Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer

Abstract

BackgroundSomatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line.MethodsColonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion.ResultsIn case of normal aging SST mRNA expression did not alter, but decreased in cancer (p<0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70%±0.79%) compared to CRC (0%±0%) (p<0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2%±11.6%) compared to healthy young individuals (3.5%±1.9%) (p<0.05).ConclusionsIn cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation.

Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization

“…SST is a neuropeptide that has been shown in models of breast cancer to both inhibit growth factors and hormones known to promote tumour growth, as well as prevent receptor signalling that can trigger apoptosis [ 12 ]. Additionally, the role of epigenetic silencing as a means of suppressing SST expression in tumour cells has previously been suggested by the observed hypermethylation of the SST promoter CpG island in multiple tumour types including cervical cancer [ 13 ], colorectal cancer [ 14 , 15 ], gastric cancer [ 16 ], and renal cell carcinoma [ 17 ]. VGLL4 has also been identified as a potential tumour suppressor gene across multiple tumour types including breast cancer [ 18 ], gastric cancer [ 19 ], and lung cancer [ 20 ] and overexpression of VGLL4 has been found to suppress breast tumour growth in vivo [ 18 ].…”

Identification of aberrantly methylated differentially expressed genes in glioblastoma multiforme and their association with patient survival

“…Somatostatin, encoded by the SST gene, is a peptide hormone secreted by parts of the CNS that affect neurotransmission and cell proliferation (36,37). A hypermethylation-associated decrease in somatostatin expression was reported to be important for uncontrolled proliferation of colorectal cancer and gastric cancer (38–40).…”

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

“…Most of the genes evaluated in this study were reported to have a (putative) tumor suppressive function (i.e., C13orf18 [24], EPB41L3 [25–29], PRDM14 [30], SOX1 [31,32], SST [33,34], ZIC1 [35,36], and ZSCAN1 [37,38]). The remaining genes with a currently unknown function await further study.…”