Abstract:
:Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcΔ716 Trp53LSL•R270H villin-CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcΔ716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcΔ716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcΔ716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs.
journal_name
Oncogenejournal_title
Oncogeneauthors
Nakayama M,Sakai E,Echizen K,Yamada Y,Oshima H,Han TS,Ohki R,Fujii S,Ochiai A,Robine S,Voon DC,Tanaka T,Taketo MM,Oshima Mdoi
10.1038/onc.2017.194subject
Has Abstractpub_date
2017-10-19 00:00:00pages
5885-5896issue
42eissn
0950-9232issn
1476-5594pii
onc2017194journal_volume
36pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::We show that expression of the microtubule depolymerizing kinesin KIF2C is induced by transformation of immortalized human bronchial epithelial cells (HBEC) by expression of K-Ras(G12V) and knockdown of p53. Further investigation demonstrates that this is due to the K-Ras/ERK1/2 MAPK pathway, as loss of p53 had little...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.486
更新日期:2014-11-20 00:00:00
abstract::Recent studies suggest that the action of platelet-activating factor (PAF), a potent phospholipid modulator of allergic and inflammatory reactions, is diverse and functions as a modulator of a variety of physiological and pathological events in many cell types and tissues. Its role (if any) in modulating the prolifera...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206348
更新日期:2003-04-10 00:00:00
abstract::The tumor suppressor protein, p53, plays a critical role as a transcriptional activator of downstream target genes involved in the cellular response to DNA damaging agents. We examined the cell cycle checkpoint response of human mammary epithelial cells (HMEC) and their isogenic fibroblast counterparts to ionizing (IR...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202977
更新日期:1999-10-14 00:00:00
abstract::An integrative functional genomics study of multiple forms of data are vital for discovering molecular drivers of cancer development and progression. Here, we present an integrated genomic strategy utilizing DNA methylation and transcriptome profile data to discover epigenetically regulated genes implicated in cancer ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2016.176
更新日期:2017-01-05 00:00:00
abstract::We present an approach making use of technology established in the context of the genome project to describe a pancreatic cancer-specific expression profile and to identify new potential disease genes or disease-associated-genes. By use of gridded arrays of pancreatic cancer cDNA libraries and differential hybridizati...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-10-17 00:00:00
abstract::Previous studies have demonstrated that activation of Kit by stem cell factor (SCF), its natural ligand, or by gain-of-function point mutation in its intracellular domain, confers significant protection against apoptosis induced by growth factor deprivation or radiation. However, the effects of Kit activation on the c...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1204877
更新日期:2001-10-11 00:00:00
abstract::Polyoma virus (Py) differs from other small DNA tumor viruses in not encoding a protein that inactivates p53. The complete Py early region encoding the large T-antigen (PyLT), middle T-antigen (PyMT) and small T-antigen (PyST) will transform primary rodent cells and REF52 cells, but PyMT, the main Py oncogene, by itse...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1204717
更新日期:2001-08-16 00:00:00
abstract::We have found that a malignant mesothelioma cell line, NCI-H28, had a chromosome 3p21.3 homozygous deletion containing the beta-catenin gene (CTNNB1), which suggested that the deletion of beta-catenin might have a growth advantage in the development of this tumor. To determine whether beta-catenin has a growth-inhibit...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206533
更新日期:2003-09-11 00:00:00
abstract::The cellular transcription factor Brn-3a differentially regulates different human papilloma virus (HPV)-16 variants that are associated with different risks of progression to cervical carcinoma in infected humans. The upstream regulatory regions (URRs) of high- and intermediate-risk HPV-16 variants are activated by th...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.33
更新日期:2010-05-06 00:00:00
abstract::Upregulation and activation of epidermal growth factor receptor and/or urokinase-type plasminogen activator receptor in a variety of cancers have been shown to be associated with poor prognosis. High-molecular-weight kininogen can be hydrolysed by plasma kallikrein to bradykinin and cleaved high-molecular-weight kinin...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.132
更新日期:2009-07-30 00:00:00
abstract::Resistance to anti-HER2 (human epithelial growth factor receptor 2) trastuzumab therapy occurs commonly in HER2-positive breast cancer and involves overactivation of HER2 and/or AKT1. Using the model of trastuzumab-sensitive or trastuzumab-resistant HER2-positive cells with wild-type PTEN, negative regulator of AKT1, ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.422
更新日期:2010-03-04 00:00:00
abstract::Oligonucleotide microarray analysis was applied to assess the expression profile of 332 probe sets representing 308 genes or expressed sequence tags (ESTs) that map to chromosome 17 in order to address epigenetic events that result in alterations in gene expression in epithelial ovarian cancer (EOC). Expression profil...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206219
更新日期:2003-03-13 00:00:00
abstract::MyD88 was first characterized as a myeloid differentiation primary response gene in mice, activated in M1 myeloleukemic cells following interleukin-6 (IL-6) induced growth arrest and terminal differentiation. Analysis of expressed sequence tags (ESTs) from activated dendritic cell libraries led to the indentification ...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-12-05 00:00:00
abstract::Constitutive activation of the JAK/STAT3 pathway is a major contributor to oncogenesis. In the present study, structure-activity relationship (SAR) studies with five cucurbitacin (Cuc) analogs, A, B, E, I, and Q, led to the discovery of Cuc Q, which inhibits the activation of STAT3 but not JAK2; Cuc A which inhibits J...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208470
