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Conversion of glioma cells to glioma stem-like cells by angiocrine factors
Kim, Jun-Kyum,Jeon, Hye-Min,Jeon, Hee-Young,Oh, Se-Yeong,Kim, Eun-Jung,Jin, Xiong,Kim, Se-Hoon,Kim, Sung-Hak,Jin, Xun,Kim, Hyunggee Elsevier 2018 Biochemical and biophysical research communication Vol.496 No.4
<P><B>Abstract</B></P> <P>Glioma stem-like cells (GSCs) contribute to tumor initiation, progression, and therapeutic resistance, but their cellular origin remains largely unknown. Here, using a stem/progenitor cell-fate tracking reporter system in which eGFP is expressed by promoter of <I>OCT4</I> that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both <I>in vitro</I> cultures and <I>in vivo</I> xenografts. These eGFP-positive-GCs exhibited GSC features and primarily localized to the perivascular region in tumor xenografts, similar to the existence of OCT4-expressing GCs in the perivascular region of human glioblastoma specimens. Angiocrine factors, including nitric oxide (NO), converted eGFP-negative-GCs into eGFP-positive-GCs. Mechanistically, NO signaling conferred GSC features to GCs by increasing OCT4 and NOTCH signaling via ID4. NO signaling blockade and a suicide gene induction prevented tumorigenicity with a decrease in eGFP-positive-GCs in the perivascular region. Taken together, our results reveal the molecular mechanism underlying GSCs generation by cancer cell dedifferentiation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Glioma cells are converted to glioma stem-like cells in <I>in vivo</I> xenografts. </LI> <LI> Angiocrine factors convert glioma cells to glioma stem-like cells. </LI> <LI> Nitric oxide regulates ID4 and OCT4 expression in glioma stem-like cells. </LI> <LI> Blockade of nitric oxide signaling prevents tumor progression. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim, Tae-Kyung,Lee, Joong-Seob,Oh, Se-Yeong,Jin, Xun,Choi, Yun-Jaie,Lee, Tae-Hoon,Lee, Eun ho,Choi, Young-Ki,You, Seungkwon,Chung, Yong Gu,Lee, Jang-Bo,DePinho, Ronald A.,Chin, Lynda,Kim, Hyunggee American Association for Cancer Research 2007 Cancer Research Vol.67 No.23
<P>IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression.</P>
KCTD2, an adaptor of Cullin3 E3 ubiquitin ligase, suppresses gliomagenesis by destabilizing c-Myc
Kim, Eun-Jung,Kim, Sung-Hak,Jin, Xiong,Jin, Xun,Kim, Hyunggee Macmillan Publishers Limited, part of Springer Nat 2017 CELL DEATH AND DIFFERENTIATION Vol.24 No.4
<P>Cullin3 E3 ubiquitin ligase ubiquitinates a wide range of substrates through substrate-specific adaptors Bric-a-brac, Tramtrack, and Broad complex (BTB) domain proteins. These E3 ubiquitin ligase complexes are involved in diverse cellular functions. Our recent study demonstrated that decreased Cullin3 expression induces glioma initiation and correlates with poor prognosis of patients with malignant glioma. However, the substrate recognition mechanism associated with tumorigenesis is not completely understood. Through yeast two-hybrid screening, we identified potassium channel tetramerization domain-containing 2 (KCTD2) as a BTB domain protein that binds to Cullin3. The interaction of Cullin3 and KCTD2 was verified using immunoprecipitation and immunofluorescence. Of interest, KCTD2 expression was markedly decreased in patient-derived glioma stem cells (GSCs) compared with non-stem glioma cells. Depletion of KCTD2 using a KCTD2-specific short-hairpin RNA in U87MG glioma cells and primary Ink4a/Arf-deficient murine astrocytes markedly increased self-renewal activity in addition with an increased expression of stem cell markers, and mouse in vivo intracranial tumor growth. As an underlying mechanism for these KCTD2-mediated phenotypic changes, we demonstrated that KCTD2 interacts with c-Myc, which is a key stem cell factor, and causes c-Myc protein degradation by ubiquitination. As a result, KCTD2 depletion acquires GSC features and affects aerobic glycolysis via expression changes in glycolysis-associated genes through c-Myc protein regulation. Of clinical significance was our finding that patients having a profile of KCTD2 mRNA-low and c-Myc gene signature-high, but not KCTD2 mRNA-low and c-Myc mRNA-high, are strongly associated with poor prognosis. This study describes a novel regulatory mode of c-Myc protein in malignant gliomas and provides a potential framework for glioma therapy by targeting c-Myc function.</P>
IRF7 promotes glioma cell invasion by inhibiting AGO2 expression.
