Chen Chang-Han, Lai Jin-Mei, Chou Teh-Ying, Chen Cheng-Yu, Su Li-Jen, Lee Yuan-Chii, Cheng Tai-Shan, Hong Yi-Ren, Chou Chen-Kung, Whang-Peng Jacqueline, Wu Yu-Chung, Huang Chi-Ying F
Department of Otolaryngology and Kaohsiung Chang Gung Head and Neck Oncology Group, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
PLoS One. 2009;4(4):e5052. doi: 10.1371/journal.pone.0005052. Epub 2009 Apr 1.
Lung adenocarcinoma is the leading cause of cancer-related deaths among both men and women in the world. Despite recent advances in diagnosis and treatment, the mortality rates with an overall 5-year survival of only 15%. This high mortality is probably attributable to early metastasis. Although several well-known markers correlated with poor/metastasis prognosis in lung adenocarcinoma patients by immunohistochemistry was reported, the molecular mechanisms of lung adenocarcinoma development are still not clear. To explore novel molecular markers and their signaling pathways will be crucial for aiding in treatment of lung adenocarcinoma patients.
METHODOLOGY/PRINCIPAL FINDINGS: To identify novel lung adenocarcinoma-associated /metastasis genes and to clarify the underlying molecular mechanisms of these targets in lung cancer progression, we created a bioinformatics scheme consisting of integrating three gene expression profile datasets, including pairwise lung adenocarcinoma, secondary metastatic tumors vs. benign tumors, and a series of invasive cell lines. Among the novel targets identified, FLJ10540 was overexpressed in lung cancer tissues and is associated with cell migration and invasion. Furthermore, we employed two co-expression strategies to identify in which pathway FLJ10540 was involved. Lung adenocarcinoma array profiles and tissue microarray IHC staining data showed that FLJ10540 and VEGF-A, as well as FLJ10540 and phospho-AKT exhibit positive correlations, respectively. Stimulation of lung cancer cells with VEGF-A results in an increase in FLJ10540 protein expression and enhances complex formation with PI3K. Treatment with VEGFR2 and PI3K inhibitors affects cell migration and invasion by activating the PI3K/AKT pathway. Moreover, knockdown of FLJ10540 destabilizes formation of the P110-alpha/P85-alpha-(PI3K) complex, further supporting the participation of FLJ10540 in the VEGF-A/PI3K/AKT pathway.
CONCLUSIONS/SIGNIFICANCE: This finding set the stage for further testing of FLJ10540 as a new therapeutic target for treating lung cancer and may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in lung cancer cells.
肺腺癌是全球男性和女性癌症相关死亡的主要原因。尽管在诊断和治疗方面取得了最新进展，但死亡率仍然很高，总体5年生存率仅为15%。这种高死亡率可能归因于早期转移。虽然通过免疫组织化学报道了几种与肺腺癌患者不良/转移预后相关的著名标志物，但肺腺癌发展的分子机制仍不清楚。探索新的分子标志物及其信号通路对于辅助治疗肺腺癌患者至关重要。
方法/主要发现：为了鉴定新的肺腺癌相关/转移基因，并阐明这些靶点在肺癌进展中的潜在分子机制，我们创建了一个生物信息学方案，该方案包括整合三个基因表达谱数据集，包括成对的肺腺癌、继发性转移瘤与良性肿瘤，以及一系列侵袭性细胞系。在鉴定出的新靶点中，FLJ10540在肺癌组织中过表达，并且与细胞迁移和侵袭相关。此外，我们采用了两种共表达策略来确定FLJ10540参与了哪条通路。肺腺癌阵列图谱和组织微阵列免疫组化染色数据显示，FLJ10540与VEGF-A以及FLJ10540与磷酸化AKT分别呈现正相关。用VEGF-A刺激肺癌细胞会导致FLJ10540蛋白表达增加，并增强与PI3K的复合物形成。用VEGFR2和PI3K抑制剂处理通过激活PI3K/AKT通路影响细胞迁移和侵袭。此外，敲低FLJ10540会破坏P110-α/P85-α-(PI3K)复合物的形成，进一步支持FLJ10540参与VEGF-A/PI3K/AKT通路。
结论/意义：这一发现为进一步测试FLJ10540作为治疗肺癌的新治疗靶点奠定了基础，并可能有助于开发能够阻断肺癌细胞中PI3K/AKT通路的新治疗策略。
