Targeting L1 Cell Adhesion Molecule Using Lentivirus-Mediated Short Hairpin RNA Interference Reverses Aggressiveness of Oral Squamous Cell Carcinoma
Targeting L1 Cell Adhesion Molecule Using Lentivirus-Mediated Short Hairpin RNA Interference Reverses Aggressiveness of Oral Squamous Cell Carcinoma
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DOI：
10.1021/mp1002834
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发表时间：
2010-11-01
影响因子：
4.9
通讯作者：
Hsieh, Chia-Ling
中科院分区：
文献类型：
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作者：
Hung, Shiao-Chen;Wu, I-Hui;Hsieh, Chia-Ling
L1细胞黏附分子（L1CAM）与多种癌症的肿瘤进展有关，但其在口腔鳞状细胞癌（OSCC）中的作用尚未得到研究。在本研究中，我们利用临床标本和细胞系证明了L1CAM在OSCC细胞中过度表达，而在正常角质形成细胞中不表达。这种过度表达与癌细胞的低分化和高侵袭潜能密切相关，支持了L1CAM在人类OSCC肿瘤进展中的重要性。利用慢病毒介导的小发夹RNA（shRNA）靶向在过度表达L1CAM的SCC4细胞中的L1CAM基因表达，通过使细胞周期阻滞在G1期，导致体外细胞增殖显著减少。此外，L1CAM的shRNA敲低强烈减弱了SCC4细胞的迁移和侵袭，并且还观察到这与E - 钙黏蛋白水平升高以及波形蛋白、纤连蛋白和Snail家族转录因子水平降低相关，表明L1CAM表达与上皮 - 间质转化有关。此外，接受原位植入对照SCC4细胞的小鼠由于侵袭性肿瘤生长和区域淋巴结转移在40天内死亡，而在植入L1CAM缺陷型SCC4细胞的小鼠中观察到动物生存期延长以及肿瘤进展被完全抑制，进一步证实了L1CAM在OSCC病理生理学中的根本重要性。我们的研究结果表明，L1CAM是OSCC肿瘤进展的关键介质，利用慢病毒介导的shRNA靶向L1CAM可能是治疗晚期OSCC的一种有用的分子药物方法。
The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in oral squamous cell carcinoma (OSCC) has not been investigated. In the present study, we demonstrated overexpression of L1CAM in OSCC cells, but not in normal keratinocytes, using both clinical specimens and cell lines. This overexpression demonstrated a strong correlation with less differentiation and a higher invasion potential of cancer cells, supporting the significance of L1 CAM in human OSCC tumor progression. Targeting L1CAM gene expression in SCC4 cells overexpressing L1CAM using a lentivirus-mediated small hairpin RNA (shRNA) led to a significant reduction in cell proliferation in vitro via retardation of cell cycle at the G1 phase. In addition, shRNA knockdown of L1CAM strongly attenuated the migration and invasion of SCC4 cells, and this was also observed to parallel increased E-cadherin levels and decreased levels of vimentin, fibronectin, and Snail-family transcription factors, indicating that L1CAM expression was related to the epithelial-mesenchymal transition. Furthermore, while mice receiving orthotopically placed control SCC4 cells died within 40 days due to invasive tumor growth and regional lymph node metastasis, prolonged animal survival and complete suppression of tumor progression was observed in mice implanted with L1CAM-deficent SCC4 cells, further substantiating the fundamental importance of L1CAM in OSCC pathophysiology. Our findings suggested that L1CAM is a critical mediator of tumor progression in OSCC, and targeting L1CAM using lentivirus-mediated shRNA may be a useful molecular pharmaceutical approach for the treatment of advanced OSCC.