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  • MinireviewFebruary 28, 2018

    0 171 3095

    Cancer Prevention with Green Tea and Its Principal Constituent, EGCG: from Early Investigations to Current Focus on Human Cancer Stem Cells

    Hirota Fujiki, Tatsuro Watanabe, Eisaburo Sueoka, Anchalee Rawangkan, and Masami Suganuma

    Mol. Cells 2018; 41(2): 73-82 https://doi.org/10.14348/molcells.2018.2227
    Abstract

    Abstract : Cancer preventive activities of green tea and its main constituent, (?)-epigallocatechin gallate (EGCG) have been extensively studied by scientists all over the world. Since 1983, we have studied the cancer chemopreventive effects of EGCG as well as green tea extract and underlying molecular mechanisms. The first part of this review summarizes ground-breaking topics with EGCG and green tea extract: 1) Delayed cancer onset as revealed by a 10-year prospective cohort study, 2) Prevention of colorectal adenoma recurrence by a double-blind randomized clinical phase II trial, 3) Inhibition of metastasis of B16 melanoma cells to the lungs of mice, 4) Increase in the average value of Young’s moduli, i.e., cell stiffness, for human lung cancer cell lines and inhibition of cell motility and 5) Synergistic enhancement of anticancer activity against human cancer cell lines with the combination of EGCG and anticancer compounds. In the second part, we became interested in cancer stem cells (CSCs). 1) Cancer stem cells in mouse skin carcinogenesis by way of introduction, after which we discuss two subjects from our review on human CSCs reported by other investigators gathered from a search of PubMed, 2) Expression of stemness markers of human CSCs compared with their parental cells, and 3) EGCG decreases or increases the expression of mRNA and protein in human CSCs. On this point, EGCG inhibited self-renewal and expression of pluripotency-maintaining transcription factors in human CSCs. Human CSCs are thus a target for cancer prevention and treatment with EGCG and green tea catechins.

  • MinireviewFebruary 28, 2018

    0 113 3868

    The Role of Hippo Pathway in Cancer Stem Cell Biology

    Jae Hyung Park, Ji Eun Shin, and Hyun Woo Park

    Mol. Cells 2018; 41(2): 83-92 https://doi.org/10.14348/molcells.2018.2242
    Abstract

    Abstract : The biological significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. In addition to earlier studies that highlight the role of Hippo pathway in organ size control, cell proliferation, and tumor development, recent evidence demonstrates its critical role in cancer stem cell biology, including EMT, drug resistance, and self-renewal. Here we provide a brief overview of the regulatory mechanisms of the Hippo pathway, its role in cancer stem cell biology, and promising therapeutic interventions.

  • ArticleFebruary 28, 2018

    0 30 690

    MiR-199a/b-5p Inhibits Lymphangiogenesis by Targeting Discoidin Domain Receptor 1 in Corneal Injury

    Sooeun Oh, Minkoo Seo, Jun-Sub Choi, Choun-Ki Joo, and Suk Kyeong Lee

    Mol. Cells 2018; 41(2): 93-102 https://doi.org/10.14348/molcells.2018.2163
    Abstract

    Abstract : Discoidin domain receptor 1 (DDR1) is involved in tumorigenesis and angiogenesis. However, its role in lymphangiogenesis has been unknown. Here, we tested whether downregulation of DDR1 expression by miR-199a/b can suppress lymphangiogenesis. We also aimed to identify miRNA target site(s) in the 3′ untranslated region (UTR) of DDR1. Transfection with miR-199a/b-5p mimics reduced expression of DDR1 and tube formation in primary human dermal lymphatic endothelial cells, whereas miR-199a/b-5p inhibitors showed the opposite effects. Critically, injection of miR-199a/b-5p mimics suppressed DDR1 expression and lymphangiogenesis in a corneal alkali-burn rat model. The three well-conserved seed matched sites for miR-199a/b-5p in the DDR1 3′-UTR were targeted, and miRNA binding to at least two sites was required for DDR1 inhibition. Our data suggest that DDR1 promotes enhanced lymphangiogenesis during eye injury, and miR-199a/b-5p suppresses this activity by inhibiting DDR1 expression. Thus, this miRNA may be useful for the treatment of lymphangiogenesis-related eye diseases.

  • ArticleFebruary 28, 2018

    0 30 623
    Abstract

    Abstract : Calcium ions are involved in the regulation of diverse cellular processes. Fourteen genes encoding calcium binding proteins have been identified in Dictyostelium. CBP7, one of the 14 CBPs, is composed of 169 amino acids and contains four EF-hand motifs. Here, we investigated the roles of CBP7 in the development and cell migration of Dictyostelium cells and found that high levels of CBP7 exerted a negative effect on cells aggregation during development, possibly by inhibiting chemoattractant-directed cell migration. While cells lacking CBP7 exhibited normal development and chemotaxis similar that of wild-type cells, CBP7 overexpressing cells completely lost their chemotactic abilities to move toward increasing cAMP concentrations. This resulted in inhibition of cellular aggregation, a process required for forming multicellular organisms during development. Low levels of cytosolic free calcium were observed in CBP7 overexpressing cells, which was likely the underlying cause of their lack of chemotaxis. Our results demonstrate that CBP7 plays an important role in cell spreading and cell-substrate adhesion. cbp7 null cells showed decreased cell size and cell-substrate adhesion. The present study contributes to further understanding the role of calcium signaling in regulation of cell migration and development.

