Novel Mutations in c-Cbl Ubiquitin Ligase Gene in Taiwanese Lung Cancer

台灣肺癌病人c-Cbl 泛素連接酶基因之新型突變發現與探討

譚一泓(Yi-Hung Tan) ； Ravi Salgia ； 謝秀梅(Hsiu-Mei Hsieh-Li) ； 王憶卿(Yi-Ching Wang)

《Bio Formosa》 44卷1期 (2009/06) Pp. 1-10

https://doi.org/10.6248/BF.2009.44(1).01

摘要

目的：Cbl(Casitas B-lineage lymphoma)是一個哺乳類動物基因，位於人類染色體11q23.3的位置，參與細胞訊息傳導，以及蛋白質泛蛋白化(ubiquitination)。c-Cbl蛋白是Cbl家族的一員，目前已被發現主要參與細胞訊息傳導路徑以及酪氨酸激酶接受器的負調控角色。最新的研究發現，許多酪氨酸激酶接受器，像是c-Met和EGFR，在許多癌症中都有過度表現的情形。因此，本研究推測c-Cbl的突變或許是造成c-Met和EGFR過度表現的原因之一。 材料與方法：本研究利用基因定序及生物功能探討的方式，在三十個台灣肺癌病人腫瘤組織中來研究c-Cbl的基因突變圖譜，並在二株細胞株探討c-Cbl基因突變後影響細胞生長的狀況。 結果：本研究發現，三十個肺癌病人樣本中，有九個c-Cbl突變型。此外，有兩個變異存在於c-Cbl的表現子(exon)；其中一個為新發現的體細胞突變型Q249E，而另一個為已知的基因多型性變異L620F。因此c-Cbl突變機率於腫瘤組織為百分之三十(9/30)，於正常組織為百分之二十七(8/30)。另一方面，Q249E突變在A549細胞中會導致細胞生長率增加。 結論：c-Cbl的突變很有可能是造成肺癌發生的原因之一。基於c-Cbl可以負調控酪氨酸激酶接受器的表現，或許將來可以發展c-Cbl之基因治療，針對沒有酪氨酸激酶接受器突變而對酪氨酸激酶接受器的抑制劑有抗藥性的病人給予治療，這將會是新的癌症治療方向。

關鍵字

c-Cbl ； c-Met ； EGFR ； 泛素連接酶 ； 突變

並列摘要

BACKGROUND. Cbl (Casitas B-lineage lymphoma) is a mammalian gene located on human chromosome 11q23.3 and involves in cell signaling and protein ubiquitination. One of the Cbl family proteins, c-Cbl, has been recognized as a key player in the negative regulation of signaling pathways such as receptor tyrosine kinase (RTK) pathway. Recent studies found that RTKs, such as c-Met and EGFR, are overexpressed in many cancers. Thus, we hypothesized that the alteration of their negative regulators, such as c-Cbl mutations, may contribute to the oncogenic potential of c-Met and EGFR.
METHODS. We investigated c-Cbl mutation spectrum in tumor and corresponding normal tissues from 30 Taiwanese lung cancer patients by polymerase chain reaction and direct sequencing and examined biological function of these c-Cbl mutations in cell models. RESULTS. We identified 9 c-Cbl mutations in 30 Taiwanese lung cancer samples. Only Q249E mutant did not appear in corresponding normal tissue, suggesting that Q249E is a novel somatic mutation. The total mutation rate for tumor was 30% (9/30) and for normal was 27% (8/30). The other 8 mutations included a known single nucleotide polymorphism L620F and 7 novel or known intronic polymorphisms in c-Cbl. In addition, transient expression of Q249E mutant increased cell viability in A549 lung cancer cell line.
CONCLUSIONS. Our results provide new evidence that c-Cbl mutations play a role in lung tumorigenesis. In addition, c-Cbl may be a therapeutic target for patient who does not carry mutations in the RTK itself and is resistant to RTK inhibitors treatments.

並列關鍵字

c-Cbl ； c-Met ； EGFR ； ubiquitin ligase ； mutation