生物谷报道：8月5日在线出版的一篇《自然》杂志的研究报告报道说，在肿瘤抑制基因LKB1变异的小鼠体内，肺癌的发生更加迅猛，这一发现可能有助于确定那些患者预后不良，从而制订更有小的治疗方案。
来自Chapl山北卡罗来娜大学（UNC）的高级研究员Norman Sharpless表示，这种基因缺陷似乎会导致一种更为凶险的肺癌，而肺癌一旦开始就很难对付。非小细胞性肺癌（USCLC）是最致命的恶性肿瘤，因此LKB1的抑制对于人类癌症来说是一个最致命的基因事件。”
研究人员认为LKB1的灭活将预示非小细胞性肺癌出现不良结果，可作为更好的风险评估和疗效预测。研究者期望在接下来的几年时间里能看到有关LKB1 缺陷性非小细胞性肺癌的临床特点。该研究小组已开始这方面的研究，他们从北卡罗来娜大学及其附属医院中招募了144名NSCLC病人进行了人体组织的分析。34%的人肺腺癌，19%的鳞癌以及10 %的大细胞癌病人都发现了LKB1基因的缺陷。现在，小组正追踪这些病人，以确定LKB1的特定变异和临床病型之间的关系。基于本项研究及其相关研究，研究人员能够按照具体致癌基因损伤类型把病人分成不同的组别，根据每个致癌基因的特定疗法，来确定更好的治疗方案。
这项研究是在首个小鼠鳞癌模型上进行的，该模型是KRAS基因突变体细胞所致的一种小鼠肺癌。其他所有基因突变的小鼠肺癌模型都是腺癌,但是鳞癌才是全世界最常见的肺癌类型。同时，研究小组的报告指出，和已知的其他基因缺陷（如p16,p53）所造成的肺癌相比，LKB1基因缺陷肿瘤潜伏期更短，组织学谱更广，转移更频繁。这些研究表明LKB1基因在肺癌发生中的具有关键屏障作用，控制了肿瘤的发生、分化和转移。因此，在LKBI型肿瘤中，确定相关的激活通路(如低氧信号通路)，将可能为该类肿瘤治疗药物设计提供新的思路。
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.
原文出处：
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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作者简介：
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.
相关基因：
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
