演題抄録

一般口演

開催概要
開催回
第56回・2018年・横浜
 

ALK融合遺伝子により誘導される正常および不死化ヒト細胞における細胞老化と形質転換

演題番号 : O1-1

[筆頭演者]
演者)宮永 晃彦:1,2 
[共同演者]
Izumi Horikawa:1、尾池 貴洋:1、Jessica Beck:1、Ana I. Robles:1、Delphine Lissa:1、清家 正博:2、弦間 昭彦:2、間野 博行:3、Curtis C. Harris:1

1:Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, USA、2:日本医科大学・呼吸器内科、3:国立がん研究センター研究所

 

Chromosomal inversions involving ALK and EML4 generate a fusion protein EML4-ALK with the constitutive ALK kinase activity in non-small cell lung carcinoma (NSCLC). The basic understanding of EML4-ALK remains insufficient due to the lack of functional studies using normal human cells. We here investigate the activities of EML4-ALK in mortal and immortalized normal human cells. The expression of EML4-ALK in normal, mortal human fibroblasts resulted in proliferation arrest with characteristics of cellular senescence. The EML4-ALK-induced senescence occurred later than Ras-induced senescence but earlier than natural replicative senescence, which may be explained by the differential rates of DNA damage accumulation. In contrast, when EML4-ALK was expressed in telomerase reverse transcriptase (hTERT)-immortalized normal human fibroblasts, the cells showed accelerated proliferation and anchorage-independent growth, revealing its transformation activity. No chromosome aberration, no mutation or loss of p53, nor impairment of the p16INK4A response was associated with this transformation. In both mortal and immortalized cells, EML4-ALK induced the phosphorylation of STAT3, which is involved in both cellular senescence and transformation. EML4-ALK was also able to transform hTERT-immortalized human bronchial epithelial cells, a cell type relevant to NSCLC. Our data not only validate that EML4-ALK functions as an oncogene in human cells, but also suggest that telomerase-mediated immortalization manifests the oncogenic activity of EML4-ALK, switching from its senescence-inducing activity. This study also provides the isogenic pairs of human cell lines with and without EML4-ALK as a novel in vitro model for screening and testing candidate drugs.

前へ戻る