Abstract
Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR-652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC.
Highlights
Emerging evidences have indicated extracellular acidity is an environmental stimulus that may play a key role in tumorigenesis [1,2,3]
In order to address whether acidic microenvironment potentiated epithelial mesenchymal transition (EMT) process, pancreatic cancer cell lines (AsPC-1, BxPC-3, PANC-1, MIAPaCa-2, SW1990) were incubated under normal and different acidic conditions up to 72 h
Corresponding data of cell cycle exhibited acidity-induced G1-phase arrest in pancreatic cancer cells (PANC-1 and BxPC-3, Fig. S1C). These data revealed that acidic microenvironment could induce EMT of pancreatic cancer cells (Table 1)
Summary
Emerging evidences have indicated extracellular acidity is an environmental stimulus that may play a key role in tumorigenesis [1,2,3]. Resulted from high glycolytic rate and lactic acid production coinciding with an insufficient drainage by convective and/or diffusive transport, H+ ions accumulate in the respective tissues of cancer [4]. As a consequence, both in vitro cell culture studies and in situ tumor spectroscopic studies utilizing the 31P isotope have reported that tumor cells have acidic interstitial extracellular pH (pHe) values compared to normal tissues (6.2–6.9 vs 7.3–7.4), especially in bulky and/or low-flow tumors [5, 6]. The remarkable extracellular acidity is augmented by the characterized hypovascular of pancreatic cancer [12, 13]. It draws our intensive interesting whether the vigorous acidic extracellular microenvironment contributes to the development and progression of pancreatic cancer
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