Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

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.

Transient Receptor Potential Melastatin 7 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma

“…There have been other reports about the clinicopathological role of TRPM7 in several type of cancer (24)(25)(26) (26). Contrary to these reports, our results suggest that TRPM7 is negative correlated with pT and pN category and pStage in ESCC.…”

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

“…Several studies have reported the involvement of TRPM7 in cell migration and invasion induced by fetal calf serum (FCS) as chemoattractant in breast [18], [26], nasopharyngeal [20], [21], and pancreatic cancer cells [25]. In our work, it is important to note that we do not use any stimulation (by chemotaxis or activator) to promote cell invasion.…”

“…Among TRP channels, the transient receptor potential melastatin related 7 (TRPM7) channel is a Ca 2+ /Mg 2+ channel fused with a functional kinase domain that belongs to the α-kinase family [13], [14]. We and others showed that TRPM7 is involved in migration and/or invasion of epidermal cancer cells including neuroblastoma [15], [16], glioblastoma [17], breast cancer [18], [19], nasopharynx cancer [20], [21], lung cancer [22], prostate cancer [23], and PDAC [24], [25]. Importantly, TRPM7 is required for breast cancer metastasis formation in mouse xenograft, and high channel expression is an independent marker of poor outcome in breast cancer patients [26].…”

Emerging role of transient receptor potential (TRP) channels in cancer progression

“…The contribution of TRPM7 to migration of human nasopharyngeal cancer cells is attributed to ryanodine receptor (RyR) activation, which consequently increases [Ca 2+ ]i levels and cellular migration (68). Thus, TRPM7 directly affects the migration of diverse cancer cell types via mechanotransduction mediated by [Ca 2+ ]i. TRPM7 is also essential for progression and invasion of pancreatic ductal adenocarcinoma (PDAC) (69,70). Increased expression of TRPM7 is correlated with poor patient prognosis (69,71) and silencing of TRPM7 in PDAC cells reduces cancer cell invasion (70).…”