Kim, Jun-Kyum,Jin, Xiong,Ham, Seok Won,Lee, Seon Yong,Seo, Sunyoung,Kim, Sung-Chan,Kim, Sung-Hak,Kim, Hyunggee Saikon Pub. Co 2015 TUMOR BIOLOGY Vol.36 No.7
<P>Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.</P>
KHO, Yoonjung,KIM, Sungchan,YOON, Byung Sun,MOON, Jai-Hee,KIM, Bona,KWAK, Sungwook,WOO, Junghee,OH, Sejong,HONG, Kichang,KIM, Saehun,KIM, Hyunggee,YOU, Seungkwon,CHOI, Yunjaie Japan Society for Bioscience, Biotechnology, and A 2008 Bioscience, Biotechnology, and Biochemistry Vol.72 No.1
<P>In this study, we examined the expression and functions of serum amyloid A (SAA) isoforms during apoptosis of HC11 mammary gland epithelial cells. Expression of SAA mRNAs and apoptosis were increased in HC11 cells by serum withdrawal and gradually decreased upon the addition of serum, or epidermal growth factor (EGF). TNFα treatment of HC11 cells also induced expression of SAA genes, and the effect on SAA1 and SAA2 expression was suppressed by treatment with MG132, and in cells transfected with a dominant negative mutant form of IκBα. Similar results were observed in response to interleukin-1 (IL-1), IL-6 and interferon γ (IFNγ). Furthermore, overexpression of the SAA1 and SAA2 isoforms suppressed growth and accelerated apoptosis of HC11 cells by increasing caspase 3/7 and caspase 8 activities, but the apoptotic effect of tumor necrosis factor α (TNFα) on HC11 cells was not enhanced. We found that expression of <I>SAA1</I> and <I>SAA2</I>, but not <I>SAA3</I>, was regulated by an NFκB-dependent pathway, and that overexpression of SAA isoforms accelerated the apoptosis of HC11 cells.</P>
WDNM1 is associated with differentiation and apoptosis of mammary epithelial cells.
Kho, Yoonjung,Kim, Sungchan,Yoon, Byung Sun,Moon, Jai-Hee,Kwak, Sungwook,Park, Gyuman,Woo, Junghee,Oh, Sejong,Hong, Kichang,Kim, Saehun,Kim, Hyunggee,You, Seungkwon,Choi, Yunjaie Marcel Dekker 2008 Animal biotechnology Vol.19 No.2
<P>In this study, we show that expression of the Westmead DMBA8 nonmetastatic cDNA 1 (WDNM1) gene was increased upon SFM and/or TNFalpha treatment, with a corresponding increase in apoptotic cells, and gradually decreased following re-stimulation with serum in HC11 mammary epithelial cells. TNFalpha induced WDNM1 expression showed the NFkappaB-dependent mechanism since it's expression was abrogated in IkappaBalphaM (super-repressor of NFkappaB)-transfected cells, but not those transfected with control vector. Furthermore, overexpression of WDNM1 suppressed growth and differentiation, and accelerated apoptosis of HC11 cells. Thus, our results demonstrate that WDNM1 gene expression, regulated by the TNFalpha-NFkappaB signal pathway, is associated with HC11 cell apoptosis.</P>
Sung Jin KIM,Cheol Gyu PARK,Sang-Hun CHOI,Seon Yong LEE,Kiyoung EUN,Min Gi PARK,Junseok JANG,Hyunggee KIM 한국생물공학회 2021 한국생물공학회 학술대회 Vol.2021 No.10
Although the oncogenic role of LIM domain only 2 (LMO2) as a transcriptional regulator is well established, the cytosolic functions of LMO2 are not known. Here, we have identified LMO2 as a cytosolic adaptor of signal transducer and activator of transcription 3 (STAT3) signaling proteins in glioma stem cells (GSCs) through biochemical purification. The interaction between LMO2 and STAT3 signaling proteins, membrane glycoprotein (GP130), and Janus kinase (JAK) induces STAT3 activation in a cytokine-independent manner, which activates a master regulator of cancer stemness, inhibitor of differentiation 1 (ID1). Furthermore, results from in vitro and in vivo studies showed that LMO2-induced ID1 promotes cancer cell migration. Collectively, our findings indicate that cytosolic LMO2 induces cytokine-independent STAT3 activation and maintenance of GSC characteristics.