Abstract
MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary-mucinous neoplasia (IPMN) harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level.
Highlights
Homeobox-containing genes regulate the morphological development of a variety of organs and their expression levels vary according to the development stages of organ (Wolgemuth et al, 1989; Morgan et al, 1992)
MSX2 has been suggested to be a downstream target of the Ras signaling pathway because MSX2 was up-regulated in v-Ki-ras transfected NIH3T3 cells and antisense MSX2 cDNA and truncated MSX2 cDNA interfered with the transforming activities of both the v-K-ras and v-raf oncogene (Takahashi et al, 1996)
In human pancreatic ductal adenocarcinoma (PDAC) tissues, frequent MSX2 expression in cancer cells was observed by immunohistochemistry and a significant correlation was found between MSX2 expression and histological differentiation and vascular invasion, whereas there was no association between this gene expression and the tumor stage (Table 2) (Satoh et al, 2008a), suggesting that MSX2 expression may be associated with the aggressiveness of PDAC because poor differentiation of PDAC is correlated with reduced survival time (Cleary et al, 2004)
Summary
Homeobox-containing genes regulate the morphological development of a variety of organs and their expression levels vary according to the development stages of organ (Wolgemuth et al, 1989; Morgan et al, 1992). Until recently there has been little information about the expression or function of MSX2 in pancreatic tumors, both PDAC and IPMN harbor frequent K-ras gene mutations at codon 12 (Satoh et al, 1993b, 1996) and MSX2 was suggested to be a downstream target of the ras signal. In human PDAC tissues, frequent MSX2 expression in cancer cells was observed by immunohistochemistry and a significant correlation was found between MSX2 expression and histological differentiation and vascular invasion, whereas there was no association between this gene expression and the tumor stage (Table 2) (Satoh et al, 2008a), suggesting that MSX2 expression may be associated with the aggressiveness of PDAC because poor differentiation of PDAC is correlated with reduced survival time (Cleary et al, 2004). Knockdown of MSX2 by small interfering RNA (siRNA) or small hairpin RNA (shRNA) inhibited the cell growth of gastric (Ohta et al, 2009) and ovarian (Zhai et al, 2011) carcinoma, indicating that the function of MSX2 is likely to be relevant to the regulation of the proliferation of epithelial cells as well as
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