Abstract
Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7) ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the MatrigelTM-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment.
Highlights
Pancreatic adenocarcinoma is the most common malignant tumor of the pancreas, and it is almost uniformly fatal
Expression of transient receptor potential melastatin-subfamily member 7 (TRPM7) in normal and pre-malignant pancreatic tissues Microarrays containing 366 specimens of human pancreatic tissues were evaluated for expression of TRPM7 by immunohistochemistry (IHC) using specific antibodies raised against TRPM7
The pancreatic tissue from each patient was processed as triplicates, and the IHC analysis of TRPM7 is consistent among the triplicate samples of each specimen, supporting the validity of the data
Summary
Pancreatic adenocarcinoma is the most common malignant tumor of the pancreas, and it is almost uniformly fatal. Histopathologic and genetic analyses have elucidated the biological events during transformation of pancreatic epithelia into pancreatic intra-epithelial neoplasms (PanINs) and their progression to invasive adenocarcinoma. These events are associated with oncogene-induced senescence, followed by aberrant regulation of developmental pathways, tumor suppressor genes, and oncogenes, as well as epigenetic alterations (Chun and Yee, 2010; Hasanali et al, 2012; Yee, 2011; Yee, 2013; Yee et al, 2003; Zhou et al, 2011). Increasing evidence has implicated fundamental roles of ion channels in human cancers Their identities and functional roles in have recently been discovered in pancreatic cancer; in particular, the transient receptor potential (TRP) channels TRPM7 and TRPM8
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