Inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering RNAs targeting HER2eu.

摘要

Amplification and over-expression of HER2eu oncogene is found in diverse types of human cancers, and is closely related to tumor occurrence, metastasis, angiogenesis and chemotherapy resistance. Therapeutic agents targeting HER2eu have been intensively addressed over the past decades. In non-small cell lung cancers (NSCLCs), the prevalence of HER2eu activation, its role in prognosis, and its possible implications as a therapeutic target, are still to be elucidated. Here we show that the abundant or moderate over-expression of HER2eu could be detected in both pulmonary adenocarcinoma and pulmonary large cell carcinoma cell lines. Stable knockdown of HER2eu expression in the NSCLC cell line SPC-A-1 was achieved by vector-based small interfering RNAs (siRNAs), which consequently caused significant decrease in cell proliferation and clone forming efficiency, as well as cell cycle arrest at G(1) phase. Compared with the parental NSCLC cells, HER2eu knockdown cells exhibited attenuated capacities in developing tumors in nude mice, and the growth tumors xenografts derived from these cells were dramatically regressed. These data provided direct evidence that HER2eu signaling is essential for tumorigenicity of NSCLC cells, and suggested that siRNAs targeted to HER2eu may provide a novel therapeutic strategy in the treatment of NSCLC, especially when combined with traditional therapeutics or via development of vector-based siRNAs of multiple targets that synergistically contribute to carcinogenesis, e.g. EGFR and HER2eu.