  • ArticleFebruary 28, 2018

    0 40 791

    Generation of Isthmic Organizer-Like Cells from Human Embryonic Stem Cells

    Junwon Lee, Sang-Hwi Choi, Dongjin R Lee, Dae-Sung Kim, and Dong-Wook Kim

    Mol. Cells 2018; 41(2): 110-118 https://doi.org/10.14348/molcells.2018.2210
    Abstract

    Abstract : The objective of this study was to induce the production of isthmic organizer (IsO)-like cells capable of secreting fibroblast growth factor (FGF) 8 and WNT1 from human embryonic stem cells (ESCs). The precise modulation of canonical Wnt signaling was achieved in the presence of the small molecule CHIR99021 (0.6 μM) during the neural induction of human ESCs, resulting in the differentiation of these cells into IsO-like cells having a midbrain-hindbrain border (MHB) fate in a manner that recapitulated their developmental course in vivo. Resultant cells showed upregulated expression levels of FGF8 and WNT1. The addition of exogenous FGF8 further increased WNT1 expression by 2.6 fold. Gene ontology following microarray analysis confirmed that IsO-like cells enriched the expression of MHB-related genes by 40 fold compared to control cells. Lysates and conditioned media of IsO-like cells contained functional FGF8 and WNT1 proteins that could induce MHB-related genes in differentiating ESCs. The method for generating functional IsO-like cells described in this study could be used to study human central nervous system development and congenital malformations of the midbrain and hindbrain.

  • ArticleFebruary 28, 2018

    0 51 825
    Abstract

    Abstract : microRNA (miR)-612 shows anticancer activity in several types of cancers, yet its function in melanoma is still unclear. This study was undertaken to investigate the expression of miR-612 and its biological relevance in melanoma cell growth, invasion, and tumorigenesis. The expression and prognostic significance of miR-612 in melanoma were examined. The effects of miR-612 overexpression on cell proliferation, colony formation, tumorigenesis, and invasion were determined. Rescue experiments were conducted to identify the functional target gene(s) of miR-612. miR-612 was significantly downregulated in melanoma tissues compared to adjacent normal tissues. Low miR-612 expression was significantly associated with melanoma thickness, lymph node metastasis, and shorter overall, and disease-free survival of patients. Overexpression of miR-612 significantly decreased cell proliferation, colony formation, and invasion of SK-MEL-28 and A375 melanoma cells. In vivo tumorigenic studies confirmed that miR-612 overexpression retarded the growth of A375 xenograft tumors, which was coupled with a decline in the percentage of Ki-67-positive proliferating cells. Mechanistically, miR-612 targeted Espin in melanoma cells. Overexpression of Espin counteracted the suppressive effects of miR-612 on melanoma cell proliferation, invasion, and tumorigenesis. A significant inverse correlation (r = ?0.376, P = 0.018) was observed between miR-612 and Espin protein expression in melanoma tissues. In addition, overexpression of miR-612 and knockdown of Espin significantly increased the sensitivity of melanoma cells to doxorubicin. Collectively, miR-612 suppresses the aggressive phenotype of melanoma cells through downregulation of Espin. Delivery of miR-612 may represent a novel therapeutic strategy against melanoma.

  • ArticleFebruary 28, 2018

    0 31 920

    Post-Translational Regulation of the RSF1 Chromatin Remodeler under DNA Damage

    Sunwoo Min, Yong Won Choi, Hansol Yun, Sujin Jo, Jae-Hoon Ji, and Hyeseong Cho

    Mol. Cells 2018; 41(2): 127-133 https://doi.org/10.14348/molcells.2018.2244
    Abstract

    Abstract : Chromatin remodeling factors are involved in many cellular processes such as transcription, replication, and DNA damage response by regulating chromatin structure. As one of chromatin remodeling factors, remodeling and spacing factor 1 (RSF1) is recruited at double strand break (DSB) sites and regulates ataxia telangiectasia mutated (ATM) -dependent checkpoint pathway upon DNA damage for the efficient repair. RSF1 is overexpressed in a variety of cancers, but regulation of RSF1 levels remains largely unknown. Here, we showed that protein levels of RSF1 chromatin remodeler are temporally upregulated in response to different DNA damage agents without changing the RSF1 mRNA level. In the absence of SNF2h, a binding partner of RSF1, the RSF1 protein level was significantly diminished. Intriguingly, the level of RSF1-3SA mutant lacking ATM-mediated phosphorylation sites significantly increased, and upregulation of RSF1 levels under DNA damage was not observed in cells overexpressing ATM kinase. Furthermore, failure in the regulation of RSF1 level caused a significant reduction in DNA repair, whereas reconstitution of RSF1, but not of RSF1-3SA mutants, restored DSB repair. Our findings reveal that temporal regulation of RSF1 levels at its post-translational modification by SNF2h and ATM is essential for efficient DNA repair.

