Down-Regulation of DUSP6 Expression in Lung Cancer Its Mechanism and Potential Role in Carcinogenesis
Down-Regulation of DUSP6 Expression in Lung Cancer Its Mechanism and Potential Role in Carcinogenesis
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DOI：
10.2353/ajpath.2009.080489
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发表时间：
2009-08-01
影响因子：
6
通讯作者：
Kitamura, Hitoshi
中科院分区：
文献类型：
--
作者：
Okudela, Koji;Yazawa, Takuya;Kitamura, Hitoshi
我们的初步研究表明，致癌的ICRAS （KRAS/V12）显著抑制永活气道上皮细胞（NHBE-T，病毒抗原灭活的P53和RB蛋白）的生长。这一过程似乎是一个新的事件，不同于由P53或RB诱导的所谓的过早衰老，这表明存在一种新的肿瘤抑制因子，在致癌KRAS的下游起作用。在全面搜索KRAS/V12调控表达水平的基因后，我们将重点放在了DUSP6上，这是RAS-ERK通路的关键负反馈调节因子。然而，一个显性阴性DUSP6突变体未能挽救KRAS/ v12诱导的生长抑制，但对KRAS/ v12转导的NHBE-T产生的死亡存活细胞亚群具有更强的锚定非依赖性生长活性。在大多数肺癌细胞中，DUSP6的表达水平低于NHBE-T， DUSP6的恢复抑制了细胞的生长。在原发性肺癌中，DUSP6的表达水平随着肿瘤生长活性和组织学分级的增加而降低。在17.7%的病例中发现DUSP6位点的杂合性缺失，并与表达水平降低有关。这些结果表明DUSP6是一种生长抑制因子，其失活可促进肺癌的进展。通过对致癌KRAS下游靶点的全面搜索，我们在这里确定了一个与致癌有关的重要因素。（美国病理学杂志2009,175:867-881;DOI: 10.2353/ajpath.2009.080489）
Our preliminary studies revealed that oncogenic ICRAS (KRAS/V12) dramatically suppressed the growth of immoritalized airway epithelial cells (NHBE-T, with viral antigen-inactivated P53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either P53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to die surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell fines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS. (Am J Pathol 2009,175:867-881; DOI: 10.2353/ajpath.2009.080489)