Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms

Abstract

The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2 0 -deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dosedependent cell proliferation in a SOCS-1-methylated cell line (PL10, P ¼ 0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

“…On the other hand, inactivation of the negative regulator, SOCS-1, also leads to the activation of the JAK/STAT pathway. Downregulation of SOCS-1 by gene promoter hypermethylation has been recently reported in 65% of HCC cell line, 62.9% of multiple myeloma patients samples and 31.6% of pancreatic cancer cell lines with resultant activation of STAT3 (Yoshikawa et al, 2001;Fukushima et al, 2003;Galm et al, 2003). Moreover, restoration of SOCS-1 suppresses tumour growth in HCC and haematopoietic malignancy (Frantsve et al, 2001;Yoshikawa et al, 2001;Rottapel et al, 2002).…”

“…Suppressor of cytokine signalling-1 is downregulated by methylation of the CpG island in human hepatocellular carcinoma (HCC), multiple myeloma and pancreatic ductal neoplasm (Yoshikawa et al, 2001;Nagai et al, 2002;Fukushima et al, 2003;Galm et al, 2003;Okochi et al, 2003). On the other hand, restoration of SOCS-1 suppressed growth in HCC cell lines and oncogene-activated haematopoietic cells (Yoshikawa et al, 2001;Rottapel et al, 2002).…”

Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNα

“…[11][12][13][14][15] Mouse embryo fibroblasts from SOCS-1 knockout mice are less sensitive to contact inhibition and more sensitive to oncogene-induced transformation, leading to the hypothesis that SOCS-1 is a tumour suppressor. 16 Furthermore, SOCS-1 inhibits cell growth or transformation induced by some, but not all, oncogenes.…”

SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition

“…Recently, SOCS-1 was found to be frequently silenced by hypermethylation in hepatocellular carcinoma (HCC) (Yoshikawa et al, 2001), pancreatic carcinoma (Fukushima et al, 2003), and hepatoblastomas . SOCS-1 appears to have tumor suppressor activity, since restoration of the SOCS-1 gene expression in HCC cells caused growth suppression and induction of apoptosis (Yoshikawa et al, 2001).…”