pathway of IL-8 gene induction. The present study identifies the cis-acting elements and trans-acting factors involved in this induction by transfecting DNA constructs containing the 5'-flanking region of the IL-8 gene linked to the chloramphenicol acetyltransferase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activate...

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Research paper thumbnail of Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia

International Journal of Molecular Sciences, 2017

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Research paper thumbnail of Gemcitabine induces cell senescence in human pancreatic cancer cell lines

Biochemical and biophysical research communications, Aug 14, 2016

Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they ... more Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteri...

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Research paper thumbnail of Polytpeptide Specific To Liver Cancer, Polynucleotide Coding For The Polypeptide, And Rna Molecule Inhibiting Expression Of The Polypeptide

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Research paper thumbnail of Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

Cancer letters, Jan 10, 2016

From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently ... more From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth facto...

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Research paper thumbnail of C Chheemmookkiinneess iinn b brroonncchhooaallvveeoollaarr llaavvaaggee fflluuiidd iinn s suummmmeerr--ttyyppee h hyyppeerrsseennssiittiivviittyy p pnneeuummoonniittiiss

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Research paper thumbnail of Absence of IL-6 accelerates thrombus formation through reduced MMPs and uPA expression in murine deep vein thrombosis model

Cytokine

Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of deat... more Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of death in individuals with DVT. And DVT is multifactorial and often results from a combination of risk factors such as genetic conditions, obesity, drugs, pregnancy, aging, trauma, and malignancy. We demonstrated the pathophysiological roles of cytokines such as IFN-g and TNF-α in the processes of thrombus resolution using genetically engineered mice. In this study, we examined the pathophysiological roles of IL-6 in the resolution of DVT by the use of Il6 KO mice. Upon the ligation of the inferior vena cava (IVC) of WT mice, venous thrombi formed and grew progressively until 5 days, and the thrombus weight decreased after that. Concomitantly, the gene expression of Il6 was detected in the thrombi. When Il6 KO mice were treated in the same manner, thrombus size was much larger than WT mice. The intrathrombotic IL-6 was produced by intrathrombotic infiltrated macrophages on double color immunofluorescence staining of thrombi. And the number of intrathrombotic IL-6-positive cells changed in proportion to the number of macrophages. Moreover, the blood flow of the IVC was more recovered in WT than in Il6 KO mice. And intrathrombotic Mmp2 , Mmp9 , and Plau mRNA expression was significantly reduced in Il6 KO mice than WT mice. Supportingly, the administration of anti-IL-6 antibody delayed the thrombus resolution in WT mice. Furthermore, IL-6 treatment enhanced gene expression of Plau , Mmp2 , and Mmp9 in WT-derived macrophages. These IL-6 effects were significantly suppressed by Stat3 inhibitor. Collectively, IL-6 can have a beneficial role in the thrombus resolution by upreglation of MMP-2, MMP-9 and alpha expression. IL-6 can be a good molecular target for the DVT treatment.

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Research paper thumbnail of biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-icB and regulation of cytokine production/action through 132 integrin in vivo

Lipopolysaccharide (LPS), a constituent of gram-negative bacteria cell wall, plays an essential r... more Lipopolysaccharide (LPS), a constituent of gram-negative bacteria cell wall, plays an essential role in the pathogenesis of septic shock by generating endogenous mediators such as cytokines, nitrous oxide, superoxide anions, and lipid mediators. In vitro, LPS induces the transcription of a set of genes involved in inflammatory reactions by activating 5ev- eral types of transcription factors, particularly nu- clear factor-KB (NF-KB). An analysis of NF-KB activation using a cell-free system demonstrated that two pathways converge to activate NF-KB; one is staurosporine-sensitive, the other is staurosporine- insensitive and tyrosine kinase-dependent. Further- more, the latter pathway culminates in IKBa phosphorylation at serine/threonine residues in its carboxyl-terminal acidic region with dissociation of IKBa from NF-KB, thereby activating NF-KB. The requirement for the phosphorylation at this site was confirmed by the specific inhibition of NF-KB acti- vation in a cell-free system by...

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Research paper thumbnail of Establishment of Lipopolysaccharide-dependent Nuclear Factor κB Activation in a Cell-free System

Journal of Biological Chemistry, 1995

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Research paper thumbnail of Mechanisms involved in Helicobacter pylori—Induced inflammation

Gastroenterology, 1993

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Research paper thumbnail of Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis

Cancer Science, 2007

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Research paper thumbnail of PEA3 and AP-1 Are Required for Constitutive IL-8 Gene Expression in Hepatoma Cells

Biochemical and Biophysical Research Communications, 2000

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Research paper thumbnail of Interleukin-8 Gene Repression by Clarithromycin Is Mediated by the Activator Protein-1 Binding Site in Human Bronchial Epithelial Cells

American Journal of Respiratory Cell and Molecular Biology, 2000

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Research paper thumbnail of Involvement of Prokineticin 2–expressing Neutrophil Infiltration in 5-Fluorouracil–induced Aggravation of Breast Cancer Metastasis to Lung

