Abstract
BackgroundThe epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear.MethodsThe expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo.ResultsTRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells.ConclusionsTRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer.
Highlights
Ovarian cancer is one of the common malignant tumors in women and its incidence is increasing in the world [1]
Given that lower E-cadherin but higher Vimentin and Twist expression are hallmarks of epithelial-mesenchymal transition (EMT) process in cancer our data indicated that up-regulated transient receptor potential melastatin 7 (TRPM7) expression was associated with the EMT process of ovarian cancer
Given that the high levels of EMT process are associated with metastasis our findings suggest that up-regulated TRPM7 expression may a valuable factor to predict the metastasis of ovarian cancer [33,34,35]
Summary
Ovarian cancer is one of the common malignant tumors in women and its incidence is increasing in the world [1]. Ovarian cancer has unique characters of difficult diagnosis and early metastasis. The molecular mechanisms underlying the metastasis of ovarian cancer have not been clarified. Previous studies have shown that the epithelial-mesenchymal transformation (EMT) process is an early event of tumor invasion and metastasis [3]. Many factors can induce the EMT process in tumor cells [6,7,8,9] the precise mechanisms by which regulate the EMT process in ovarian cancer remain unclear. The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. The mechanisms underlying the action of TRPM7 in ovarian cancer are unclear
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