生物谷報道：8月5日在線出版的一篇《自然》雜志的研究報告報道說,，在腫瘤抑制基因LKB1變異的小鼠體內(nèi),，肺癌的發(fā)生更加迅猛,，這一發(fā)現(xiàn)可能有助于確定那些患者預(yù)后不良，從而制訂更有小的治療方案,。
來自Chapl山北卡羅來娜大學(xué)（UNC）的高級研究員Norman Sharpless表示,，這種基因缺陷似乎會導(dǎo)致一種更為兇險的肺癌，而肺癌一旦開始就很難對付,。非小細胞性肺癌（USCLC）是最致命的惡性腫瘤，因此LKB1的抑制對于人類癌癥來說是一個最致命的基因事件,。”
研究人員認為LKB1的滅活將預(yù)示非小細胞性肺癌出現(xiàn)不良結(jié)果,，可作為更好的風險評估和療效預(yù)測。研究者期望在接下來的幾年時間里能看到有關(guān)LKB1 缺陷性非小細胞性肺癌的臨床特點,。該研究小組已開始這方面的研究,，他們從北卡羅來娜大學(xué)及其附屬醫(yī)院中招募了144名NSCLC病人進行了人體組織的分析。34%的人肺腺癌,，19%的鱗癌以及10 %的大細胞癌病人都發(fā)現(xiàn)了LKB1基因的缺陷?，F(xiàn)在，小組正追蹤這些病人,，以確定LKB1的特定變異和臨床病型之間的關(guān)系,。基于本項研究及其相關(guān)研究,，研究人員能夠按照具體致癌基因損傷類型把病人分成不同的組別,，根據(jù)每個致癌基因的特定療法，來確定更好的治療方案,。
這項研究是在首個小鼠鱗癌模型上進行的,，該模型是KRAS基因突變體細胞所致的一種小鼠肺癌。其他所有基因突變的小鼠肺癌模型都是腺癌,但是鱗癌才是全世界最常見的肺癌類型,。同時,，研究小組的報告指出，和已知的其他基因缺陷（如p16,p53）所造成的肺癌相比,，LKB1基因缺陷腫瘤潛伏期更短,，組織學(xué)譜更廣，轉(zhuǎn)移更頻繁,。這些研究表明LKB1基因在肺癌發(fā)生中的具有關(guān)鍵屏障作用,，控制了腫瘤的發(fā)生、分化和轉(zhuǎn)移,。因此,，在LKBI型腫瘤中，確定相關(guān)的激活通路(如低氧信號通路),，將可能為該類腫瘤治療藥物設(shè)計提供新的思路,。
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.
原文出處：
LKB1 modulates lung cancer differentiation and metastasis
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
Nature (05 Aug 2007) Letters to Editor
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作者簡介：
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
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.
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