Molecular Cancer Therapeutics, 2018

Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of pr... more Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of primary tumor, to prevent tumor recurrence primarily as a form of metastasis. However, anticancer drugs can accelerate metastasis in several mouse metastasis models. Hence, we examined the effects of postsurgical administration with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide, on lung metastasis process, which developed after the resection of the primary tumor arising from the orthotopic injection of a mouse triple-negative breast cancer cell line, 4T1. Only 5-FU markedly increased the numbers and sizes of lung metastasis foci, with enhanced tumor cell proliferation and angiogenesis as evidenced by increases in Ki67-positive cell numbers and CD31-positive areas, respectively. 5-FU–mediated augmented lung metastasis was associated with increases in intrapulmonary neutrophil numbers and expression of neutrophilic chemokines, Cxcl1 and Cxcl2 in tumor cells, with few effects on in...

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Research paper thumbnail of Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

International Journal of Molecular Sciences, 2018

Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple ... more Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophag...

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Research paper thumbnail of Essential Involvement of IFN-  in Clostridium difficile Toxin A-Induced Enteritis

The Journal of Immunology, 2004

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Research paper thumbnail of A New Anti-Inflammatory Compound, FR167653, Ameliorates Crescentic Glomerulonephritis in Wistar-Kyoto Rats

Journal of the American Society of Nephrology

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Research paper thumbnail of CCL4 Signaling in the Tumor Microenvironment

Advances in Experimental Medicine and Biology

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Research paper thumbnail of Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia

Molecular Biomedicine

A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia u... more A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia upon their transplantation into animals, and therefore, are named as leukemia stem cells, in the early 1990’s. Subsequently, cell subpopulations with similar characteristics were detected in various kinds of solid cancers and were denoted as cancer stem cells. Cancer stem cells are presently presumed to be crucially involved in malignant progression of solid cancer: chemoresitance, radioresistance, immune evasion, and metastasis. On the contrary, less attention has been paid to cancer non-stem cell population, which comprise most cancer cells in cancer tissues, due to the lack of suitable markers to discriminate cancer non-stem cells from cancer stem cells. Chronic myeloid leukemia stem cells generate a larger number of morphologically distinct non-stem cells. Moreover, accumulating evidence indicates that poor prognosis is associated with the increases in these non-stem cells including b...

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Research paper thumbnail of Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

Cancers

Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, ... more Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-de...

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Research paper thumbnail of Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter

Molecular and Cellular Biology, 1997

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian ... more Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers. Although the primary target of paclitaxel is microtubules, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that it may have additional cellular effects. Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in subsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lipopolysaccharide pathway of IL-8 gene induction. The present study identifies the cis-acting elements and trans-acting factors involved in this induction by transfecting DNA constructs containing the 5'-flanking region of the IL-8 gene linked to the chloramphenicol acetyltransferase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activate...

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Research paper thumbnail of Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia

International Journal of Molecular Sciences, 2017

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Research paper thumbnail of Gemcitabine induces cell senescence in human pancreatic cancer cell lines

Biochemical and biophysical research communications, Aug 14, 2016

Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they ... more Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteri...

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Research paper thumbnail of Polytpeptide Specific To Liver Cancer, Polynucleotide Coding For The Polypeptide, And Rna Molecule Inhibiting Expression Of The Polypeptide

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

Cancer letters, Jan 10, 2016

From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently ... more From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth facto...

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Research paper thumbnail of C Chheemmookkiinneess iinn b brroonncchhooaallvveeoollaarr llaavvaaggee fflluuiidd iinn s suummmmeerr--ttyyppee h hyyppeerrsseennssiittiivviittyy p pnneeuummoonniittiiss

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Research paper thumbnail of Absence of IL-6 accelerates thrombus formation through reduced MMPs and uPA expression in murine deep vein thrombosis model

Cytokine

Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of deat... more Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of death in individuals with DVT. And DVT is multifactorial and often results from a combination of risk factors such as genetic conditions, obesity, drugs, pregnancy, aging, trauma, and malignancy. We demonstrated the pathophysiological roles of cytokines such as IFN-g and TNF-α in the processes of thrombus resolution using genetically engineered mice. In this study, we examined the pathophysiological roles of IL-6 in the resolution of DVT by the use of Il6 KO mice. Upon the ligation of the inferior vena cava (IVC) of WT mice, venous thrombi formed and grew progressively until 5 days, and the thrombus weight decreased after that. Concomitantly, the gene expression of Il6 was detected in the thrombi. When Il6 KO mice were treated in the same manner, thrombus size was much larger than WT mice. The intrathrombotic IL-6 was produced by intrathrombotic infiltrated macrophages on double color immunofluorescence staining of thrombi. And the number of intrathrombotic IL-6-positive cells changed in proportion to the number of macrophages. Moreover, the blood flow of the IVC was more recovered in WT than in Il6 KO mice. And intrathrombotic Mmp2 , Mmp9 , and Plau mRNA expression was significantly reduced in Il6 KO mice than WT mice. Supportingly, the administration of anti-IL-6 antibody delayed the thrombus resolution in WT mice. Furthermore, IL-6 treatment enhanced gene expression of Plau , Mmp2 , and Mmp9 in WT-derived macrophages. These IL-6 effects were significantly suppressed by Stat3 inhibitor. Collectively, IL-6 can have a beneficial role in the thrombus resolution by upreglation of MMP-2, MMP-9 and alpha expression. IL-6 can be a good molecular target for the DVT treatment.

