Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice

Abstract

Abstract. Lung cancer is commonly associated with multiorgan metastasis, and the bone is a frequent metastatic site for lung cancer. However, the molecular mechanism of organspecific metastasis remains poorly understood. To elucidate this issue, we analyzed in this study genome-wide gene expression profiles of 15 metastatic lesions from three organs (bone, lung and liver) in a mouse model with multi-organ metastasis properties of human non-small cell lung cancer cells (ACC-LC319/ bone2), using a combination of laser-microbeam microdissection and DNA microarrays. We identified 299 genes that could potentially be involved in the organ-selective nature of lung cancer metastasis. Among them, 77 were bone-specifically expressed elements, including genes involved in cell adhesion, cytoskeleton/cell motility, extracellular matrix remodeling and cell-cell signaling as well as genes already known to be involved in the bone metastasis of breast cancers. Quantitative RT-PCR confirmed the specific upregulation of eight genes in bone metastasis tumors, suggesting that these genes may be involved in bone metastasis. Our findings should be helpful for a better understanding of the molecular aspects of the metastatic process in different organs, and could lead to molecular target-based anticancer drugs and prevention of metastasis, especially bone metastasis.

FGFR3 silencing by siRNA inhibits invasion of A549 cells

“…FGFR3 is a member of the FGFR family of tyrosine kinase receptors, and consists of an extracellular domain that includes a signal peptide, followed by 3 Ig-like domains, an acidic box, a transmembrane domain and an intracellular tyrosine kinase domain (32). FGFR3 is activated by binding of the FGF ligand to the extracellular Ig-like domains II and III (3). Subsequently, the trans-autophosphorylation of tyrosine residues in the cytoplasmic domain of FGFR3 stimulates the intrinsic catalytic activity of the receptor, and leads to the activation of downstream signaling pathways (13,33).…”

“…Previous studies have reported that FGFR3 is overexpressed in lung cancer and bone metastasis of lung adenocarcinoma; thus, FGFR3 may be regarded as a potential target for cancer therapy (3,10,11). However, the effect of silencing FGFR3 on the inhibition of invasion of lung carcinoma remains unknown.…”

“…Fibroblast growth factor receptor 3 (FGFR3) is a member of the transmembrane receptor tyrosine kinase (RTK) family, which interacts with FGF ligands and participates in the regulation of cell proliferation, differentiation and tumorigenesis (10,11). Previous studies demonstrated that the expression levels of FGFR3 were significantly upregulated in metastasis of NSCLC, compared with normal lung tissues, according to the results of quantitative analysis of FGFR3 expression in humans (3,10,12). In addition, FGFR3 has been demonstrated to be involved in the RAS/RAF/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK signaling pathway through the activation of p90 ribosomal S6 kinase (13).…”

“…The 5-year survival rate of advanced lung cancer has been reported to be <15% (2). It has been recognized that certain tumors present a predilection for metastasis to specific organs (3,4), being bone, brain, liver and lung the most frequent target organs of metastasis (4). The mechanism of tumor development in lung cancer is likely to be associated with genetic diseases that occur when certain genes are mutated or exhibit abnormalities such as deletions (3).…”

“…It has been recognized that certain tumors present a predilection for metastasis to specific organs (3,4), being bone, brain, liver and lung the most frequent target organs of metastasis (4). The mechanism of tumor development in lung cancer is likely to be associated with genetic diseases that occur when certain genes are mutated or exhibit abnormalities such as deletions (3). Novel strategies for the treatment of lung cancer require the identification of novel molecules that are able to inhibit the invasiveness and metastasis of lung cancer cells (5).…”