Gene Expression Profiling Identifies Genes Associated with Invasive Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

The molecular pathology of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has not been well characterized, and there are no reliable markers to predict the presence of an associated invasive carcinoma in IPMNs. Using oligonucleotide microarrays, we performed a large-scale gene expression profiling of 12 IPMNs with or without an associated invasive carcinoma. A subset of genes identified was validated for the gene expression patterns in a large panel of IPMNs by reverse-transcription polymerase chain reaction and/or immunohistochemistry. A total of 673 transcripts were identified as expressed at significantly higher levels (P < 0.05 and at fivefold or greater) in IPMNs relative to normal pancreatic ductal epithelial samples. Of interest, many of the genes identified as overexpressed in IPMNs have also been previously reported to be highly expressed in infiltrating ductal adenocarcinoma of the pancreas. By analyzing genes overexpressed selectively in IPMNs with an associated invasive carcinoma (n ‫؍‬ 7), we also identified a panel of genes potentially associated with the invasive phenotype of the neoplasms. Immunohistochemical validation revealed that claudin 4, CXCR4, S100A4, and mesothelin were expressed at significantly high frequency in invasive IPMNs than in noninvasive IPMNs. Notably, the expression of at least two of the four proteins was observed in 73% of 22 invasive IPMNs but in none of 16 noninvasive IPMNs (P < 0.0001). Our findings suggest that preoperative assessment of gene expression profiles may be able to differentiate invasive from noninvasive IPMNs.

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

“…20,27 Immunohistochemical analysis revealed overexpression of CLDN4 protein in virtually all primary (99%) and metastatic (100%) pancreatic tissue samples and in 10 out of 11 samples of PanIN, a known precursor lesion to pancreatic ductal adenocarcinoma. 21 Moreover, CLDN4 has been shown to be overexpressed in intraductal papillary mucinous neoplasms as well by gene expression profiling, 14,28 although the expression analysis was limited within a small number of patients. In the present study, we demonstrated an increase in the CLDN4 mRNA expression along the progression of intraductal papillary mucinous neoplasms.…”

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

“…In addition to its role as a putative tumor suppressor in normal cellular growth, some other studies also suggest that PC4 may also be involved in the tumorigenesis, probably through the activation or synergizing of other genes required in the pathogenesis of cancer. [20][21][22][23][24] A possible involvement of PC4 in oncogenesis in a chemically induced rat pancreatic B-cell tumor was first observed in 1984. 21 Using a general cDNA screen method, Soma et al were able to identify a clone encoding for 119 amino-acid residues that showed a clearly positive reaction only with a probe derived from rat pancreatic B-cell tumor, but not the probe derived from normal islet B cells.…”

“…However, in contrast to the proposed statement as a tumor suppressor, PC4 has been recently found to show an upregulated level in several kinds of cancer. [20][21][22][23][24] Moreover, our previous work indicated that overexpression of PC4 in a population of normal dermal multipotent fibroblasts results in the tumorigenic transformation of the cells, indicating the role of PC4 in tumor development and progression. 20 This prompted us to further study the significance of PC4 in cancer therapy.…”

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…Several studies have shown that the epigenetic changes that occur in cancer include not only promoter CpG island hypermethylation and silencing of tumor suppressor genes (Herman and Baylin, 2003), but also promoter CpG island hypomethylation (Feinberg and Vogelstein, 1983;Kaneda et al, 2004). Such promoter hypomethylations in different cancers were associated with upregulated expression of tumor promoting genes such as BCL2 (Hanada et al, 1993), MDR1 (Nakayama et al, 1998), HOX11 (Watt et al, 2000), MYC, c-Ha-RAS, c-FOS and ALPHA FETOPROTEIN (Fang and Xiao, 2001), MASPIN (Ogasawara et al, 2004), MEL1S (Yoshida et al, 2004), EGR1 that upregulates expression of heparanase (Ogishima et al, 2005), SYNUCLEIN GAMMA (Gupta et al, 2003;Liu et al, 2005) and some other genes (Sato et al, 2003). Exogenously added estrogen or tamoxifen can induce promoter hypomethylation of PAX2 , and treatment with chemotherapeutic compounds can induce Histone-H3 acetylation and Histone-H3 lysine-4 methylation at the MDR1 promoter (Baker et al, 2005) that result in upregulation of these tumor promoting genes.…”