Abstract
Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca2+ concentration ([Ca2+]i). Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca2+]i and its downstream RhoA during acidity and, thus, suppressed acidity-induced epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Meanwhile, downregulating [Ca2+]i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA also significantly repressed acidity-induced EMT of pancreatic cancer cells. Significantly, although without obvious effect on proliferation, knockdown of ASIC1 and ASIC3 in pancreatic cancer cells significantly suppresses liver and lung metastasis in xenograft model. In addition, ASIC1 and ASIC3 are positively correlated with expression of mesenchymal marker vimentin, but inversely correlated with epithelial marker E-cadherin in pancreatic cancer cells. In conclusion, this study indicates that ASICs are master regulator of acidity-induced EMT. In addition, the data demonstrate a functional link between ASICs and [Ca2+]i/RhoA pathway, which contributes to the acidity-induced EMT.
Highlights
Extracellular acid can have important effects on cancer cells
Western blot confirmed that the protein of ASIC1 and ASIC3 in pancreatic cancer cell lines was increased compared with normal pancreatic ductal cells (Figure 1b)
As our previous results showed that the enhanced migration and invasion of pancreatic cancer cell in acidity were attributed to the acidityinduced epithelial–mesenchymal transition (EMT), we further investigated whether ASIC1 and ASIC3 contributed to the acidity-induced EMT
Summary
Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca2+]i and its downstream RhoA during acidity and, suppressed acidity-induced epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Downregulating [Ca2+]i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA significantly repressed acidity-induced EMT of pancreatic cancer cells. This study indicates that ASICs are master regulator of acidity-induced EMT. Our previous work reveals that acidic microenvironment induces EMT of pancreatic cancer cells through regulating miR-652/ZEB1 pathway.[15] In this study, we work to investigate how the acidic extracellular pH, a chemical signaling of metabolic microenvironment, is detected by pancreatic cancer cells and further promotes the transduction of EMT as biological signaling. Acid-sensing ion channels (ASICs), an H+-gated subgroup of the epithelial Na+ channel/degenerin (ENaC/DEG)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
