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He, Ningning,Kim, Nayoung,Song, Mee,Park, Choa,Kim, Somin,Park, Eun Young,Yim, Hwa Young,Kim, Kyunga,Park, Jong Hoon,Kim, Keun Il,Zhang, Fan,Mills, Gordon B.,Yoon, Sukjoon American Association for Cancer Research 2014 Molecular cancer therapeutics Vol.13 No.10
<P>The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (<I>STK11</I>)/liver kinase B1 (<I>LKB1</I>) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate–activated protein kinase (AMPK). Subsequently, we found that the knockdown of <I>PDE4D</I> gene expression inhibited proliferation of <I>STK11</I>-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of <I>STK11</I>-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets. <I>Mol Cancer Ther; 13(10); 2463–73. ©2014 AACR</I>.</P>
Loss-of-function screens of druggable targetome against cancer stem–like cells
Song, Mee,Lee, Hani,Nam, Myung-Hee,Jeong, Euna,Kim, Somin,Hong, Yourae,Kim, Nayoung,Yim, Hwa Young,Yoo, Young-Ji,Kim, Jung Seok,Kim, Jin-Seok,Cho, Yong-Yeon,Mills, Gordon B.,Kim, Woo-Young,Yoon, Sukjo Federation of American Societies for Experimental 2017 The FASEB Journal Vol.31 No.2
<P>Cancer stem–like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.—Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem–like cells.</P>
Systematic analysis of genotype‐specific drug responses in cancer
Kim, Nayoung,He, Ningning,Kim, Changsik,Zhang, Fan,Lu, Yiling,Yu, Qinghua,Stemke‐,Hale, Katherine,Greshock, Joel,Wooster, Richard,Yoon, Sukjoon,Mills, Gordon B Wiley Subscription Services, Inc., A Wiley Company 2012 International journal of cancer: Journal internati Vol.131 No.10
<P><B>Abstract</B></P><P>A systematic understanding of genotype‐specific sensitivity or resistance to anticancer agents is required to provide improved patient therapy. The availability of an expansive panel of annotated cancer cell lines enables comparative surveys of associations between genotypes and compounds of various target classes. Thus, one can better predict the optimal treatment for a specific tumor. Here, we present a statistical framework, cell line enrichment analysis (CLEA), to associate the response of anticancer agents with major cancer genotypes. Multilevel omics data, including transcriptome, proteome and phosphatome data, were integrated with drug data based on the genotypic classification of cancer cell lines. The results reproduced known patterns of compound sensitivity associated with particular genotypes. In addition, this approach reveals multiple unexpected associations between compounds and mutational genotypes. The mutational genotypes led to unique protein activation and gene expression signatures, which provided a mechanistic understanding of their functional effects. Furthermore, CLEA maps revealed interconnections between TP53 mutations and other mutations in the context of drug responses. The TP53 mutational status appears to play a dominant role in determining clustering patterns of gene and protein expression profiles for major cancer genotypes. This study provides a framework for the integrative analysis of mutations, drug responses and omics data in cancers.</P>
정보영,조경화,정강진,박윤용,김진만,라선영,박창교,Gordon B Mills,정재호,이회영 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
The small GTP-binding protein Rab25 is associated with tumor formation and progression. However, recent studies have shown discordant effects of Rab25 on cancer cell progression depending on cell lineage. In the present study, we elucidate the underlying mechanisms by which Rab25 induces cellular invasion. We demonstrate that Rab25 increases β1 integrin levels and subsequent activation of EGFR and upregulation of VEGF-A expression, leading to increased Snail expression, epithelial-tomesenchymal transition and cancer cell invasiveness. Strikingly, we identify that Snail mediates Rab25-induced cancer cell invasiveness through fascin expression and that ectopic expression of Rab25 aggravates metastasis of ovarian cancer cells to the lung. We thus demonstrate a novel role of a β1 integrin/EGFR/VEGF-A/Snail signaling cascade in Rab25-induced cancer cell aggressiveness through induction of fascin expression, thus providing novel biomarkers and potential therapeutic targets for Rab25-expressing cancer cells.
HE, NINGNING,KIM, NAYOUNG,JEONG, EUNA,LU, YILING,MILLS, GORDON B.,YOON, SUKJOON D.A. Spandidos 2016 International journal of oncology Vol.48 No.1
<P>Tolerance of glucose deprivation is an important factor for cancer proliferation, survival, migration and progression. To systematically understand adaptive responses under glucose starvation in cancers, we analyzed reverse phase protein array (RPPA) data of 115 protein antibodies across a panel of approximately 170 heterogeneous cancer cell lines, cultured under normal and low glucose conditions. In general, glucose starvation broadly altered levels of many of the proteins and phosphoproteins assessed across the cell lines. Many mTOR pathway components were selectively sensitive to glucose stress, although the change in their levels still varied greatly across the cell line set. Furthermore, lineage- and genotype-based classification of cancer cell lines revealed mutation-specific variation of protein expression and phosphorylation in response to glucose starvation. Decreased AKT phosphorylation (S473) was significantly associated with PTEN mutation under glucose starvation conditions in lung cancer cell lines. The present study (see TCPAportal.org for data resource) provides insight into adaptive responses to glucose deprivation under diverse cellular contexts.</P>
Systems Biology Approaches to Decoding the Genome of Liver Cancer
Ju-Seog Lee,Ji Hoon Kim,Yun-Yong Park,Gordon B. Mills 대한암학회 2011 Cancer Research and Treatment Vol.43 No.4
Molecular classification of cancers has been significantly improved patient outcomes through the implementation of treatment protocols tailored to the abnormalities present in each patient’s cancer cells. Breast cancer represents the poster child with marked improvements in outcome occurring due to the implementation of targeted therapies for estrogen receptor or human epidermal growth factor receptor-2 positive breast cancers. Important subtypes with characteristic molecular features as potential therapeutic targets are likely to exist for all tumor lineages including hepatocellular carcinoma (HCC) but have yet to be discovered and validated as targets. Because each tumor accumulates hundreds or thousands of genomic and epigenetic alterations of critical genes, it is challenging to identify and validate candidate tumor aberrations as therapeutic targets or biomarkers that predict prognosis or response to therapy. Therefore, there is an urgent need to devise new experimental and analytical strategies to overcome this problem. Systems biology approaches integrating multiple data sets and technologies analyzing patient tissues holds great promise for the identification of novel therapeutic targets and linked predictive biomarkers allowing implementation of personalized medicine for HCC patients.
Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression
Federico, Lorenzo,Jeong, Kang Jin,Vellano, Christopher P.,Mills, Gordon B. American Society for Biochemistry and Molecular Bi 2016 Journal of lipid research Vol.57 No.1
<P>The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human <I>ENNP2</I> gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, inflammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers.</P>
Wang, Chao,Gu, Chao,Jeong, Kang Jin,Zhang, Dong,Guo, Wei,Lu, Yiling,Ju, Zhenlin,Panupinthu, Nattapon,Yang, Ji Yeon,Gagea, Mihai (Mike),Ng, Patrick Kwok Shing,Zhang, Fan,Mills, Gordon B. American Association for Cancer Research 2017 Cancer Research Vol.77 No.7
<P>Interactions between HIPPO, YAP/TAZ, and the PI3K/AKT pathway may be therapeutically targetable, providing new approaches to treating endometrial cancers and other cancers where the HIPPO pathway is a core oncogenic driver.</P><P>The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor–induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth <I>in vivo</I>. In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. <I>Cancer Res; 77(7); 1637–48. ©2017 AACR</I>.</P>