Purpose: In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified Slug as selectively overexpressed in the highly invasive cancer cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis. Experimental Design: Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival.We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression. Results: High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse (P = 0.03) and shorter patient survival (P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2 proteins and mRNA in Slug overexpressed cells and xenograft tumors. Conclusions: Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.Lung cancer is the leading cause of cancer death worldwide.Metastasis is the most common cause of death in lung cancer patients and is a major obstacle to the successful treatment. The spread of tumor cells from a primary tumor to the secondary sites within the body is a complicated process involving cell proliferation and migration, degradation of basement membrane, invasion, adhesion, and angiogenesis (1). A variety of positive and negative factors are involved in this highly sophisticated process of metastasis (2). Current clinical means cannot accurately identify those patients who will develop metastasis. To develop effective new strategies for the prediction, diagnosis, and treatment of metastasis of lung cancer, molecular mechanisms controlling metastasis must be identified (3).Cancers are a mass of heterogeneous neoplastic cells with different properties, including metastatic potential (4). During cancer development, some tumor cells acquire metastatic phenotypes, overexpression of metastasis-promoting genes or loss of expression of metastasis-suppressing genes. Recently, several groups have successfully used gene expression profiling techniques and model systems with different invasive or metastatic ability to identify genes that correlate with invasiveness or metastatic potential (5 -9).Multiple rounds of in vitro and in vivo selection of subclones of cancer cells originating from the same primary lung adenocarcinoma may result in the establishment of several ...

Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.

Malignant pleural effusion (MPE) is a common clinical problem in non-small cell lung carcinoma (NSCLC) patients; however, the underlying mechanisms are still largely unknown. Recent studies indicate that the frequency of the L858R mutant form of the epidermal growth factor receptor (EGFR-L858R) is higher in lung adenocarcinoma with MPE than in surgically resected specimens, suggesting that lung adenocarcinoma cells harboring this mutation tend to invade the adjacent pleural cavity. The purpose of this study was to clarify the relationship between the EGFR-L858R mutation and cancer cell invasion ability and to investigate the molecular mechanisms involved in the formation of MPE. We found that expression of EGFR-L858R in lung cancer cells resulted in up-regulation of the CXCR4 in association with increased cancer cell invasive ability and MPE formation. Ectopic expression of EGFR-L858R in lung cancer cells acted through activation of ERK signaling pathways to induce the expression of CXCR4. We also indicated that Inhibition of CXCR4 with small interfering RNA, neutralizing antibody, or receptor antagonist significantly suppressed the EGFR-L858R–dependent cell invasion. These results suggest that targeting the production of CXCR4 and blocking the CXCL12-CXCR4 pathway might be effective strategies for treating NSCLCs harboring a specific type of EGFR mutation.