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Research paper thumbnail of biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-icB and regulation of cytokine production/action through 132 integrin in vivo

Lipopolysaccharide (LPS), a constituent of gram-negative bacteria cell wall, plays an essential r... more Lipopolysaccharide (LPS), a constituent of gram-negative bacteria cell wall, plays an essential role in the pathogenesis of septic shock by generating endogenous mediators such as cytokines, nitrous oxide, superoxide anions, and lipid mediators. In vitro, LPS induces the transcription of a set of genes involved in inflammatory reactions by activating 5ev- eral types of transcription factors, particularly nu- clear factor-KB (NF-KB). An analysis of NF-KB activation using a cell-free system demonstrated that two pathways converge to activate NF-KB; one is staurosporine-sensitive, the other is staurosporine- insensitive and tyrosine kinase-dependent. Further- more, the latter pathway culminates in IKBa phosphorylation at serine/threonine residues in its carboxyl-terminal acidic region with dissociation of IKBa from NF-KB, thereby activating NF-KB. The requirement for the phosphorylation at this site was confirmed by the specific inhibition of NF-KB acti- vation in a cell-free system by...

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Research paper thumbnail of Establishment of Lipopolysaccharide-dependent Nuclear Factor κB Activation in a Cell-free System

Journal of Biological Chemistry, 1995

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Research paper thumbnail of Mechanisms involved in Helicobacter pylori—Induced inflammation

Gastroenterology, 1993

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis

Cancer Science, 2007

Bookmarks Related papers MentionsView impact

Research paper thumbnail of PEA3 and AP-1 Are Required for Constitutive IL-8 Gene Expression in Hepatoma Cells

Biochemical and Biophysical Research Communications, 2000

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Interleukin-8 Gene Repression by Clarithromycin Is Mediated by the Activator Protein-1 Binding Site in Human Bronchial Epithelial Cells

American Journal of Respiratory Cell and Molecular Biology, 2000

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Research paper thumbnail of Involvement of Prokineticin 2–expressing Neutrophil Infiltration in 5-Fluorouracil–induced Aggravation of Breast Cancer Metastasis to Lung

Molecular Cancer Therapeutics, 2018

Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of pr... more Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of primary tumor, to prevent tumor recurrence primarily as a form of metastasis. However, anticancer drugs can accelerate metastasis in several mouse metastasis models. Hence, we examined the effects of postsurgical administration with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide, on lung metastasis process, which developed after the resection of the primary tumor arising from the orthotopic injection of a mouse triple-negative breast cancer cell line, 4T1. Only 5-FU markedly increased the numbers and sizes of lung metastasis foci, with enhanced tumor cell proliferation and angiogenesis as evidenced by increases in Ki67-positive cell numbers and CD31-positive areas, respectively. 5-FU–mediated augmented lung metastasis was associated with increases in intrapulmonary neutrophil numbers and expression of neutrophilic chemokines, Cxcl1 and Cxcl2 in tumor cells, with few effects on in...

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Research paper thumbnail of Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

International Journal of Molecular Sciences, 2018

Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple ... more Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophag...

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Research paper thumbnail of Essential Involvement of IFN-  in Clostridium difficile Toxin A-Induced Enteritis

The Journal of Immunology, 2004

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Research paper thumbnail of A New Anti-Inflammatory Compound, FR167653, Ameliorates Crescentic Glomerulonephritis in Wistar-Kyoto Rats

Journal of the American Society of Nephrology

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Research paper thumbnail of CCL4 Signaling in the Tumor Microenvironment

Advances in Experimental Medicine and Biology

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Research paper thumbnail of Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia

Molecular Biomedicine

A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia u... more A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia upon their transplantation into animals, and therefore, are named as leukemia stem cells, in the early 1990’s. Subsequently, cell subpopulations with similar characteristics were detected in various kinds of solid cancers and were denoted as cancer stem cells. Cancer stem cells are presently presumed to be crucially involved in malignant progression of solid cancer: chemoresitance, radioresistance, immune evasion, and metastasis. On the contrary, less attention has been paid to cancer non-stem cell population, which comprise most cancer cells in cancer tissues, due to the lack of suitable markers to discriminate cancer non-stem cells from cancer stem cells. Chronic myeloid leukemia stem cells generate a larger number of morphologically distinct non-stem cells. Moreover, accumulating evidence indicates that poor prognosis is associated with the increases in these non-stem cells including b...

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Research paper thumbnail of Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

Cancers

Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, ... more Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-de...

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