Identification of a putative prostate tumor suppressor gene on chromosome 18q22.3
Chromosomal alterations, including amplifications and deletions, are frequently observed during the progression of cancer. Although prostate cancer has a major genetic component, many of the specific genes involved in prostate cancer incidence and progression have remained elusive. Studies estimate the loss of chromosome 18q in prostate cancer to be as high as 45%. Allelic imbalance analyses performed in our laboratory on prostate tumors revealed a region of loss at 18q22.3. Additional studies demonstrated that this loss is associated with metastatic disease. Furthermore, somatic cell genetic experiments demonstrated that the introduction of chromosome 18 into metastatic prostate cancer cell lines affect both the growth and metastatic potential. Taken all together, these data provide strong evidence for at least one tumor suppressor or metastasis suppressor gene on distal chromosome 18 in prostate cancer. Expression analysis of all the known genes in the region of loss, determined by allelic imbalance studies, identified a single gene whose expression was significantly reduced in some prostate tumors and prostate cell lines when compared to controls. This gene, NETO1, codes for a neuropilin and tolloid-like protein. Sequence analysis of this gene in the prostate cancer cell line DU145 identified a frame shift mutation. Introduction of NETO1 into DU145 cells significantly reduced the cell growth capacity. The NETO1 protein contains CUB domains that are very similar to those found in neuropilins. Neuropilins are also implicated in cancer and angiogenesis. Increased levels of neuropilin 1 in prostate cancer cells are associated with metastatic potential and advanced disease and is known to interact with VEGF. Since NETO1 has high homology to neuropilin 1, it may play a role in the VEGF-Neuropilin 1 signaling pathway.