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"Tanaka, Nobuyuki"
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IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells
Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein
O
-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an
O
-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced
O
-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.
Journal Article
Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression
p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important for cancer proliferation, metastasis, and maintenance of cancer stem cells (CSCs) that self-renew and generate the diverse cells comprising the tumor. Furthermore, p53 has been demonstrated to inhibit inflammatory responses, and functional loss of p53 causes excessive inflammatory reactions. Moreover, the generation and maintenance of CSCs are supported by the inflammatory tumor microenvironment. Considering that the functions of p53 inhibit reprogramming of somatic cells to stem cells, p53 may have a major role in the inflammatory microenvironment as a tumor suppressor. Here, we review our current understanding of the mechanisms underlying the roles of p53 in regulation of the inflammatory microenvironment, tumor microenvironment, and tumor suppression.
Journal Article
The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy
Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.
Journal Article
Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with
IL6
induction and inflammatory phenotypes
in vivo
. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.
Journal Article
Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer
The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field.
Journal Article
Enhanced O-GlcNAc modification induced by the RAS/MAPK/CDK1 pathway is required for SOX2 protein expression and generation of cancer stem cells
Cancer stem cells (CSCs) have tumour initiation, self-renewal, and long-term tumour repopulation properties, and it is postulated that differentiated somatic cells can be reprogrammed to CSCs by oncogenic signals. We previously showed that oncogenic
HRAS
V12
conferred tumour initiation capacity in tumour suppressor p53-deficient (
p53
−/−
) primary mouse embryonic fibroblasts (MEFs) through transcription factor NF-κB-mediated enhancement of glucose uptake; however, the underlying mechanisms of
RAS
oncogene-induced CSC reprogramming have not been elucidated. Here, we found that the expression of the reprogramming factor
SOX2
was induced by
HRAS
V12
in
p53
−/−
MEFs. Moreover, gene knockout studies revealed that
SOX2
is an essential factor for the generation of CSCs by
HRAS
V12
in mouse and human fibroblasts. We demonstrated that HRAS
V12
-induced cyclin-dependent kinase 1 (CDK1) activity and subsequent enhancement of protein
O
-GlcNAcylation were required for SOX2 induction and CSC generation in these fibroblasts and cancer cell lines containing
RAS
mutations. Moreover, the CDK inhibitor dinaciclib and
O
-GlcNAcylation inhibitor OSMI1 reduced the number of CSCs derived from these cells. Taken together, our results reveal a signalling pathway and mechanism for CSC generation by oncogenic
RAS
and suggest the possibility that this signalling pathway is a therapeutic target for CSCs.
Journal Article
Investigation of Indoor Air Quality in Residential Buildings by Measuring CO2 Concentration and a Questionnaire Survey
Indoor air quality (IAQ) in houses is often deteriorated by chemical substances emitted from heating, building materials, or other household goods. Since it is difficult for occupants to recognize air pollution, they rarely understand the actual conditions of the IAQ. An investigation into the actual condition of IAQ in houses was therefore conducted in this study. Carbon dioxide (CO2) concentrations in 24 occupied houses was measured, and the results from our analysis showed that the use of combustion heaters increased the concentration of CO2 and led to indoor air pollution. Results indicate that as outdoor temperature decreased, the frequency of ventilation decreased simultaneously, and CO2 concentration increased. Results of the questionnaire survey revealed that the actual IAQ in each house did not match the level of awareness its occupants had regarding ventilation. Along with this difficulty in perceiving air pollution, the lack of knowledge about ventilation systems and the effects of combustion heating may be additional barriers to IAQ awareness.
Journal Article
MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in mice and its gene mutation was found in human cancers. In inflammation-induced colon cancer, tumour suppressor p53 mutations have also been detected with high frequency as early events. However, the molecular mechanism of MYD88-induced cancer development is poorly understood. Here, we demonstrated that MYD88 induced the protein accumulation of the transcription factor HIF-1α through NF-κB in p53-deficient cells. HIF-1α accumulation was not caused by enhanced protein stability but by NF-κB-mediated transcriptional activation, the enhanced translation of HIF-1α and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1α and HIF-1-target genes were attenuated in the presence of p53. Furthermore, constitutively active forms of MYD88 induced tumour-initiating cell (TIC) generation in p53-deficient cells, as determined by tumour xenografts in nude mice. TIC generating activity was diminished by the suppression of NF-κB or HIF-1α. These results indicate that MYD88 signals induce the generation of TICs through the NF-κB-HIF-1α activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.
Journal Article
Potential distribution of pine wilt disease under future climate change scenarios
Pine wilt disease (PWD) constitutes a serious threat to pine forests. Since development depends on temperature and drought, there is a concern that future climate change could lead to the spread of PWD infections. We evaluated the risk of PWD in 21 susceptible Pinus species on a global scale. The MB index, which represents the sum of the difference between the mean monthly temperature and 15 when the mean monthly temperatures exceeds 15°C, was used to determine current and future regions vulnerable to PWD (MB ≥ 22). For future climate conditions, we compared the difference in PWD risks among four different representative concentration pathways (RCPs 2.6, 4.5, 6.0, and 8.5) and two time periods (2050s and 2070s). We also evaluated the impact of climate change on habitat suitability for each Pinus species using species distribution models. The findings were then integrated and the potential risk of PWD spread under climate change was discussed. Within the natural Pinus distribution area, southern parts of North America, Europe, and Asia were categorized as vulnerable regions (MB ≥ 22; 16% of the total Pinus distribution area). Representative provinces in which PWD has been reported at least once overlapped with the vulnerable regions. All RCP scenarios showed expansion of vulnerable regions in northern parts of Europe, Asia, and North America under future climate conditions. By the 2070s, under RCP 8.5, an estimated increase in the area of vulnerable regions to approximately 50% of the total Pinus distribution area was revealed. In addition, the habitat conditions of a large portion of the Pinus distribution areas in Europe and Asia were deemed unsuitable by the 2070s under RCP 8.5. Approximately 40% of these regions overlapped with regions deemed vulnerable to PWD, suggesting that Pinus forests in these areas are at risk of serious damage due to habitat shifts and spread of PWD.
Journal Article