ANX7, a candidate tumor suppressor gene for prostate cancer

Abstract

The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P ‫؍‬ 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression.cancer genetics ͉ chromosome 10q21 ͉ loss of heterozygosity T he gene for annexin 7 (ANX7 ‡ ‡ , synexin; refs. 1-6) is located on human chromosome 10q21, where potential tumor suppressor genes (TSGs) have been hypothesized to exist for prostate and other cancers (5, 7-15). However, the specific relevance of the ANX7 gene for cancer only became apparent after we created a knockout for this gene in the mouse (16). Although the homozygous Anx7(Ϫ͞Ϫ) deletion is embryonically lethal, the phenotype of the Anx7(ϩ͞Ϫ) heterozygote includes calcium signaling deficits and growth defects such as gigantism, and selective organomegaly. As these mice aged, we also began to observe a profoundly increased frequency of disparate spontaneous tumors in both male and female Anx7(ϩ͞Ϫ) mutants (17).Because of these observations, and the chromosomal location of the gene, we hypothesized that ANX7 might be a candidate TSG associated with 10q21 locus. Commonly, TSGs can suppress growth of tumor cells, in vitro, and are frequently inactivated by mutations, deletions, or loss of expression in tumors, in vivo. In addition, loss of heterozygosity (LOH) often is observed for these genes in clinical tumor specimens. Therefore, to test this hypothesis for the ANX7 gene, we analyzed the action of the ANX7 gene on colony formation by human tumor cell lines. We also examined the expression of the ANX7 protein in hundreds of prostate cancers by using tumor tissue microarray technology. Finally, we tested a panel of primary and metastatic prostate cancers for evidence of LOH.In this paper we show that the ANX7 gene suppresses the growth of the prostate tumor cell lines DU145 and LNCaP. Consistently, in a prostate tissue microarray, we...

Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration

“…Indeed, treatment of LNCaP cells, which have completely lost annexin II expression (Figure 3, this study), with the DNA methyltransferase inhibitor 5-aza-deoxycytidine reactivated the annexin II expression in these cells (Chetcuti et al, 2001), suggesting that promoter hypermethylation might be responsible for the gene silencing. Interestingly, another annexin molecule, annexin 7, is also lost in prostate cancer cells and has been proposed as a prostate tumor suppressor (Srivastava et al, 2001). Different from annexin II, the loss of annexin 7 expression appears to be because of loss of heterozygosity, thus indicative of gene mutations (Srivastava et al, 2001).…”

“…Interestingly, another annexin molecule, annexin 7, is also lost in prostate cancer cells and has been proposed as a prostate tumor suppressor (Srivastava et al, 2001). Different from annexin II, the loss of annexin 7 expression appears to be because of loss of heterozygosity, thus indicative of gene mutations (Srivastava et al, 2001). It is of interest to note that S100A2, which, like p11 or S100A10, belongs to the S100 family of proteins, is also reduced in LNCaP cells (protein spot 4 in Figure 1b, panel d), as observed in breast cancer cells (Lee et al, 1992) and recently reported by others in prostate cancer cells (Gupta et al, 2002).…”

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

“…TP53 (14) and PTEN (15) are among tumour suppressor genes shown to be inactivated in prostate cancer. Comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses suggest further oncogenes and tumour suppressor genes (16)(17)(18)(19)(20) (reviewed in ref. 21).…”

Genome-wide screening for complete genetic loss in prostate cancer by comparative hybridization onto cDNA microarrays

“…For example, mapping of loss within the chromosome 10 region demonstrated that SFTPA1 and SFTPA2 were deleted, but that the flanking genes PPIF and Q9NQE0 were not tract and the prostate, and has been proposed to have a role in innate immune response (Khubchandani and Snyder, 2001). The SFTPA1 and SFTPA2 genes located at map position 89 Mb are flanked by two genes that have already been proposed as prostate cancer suppressor genes: the PTEN gene at 93 Mb and the ANX7 gene at 78 Mb (Li et al, 1997;Srivastava et al, 2001).…”