更新日期:2005-05-05 00:00:00
abstract::Apoptosis ligand 2 tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to a small subset of proapoptotic protein ligands in the TNF superfamily. This subset, which also includes Fas ligand and TNF-alpha, can activate the extrinsic apoptotic cell death pathway on binding to cognate death...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2010.221
更新日期:2010-08-26 00:00:00
abstract::Activation of the p53 tumor suppressor protein can lead to either cell cycle arrest or apoptosis. Several functional domains necessary for mediating cell cycle arrest and apoptosis in p53 have been mapped, e.g., the proline-rich domain. The proline-rich domain is located within residues 60-90, which comprise five PXXP...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202533
更新日期:1999-03-25 00:00:00
abstract::We have previously demonstrated that daunorubicin (DNR) induces apoptosis in some leukemic myeloid cell lines. We investigated a potential protective role for Bcl-2 in apoptosis induced by DNR in two leukemic cell lines, one myeloid and one lymphoid, overexpressing the anti-apoptotic gene Bcl-2. Parental cells treated...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201023
更新日期:1997-04-17 00:00:00
abstract::AP-1 transcription factors play a critical role in signal transduction pathways in many cells. We have investigated the role of AP-1 in controlling proliferative signals in breast cells, and have previously shown that AP-1 complexes are activated by peptide and steroid growth factors in both normal and malignant breas...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205883
更新日期:2002-10-31 00:00:00
abstract::Human hematopoietic progenitor cells (TF-1) undergo apoptosis upon deprivation of their dependent cytokine. In this report, we have isolated and characterized some spontaneously derived cytokine-independent variants from TF-1 cells. Analysis of several signaling molecules known to be activated by the GM-CSF pathway re...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1200884
更新日期:1997-02-13 00:00:00
abstract::The p53/p21Cip1/Waf1-dependent checkpoint control of G1/S and G2/M phases of the cell cycle in response to DNA damage is an important mechanism of genome stability maintenance in normal cells. In many tumor cells, due to frequent point mutations and deletions of p53, the stringent control of the cell cycle and apoptos...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202945
更新日期:1999-10-07 00:00:00
abstract::The Src family kinases c-Src, and its downstream effectors, the Rho family of small GTPases RhoA and Jun N-terminal kinase (JNK) have a significant role in tumorigenesis. In this report, using the Drosophila wing disc epithelium as a model system, we demonstrate that the actin-Capping Protein (CP) αβ heterodimer, whic...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.155
更新日期:2014-04-17 00:00:00
abstract::We previously reported the sequence of a cDNA, TIS11, cloned from TPA-treated Swiss 3T3 cells. Two laboratories have reported sequences for cDNAs that have a region of identity with the TIS11 cDNA, but differ in their 5' and 3' flanking regions. We now report that the original TIS11 cDNA is likely to be a chimeric mol...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1991-07-01 00:00:00
abstract::Increased glucose consumption is a hallmark of cancer cells. The increased consumption and subsequent metabolism of glucose during proliferation creates the need for a constant supply of NAD, a co-factor in glycolysis. Regeneration of the NAD required to support enhanced glycolysis has been attributed to the terminal ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2017.36
更新日期:2017-07-06 00:00:00
abstract::Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional respon...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2014.378
更新日期:2015-08-20 00:00:00
abstract::As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of J...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2016.478
更新日期:2017-06-08 00:00:00
abstract::Tat protein is an early nonstructural protein necessary for virus replication, which is secreted by infected cells and taken up by uninfected cells. Extensive evidence indicates that Tat may be a cofactor in the development of AIDS-related neoplasms. The molecular mechanism underlying Tat's oncogenic activity may incl...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206637
更新日期:2003-09-18 00:00:00
abstract::The maintenance cytosine DNA methyltransferase DNMT1 and de novo methyltransferase DNMT3b cooperate to establish aberrant DNA methylation and chromatin complexes to repress gene transcription during cancer development. The expression of DNMT3b was constitutively increased 5-20-fold in hTERT/CDK4-immortalized human bro...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.580
更新日期:2015-01-29 00:00:00
abstract::The E6 proteins originating from the tumour-associated Human Papillomavirus (HPV) types 16 and 18 have been shown to bind to and target the tumour suppressor protein, p53, for ubiquitin-mediated degradation. However, in cell lines derived from cervical neoplasias, the predominant early region transcripts are spliced a...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201202
更新日期:1997-07-17 00:00:00
abstract::The HER-2/neu proto-oncogene is frequently amplified or overexpressed in many different types of human cancers, a phenomenon that has been shown to correlate with shorter survival time and lower survival rate in ovarian cancer patients. We previously reported that increased HER-2/neu expression led to more severe mali...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-10-05 00:00:00
abstract::Resistance to detachment-induced apoptosis, a process commonly referred as anoikis, is emerging as a hallmark of metastatic malignancies, mainly because it can ensure anchorage-independent growth and survival during organ colonization. Besides, a sustained oxidative stress has been associated with several steps of car...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.77
更新日期:2009-05-21 00:00:00