  • ArticleFebruary 28, 2018

    0 34 1361

    Isolation and Functional Examination of the Long Non-Coding RNA Redrum

    Yerim Lee, Charny Park, Sanghyuk Lee, Daekee Lee, and Jaesang Kim

    Mol. Cells 2018; 41(2): 134-139 https://doi.org/10.14348/molcells.2018.2246
    Abstract

    Abstract : Here, we report isolation of multiple long non-coding RNAs (lncRNAs) expressed tissue-specifically during murine embryogenesis. One of these, subsequently came to be known as Redrum, is expressed in erythropoietic cells in fetal liver and adult bone marrow. Redrum transcription is also detected during pregnancy in the spleen where extramedullary hematopoiesis takes place. In order to examine the function of Redrum in vivo, we generated a gene-targeted murine model and analyzed its embryonic and adult erythropoiesis. The homozygous mutant embryo showed no apparent deficiency or defect in erythropoiesis. Adult erythropoiesis in bone marrow and in the spleen during pregnancy likewise showed no detectable phenotype as red blood cells matured in normal fashion. The phenotype is in contrast to the reported function of Redrum in vitro, and our observation implies that Redrum plays in vivo an accessory or supplementary role whose loss is compatible with normal erythropoiesis.

  • ArticleFebruary 28, 2018

    0 41 833

    PPARα-Target Gene Expression Requires TIS21/BTG2 Gene in Liver of the C57BL/6 Mice under Fasting Condition

    Allen Eugene Hong, Min Sook Ryu, Seung Jun Kim, Seung Yong Hwang, and In Kyoung Lim

    Mol. Cells 2018; 41(2): 140-149 https://doi.org/10.14348/molcells.2018.2257
    Abstract

    Abstract : The TIS21/BTG2/PC3 gene belongs to the antiproliferative gene (APRO) family and exhibits tumor suppressive activity. However, here we report that TIS21 controls lipid metabolism, rather than cell proliferation, under fasting condition. Using microarray analysis, whole gene expression changes were investigated in liver of TIS21 knockout (TIS21-KO) mice after 20 h fasting and compared with wild type (WT). Peroxisome proliferator-activated receptor alpha (PPARα) target gene expression was almost absent in contrast to increased lipid synthesis in the TIS21-KO mice compared to WT mice. Immunohistochemistry with hematoxylin and eosin staining revealed that lipid deposition was focal in the TIS21-KO liver as opposed to the diffuse and homogeneous pattern in the WT liver after 24 h starvation. In addition, cathepsin E expression was over 10 times higher in the TIS21-KO liver than that in the WT, as opposed to the significant reduction of thioltransferase in both adult and fetal livers. At present, we cannot account for the role of cathepsin E. However, downregulation of glutaredoxin 2 thioltransferase expression might affect hypoxic damage in the TIS21-KO liver. We suggest that the TIS21/BTG2 gene might be essential to maintain energy metabolism and reducing power in the liver under fasting condition.

  • ArticleFebruary 28, 2018

    0 36 765

    Mass Spectrometry-Based Screening Platform Reveals Orco Interactome in Drosophila melanogaster

    Kate E. Yu, Do-Hyoung Kim, Yong-In Kim, Walton D. Jones, and J. Eugene Lee

    Mol. Cells 2018; 41(2): 150-159 https://doi.org/10.14348/molcells.2018.2305
    Abstract

    Abstract : Animals use their odorant receptors to receive chemical information from the environment. Insect odorant receptors differ from the G protein-coupled odorant receptors in vertebrates and nematodes, and very little is known about their protein?protein interactions. Here, we introduce a mass spectrometric platform designed for the large-scale analysis of insect odorant receptor protein?protein interactions. Using this platform, we obtained the first Orco interactome from Drosophila melanogaster. From a total of 1,186 identified proteins, we narrowed the interaction candidates to 226, of which only two-thirds have been named. These candidates include the known olfactory proteins Or92a and Obp51a. Around 90% of the proteins having published names likely function inside the cell, and nearly half of these intracellular proteins are associated with the endomembrane system. In a basic loss-of-function electrophysiological screen, we found that the disruption of eight (i.e., Rab5, CG32795, Mpcp, Tom70, Vir-1, CG30427, Eaat1, and CG2781) of 28 randomly selected candidates affects olfactory responses in vivo. Thus, because this Orco interactome includes physiologically meaningful candidates, we anticipate that our platform will help guide further research on the molecular mechanisms of the insect odorant receptor family.

Mol. Cells
Nov 30, 2021 Vol.44 No.11
COVER PICTURE
3D quantitative images of the vesicular structure and the nucleolus using label free optical diffraction tomography (Kim et al., pp. 851-860).

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