生物谷報(bào)道：Lkb1腫瘤抑制基因所發(fā)生的突變見于Peutz–Jeghers綜合癥患者,，這些患者癌癥發(fā)病率增加?，F(xiàn)在,，Lkb1突變已在非小細(xì)胞肺癌的鱗狀腫瘤亞型中被發(fā)現(xiàn),。研究結(jié)果發(fā)表在最新一期的《自然》雜志上,。
在一個(gè)Lkb1缺失與K-Ras突變相結(jié)合的肺癌小鼠模型中,，出現(xiàn)了比只有K-Ras突變時(shí)更有侵略性的腫瘤,，這些腫瘤經(jīng)常被劃分為鱗狀大細(xì)胞腫瘤。所以,，Lkb1缺失調(diào)控肺癌分化,，而Lkb1缺失還可能是預(yù)測(cè)疾病發(fā)展和擴(kuò)散的一個(gè)有用的標(biāo)記。由LKB1調(diào)控的通道代表可能的治療目標(biāo),。
FIGURE 1. Lung tumours in Kras and Kras Lkb1L/L mice.
a, Quantification of lesions (<1 mm) found in Kras or Kras Lkb1L/- mice two and four weeks after adeno-Cre treatment. n = 4–6 for each group. Data are shown as mean s.e.m. b, Quantification of tumours (>3 mm) in Kras Lkb1L/- (n = 12), Kras Lkb1+/- (n = 8) and Kras (n = 10) mice 8 weeks after adeno-Cre treatment. Data are shown as mean s.e.m. c, Representative lung tumours from Kras Lkb1L/- mice showing squamous (top), mixed (middle; Ad, adenocarcinoma; Sq, SCC) or large-cell (bottom) histology. The dotted box in the left image shows the area shown on the right. d, Immunohistochemical staining for SP-C, pan-keratin and p63 in adenocarcinomas (left) or in squamous tumours (right) from Kras Lkb1L/- or Kras Lkb1L/L mice. e, Western blot of Lkb1 and p63 expression in tumours from mice of indicated genotype and histology. Histology is indicated as normal lung, adenocarcinoma or SCC. Tubulin serves as a loading control.
Volume 448 Number 7155
LKB1 modulates lung cancer differentiation and metastasis p807
Hongbin Ji, Matthew R. Ramsey, D. Neil Hayes, Cheng Fan, Kate McNamara, Piotr Kozlowski, Chad Torrice, Michael C. Wu, Takeshi Shimamura, Samanthi A. Perera, Mei-Chih Liang, Dongpo Cai, George N. Naumov, Lei Bao, Cristina M. Contreras, Danan Li, Liang Chen, Janakiraman Krishnamurthy, Jussi Koivunen, Lucian R. Chirieac, Robert F. Padera, Roderick T. Bronson, Neal I. Lindeman, David C. Christiani, Xihong Lin, Geoffrey I. Shapiro, Pasi A. Jänne, Bruce E. Johnson, Matthew Meyerson, David J. Kwiatkowski, Diego H. Castrillon, Nabeel Bardeesy, Norman E. Sharpless & Kwok-Kin Wong
doi:10.1038/nature06030
First paragraph | Full Text | PDF (470K) | Supplementary information
See also: Editor's summary
相關(guān)基因：
STK11
Official Symbol STK11 and Name: serine/threonine kinase 11 [Homo sapiens]
Other Aliases: LKB1, PJS
Other Designations: polarization-related protein LKB1; serine/threonine kinase 11 (Peutz-Jeghers syndrome); serine/threonine protein kinase 11
Chromosome: 19; Location: 19p13.3
Annotation: Chromosome 19, NC_000019.8 (1156798..1179434)
MIM: 602216
GeneID: 6794
作者簡(jiǎn)介：
Kwok-Kin Wong, MD, PhD
Instructor in Medicine, Harvard Medical School
Department
Medical Oncology
Center/Program
Thoracic Cancer
Area of Research
Pathogenesis of Human Lung Cancer
Contact Information
Kwok-Kin Wong, MD, PhD
Dana-Farber Cancer Institute
Preferred contact method: appointment phone
Research
Our research focuses on understanding the pathogenesis and genetic alterations involved in lung cancer and on testing novel lung cancer therapeutics in vivo. Our laboratory integrates genomic studies of human lung cancer, new mouse models of lung cancers, and studies of novel drug treatment in these models.
We have been using oligonucleotide array-based comparative genomic hybridization (CGH), coupled with expression profiling, to interrogate the oncogenome and transcriptome of primary human lung cancer samples. This series of experiments has revealed many novel genes that might play important roles in human lung cancer. We are now validating the roles of these genes in tumorigenesis in vitro and in vivo.
To understand the genetic role of mutated B-RAF, HER2/NEU, EGFR, and PI3 kinases in lung cancer, our laboratory generated various inducible bitransgenic mice harboring these mutations. We demonstrated that activation of EGFR and B-RAF are oncogenic in vivo, because mice expressing these activated alleles develop lung tumors de novo. We are now characterizing these mice in detail and plan to use them as a unique platform for testing therapeutics that specifically target these pathways.
In addition, we are constructing a realistic model of human lung cancer using the unique experimental attributes of the telomerase-deficient mouse model and tobacco smoke. Tobacco use accounts for 85 percent of all lung cancers, and one hypothesis explaining this relationship states that tobacco smoke induces genetic mutations and causes accelerated cell renewals; these events rapidly erode telomeres, causing chromosomes to become unstable and increasing the probability that lung cells will become cancerous. Thus, we are in the process of chronically exposing telomerase-mutant mice with dysfunctional telomeres to environmental tobacco smoke. We also constructed a mouse tobacco smoke exposure facility for these models at DFCI, which will aid in studying other cancers and diseases caused by tobacco smoke (e.g., emphysema and bladder cancer).
These three areas of research give us a better understanding of the genetic alterations involved in the initiation and progression of cancer.
Recent Awards
Sidney Kimmel Foundation Scholar, 2004
Tisch Foundation Solid Tumor Scholar Award, 2004
select Publications
Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, Halmos B. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 2005;65:7096-101.
Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, Khatry DB, Protopopov A, You MJ, Aguirre AJ, Martin ES, Yang Z, Ji H, Chin L, DePinho RA. High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A 2005;102:9625-30.
Wong KK, Maser RS, Bachoo R, Menon J, Carrasco D, Gu Y, Alt F, DePinho R. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 2003;421:643-8.
Associates
Liang Chen, PhD
Hongbin Ji, PhD
Samanthi Perera, PhD
