Oncogene:TIP30蛋白促肺癌机制

2012-07-02 Beyond 生物谷

非小细胞肺癌(Non-small-cell carcinoma )与“非小细胞癌”同义。非小细胞型肺癌,包括鳞癌、腺癌、大细胞癌,与小细胞癌相比其癌细胞生长分裂较慢,扩散转移相对较晚。非小细胞肺癌约占肺癌总数的80-85%。 肺腺癌一种人非小细胞肺癌(NSCLC)最常见的类型,临床以及基础研究发现肿瘤组织中经常高表达表皮生长因子受体(EGFR)。然而,EGFR的过度表达对肺腺癌的发病机制尚未完全

非小细胞肺癌(Non-small-cell carcinoma )与“非小细胞癌”同义。非小细胞型肺癌,包括鳞癌、腺癌、大细胞癌,与小细胞癌相比其癌细胞生长分裂较慢,扩散转移相对较晚。非小细胞肺癌约占肺癌总数的80-85%。

肺腺癌一种人非小细胞肺癌(NSCLC)最常见的类型,临床以及基础研究发现肿瘤组织中经常高表达表皮生长因子受体(EGFR)。然而,EGFR的过度表达对肺腺癌的发病机制尚未完全了解。

最近研究发现减少TIP30蛋白(30kDa艾滋病毒达相互作用蛋白-1)的表达与人非小细胞肺癌转移相关,但TIP30蛋白的不足与非小细胞肺癌之间的因果关系尚不清楚。近日,Oncogene杂志上一则研究显示,TIP30的缺失导致小鼠会自发形成肺腺瘤和腺癌。异常扩张的细支气管肺泡干/祖细胞及肺泡Ⅱ型细胞会加速肿瘤发展,也增加了TIP30敲除小鼠肺肿瘤组织中表皮生长因子受体和其下游信号分子的表达。

此外,人肺腺癌细胞敲除TIP30蛋白后,造成EGFR活性EGFR上升,导致AKT的磷酸化ERK1 /2的表达上调。重要的是,在人肺腺癌组织中,TIP30蛋白低表达与病人整体生存时间的延长成正相关性。

总之,这些结果表明TIP30蛋白作为一种肿瘤抑制基因,抑制表皮生长因子受体细胞质和核信号,抑制肺腺肿瘤组织中血管生成,降低TIP30蛋白表达靶向抑制EGFR信号可能是肺腺癌患者一种新的治疗策略。

doi:10.1038/onc.2012.253
PMC:
PMID:

TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice.

Li A, Zhang C, Gao S, Chen F, Yang C, Luo R, Xiao H.

Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses epidermal growth factor receptor (EGFR). However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 (30kDa HIV-1 Tat interacting protein) is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II (AT2) cells, and also increased expression of EGFR and its downstream signaling factors in the lung of Tip30(-/-) mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung, and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30-expression lung adenocarcinoma.

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    2012-11-22 cy0324
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    2012-07-04 zsyan

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