Epigenetic inactivation of RASSF14 in lung and breast cancers and malignant phenotype suppression
Epigenetic inactivation of RASSF14 in lung and breast cancers and malignant phenotype suppression
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DOI：
10.1093/jnci/93.9.691
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发表时间：
2001-05-02
影响因子：
10.3
通讯作者：
Minna, JD
中科院分区：
文献类型：
--
作者：
Burbee, DG;Forgacs, E;Minna, JD
背景资料：最近鉴定的RASSF 1基因座位于染色体3p21.3的120-内切酶区域内，该区域在肺癌和乳腺癌中经常发生等位基因丢失。我们探讨了RASSF 1编码肺癌和乳腺癌肿瘤抑制基因的假设。研究方法：我们评估了27个非小细胞肺癌（NSCLC）细胞系、107个切除的NSCLC、47个小细胞肺癌（SCLC）细胞系、22个乳腺癌细胞系、39个切除的乳腺癌、104个非恶性肺样本中两种RASSF 1基因产物RASSF 1A和RASSF 1C的表达及其各自启动子的甲基化状态，在三种乳腺和肺上皮细胞培养中，我们还用含有RASSF 1A互补DNA的载体转染了缺乏RASSF 1A表达的肺癌细胞系，以确定外源性表达RASSF 1A是否会影响该细胞系的体外生长和体内致瘤性。所有统计检验均为双侧检验。结果如下：RASSF 1A信使RNA在非恶性上皮细胞培养中表达，但在100%的SCLC、65%的NSCLC或60%的乳腺癌细胞系中不表达。相比之下，RASSF 1C在所有非恶性细胞培养物和几乎所有癌细胞系中表达。在100%的SCLC、63%的NSCLC、63%的乳腺癌细胞系、30%的原发性NSCLC和39%的原发性乳腺肿瘤中检测到RASSF 1A启动子高甲基化，但在非恶性肺组织中均未检测到RASSF 1A启动子高甲基化，切除的NSCLC中RASSF 1A启动子高甲基化与患者生存受损相关（P =.046），RASSF 1A在缺乏表达的细胞系中的外源性表达降低了体外集落形成和体内致瘤性。结论：RASSF 1A是一个潜在的肿瘤抑制基因，在肺癌和乳腺癌中通过其启动子区域的超甲基化而经历表观遗传失活。
Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell Lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures, We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. Ail statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 63% of breast cancer lines, in 30% of primary NSCLCs, and in 39% of primary breast tumors but in none of the nonmalignant lung tissues, RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P =.046), Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.