4041

LRP5

low density lipoprotein receptor-related protein 5;LRP5;low density lipoprotein receptor-related protein 5

low density lipoprotein receptor-related protein 7|low-density lipoprotein receptor-related protein 5

11q13.4

protein-coding

The Wingless-type (Wnt) family of proteins and its coreceptor LRP5 have recently been implicated in human skeletal development. Wnt pathway modulates cell fate and cell proliferation during embryonic development and carcinogenesis through activation of receptor-mediated signaling. Osteosarcoma (OS) is a bone-forming tumor of mesenchymal origin whose growth control has been linked to autocrine or paracrine stimulation by several growth factor families. We examined 4 OS cell lines for WNT1, WNT4, WNT5A, WNT7A, WNT11, FZD1-10 and LRP5 expression by reverse transcription polymerase chain reaction (RT-PCR). In addition, RT-PCR for LRP5 expression was performed in 44 OS patient samples and the findings were correlated with clinical data. expression profiling of Wnts and their receptors revealed the presence of several isoforms in OS cell lines. Overall, 22/44 (50%) of OS patient samples showed evidence of LRP5 expression. Presence of LRP5 correlated significantly with tumor metastasis (p = 0.005) and the chondroblastic subtype of OS (p = 0.045). In addition, patients whose tumors were positive for LRP5 showed a trend toward decreased event-free survival (p = 0.066). No significant association was found between LRP5 expression and age, gender, site of disease, site of metastasis or degree of chemotherapy-induced tumor necrosis. Sequencing of exon 3 of LRP5 in 10 OS patient-derived cell cultures showed no activating mutation of LRP5. These results showed that expression of LRP5 is a common event in OS and strongly suggest a role for LRP and Wnt signaling in the pathobiology and progression of this disease.

expression of astrocyte-elevated gene-1, a novel oncoprotein, is elevated in multiple cancers and plays a vital role in tumor cell growth, invasion, angiogenesis, and progression to metastasis. However, the functional significance of astrocyte-elevated gene-1 in non-small cell lung cancer still remains unclear. Our present study showed that the markedly up-regulated expression of astrocyte-elevated gene-1 was observed in non-small cell lung cancer cell lines and tissues at the level of both transcription and translation. Simultaneously, ectopic expression or small interfering RNA silencing of astrocyte-elevated gene-1 markedly enhanced or inhibited the invasive ability of non-small cell lung cancer cells, respectively. At the molecular level, we also revealed that the function of astrocyte-elevated gene-1 in promoting metastasis was associated with the activation of matrix metalloproteinase-9 expression. Consistent with these observations, immunostaining analysis revealed a significant positive correlation between astrocyte-elevated gene-1 and matrix metalloproteinase-9. Moreover, subcutaneous xenografts of non-small cell lung cancer cells engineered to express astrocyte-elevated gene-1 were highly invasive compared with the parental cells and expressed a high level of matrix metalloproteinase-9. In archival non-small cell lung cancer specimens, high astrocyte-elevated gene-1 expression correlated significantly with clinical staging (P = .048), differentiation (P = .023), and lymph node metastasis (P = .032). The overall survival time in patients with high astrocyte-elevated gene-1 expression was notably shorter than that in patients with low astrocyte-elevated gene-1 expression (P < .001). Taken together, our results indicate that astrocyte-elevated gene-1 plays a crucial role in the carcinogenesis and aggressiveness of non-small cell lung cancer, promoting its metastasis by modulating matrix metalloproteinase-9 expression and leading to a poor clinical prognosis.

Prostate cancer (PCa) is a common hormone-dependent malignancy associated with the development of skeletal metastases. This is due to the increased expression of a number of growth factors, cytokines, and proteases which collectively drive the metastatic cascade in general and increased propensity to develop skeletal metastasis in particular. While a number of signaling pathways have been implicated in PCa progression, the highly complex wnt/beta-catenin pathway is unique due to its ability to regulate gene expression, cell invasion, migration, survival, proliferation, and differentiation to contribute in the initiation and progression of PCa. Members of the wnt family bind to the Frizzle proteins or lipoprotein-related receptor proteins 5, 6 (LRP5, -6) to activate this key pathway. In the current study, we have investigated the role of wnt/beta-catenin pathway in PCa progression, skeletal metastasis, and gene expression using the dominant negative plasmid of LRP5 (DN-LRP5) and human PCa cells PC-3. Inactivation of LRP5 resulted in mesenchymal to epithelial shift, lack of translocation of beta-catenin to cell surface, increased tumor cell proliferation, decreased colony formation, migration and invasion in vitro. These effects were attributed to decreased expression of pro-invasive and pro-metastatic genes. In in vivo studies, PC-3-DN-LRP5 cells developed significantly smaller tumors and a marked decrease in skeletal lesion area and number as determined by X-ray, micro (mu) CT and histological analysis. Collectively results from these studies demonstrate the dominant role of this key pathway in PCa growth and skeletal metastasis and its potential as a viable therapeutic target.