6548

SLC9A1

solute carrier family 9, subfamily A (NHE1, cation proton antiporter 1), member 1;SLC9A1;solute carrier family 9, subfamily A (NHE1, cation proton antiporter 1), member 1

Na(+)/H(+) exchanger 1|Na-Li countertransporter|protein phosphatase 1, regulatory subunit 143|sodium/hydrogen exchanger 1|solute carrier family 9 (sodium/hydrogen exchanger), isoform 1 (antiporter, Na+/H+, amiloride sensitive)|solute carrier family 9 (sod

1p36.1-p35

protein-coding

BACKGROUND: CD44, a transmembrane glycoprotein expressed in a variety of cells and tissues, has been implicated in tumour metastasis. But the molecular mechanisms of CD44-mediated tumour cell metastasis remain to be elucidated. METHODS: The downregulation of CD44 was determined by immunofluorescence. Moreover, the motility of breast cancer cells was detected by wound-healing and transwell experiments. Then the spontaneous metastasis of CD44-silenced MDA-MB-231 cells was tested by histology with BALB/c nude mice. RESULTS: A positive correlation between CD44 and Na(+)/H(+) exchanger isoform 1 (NHE1) was found in two breast cancer cells. CD44 downregulation could inhibit the metastasis of MDA-MB-231 cells and the expressions of Na(+)/H(+) exchanger 1. Moreover, CD44 overexpression upregulated the metastasis of MCF-7 cells, but the elevated metastatic ability was then inhibited by Cariporide. Interestingly, during these processes only the p-ERK1/2 was suppressed by CD44 downregulation and the expression of matrix metalloproteinases and metastatic capacity of MDA-MB-231 cells were greatly inhibited by the MEK1 inhibitor PD98059, which even had a synergistic effect with Cariporide. Furthermore, CD44 downregulation inhibits breast tumour outgrowth and spontaneous lung metastasis. CONCLUSIONS: Taken together, this work indicates that CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy.

Acidosis commonly observed in solid tumors like pancreatic cancer promotes genetic instability and selection of a more malignant phenotype of cancer cells. Overexpression or activation of integral membrane proteins mediating H+ efflux may contribute to extracellular acidification. Neurotensin (NT) induces intracellular alkalinization and stimulates interleukin-8 production in pancreatic cancer cells and, as demonstrated here, the stable NT analog Lys(8)-psi-Lys(9)NT(8-13) enhances the amiloride-sensitive, Na+-dependent transmembrane H+ flux by a factor of 2.05+/-0.28 and 2.69+/-0.07 in BxPC-3 and PANC-1 pancreatic cancer cells, respectively, by phosphorylation of the Na+/H+ exchanger 1 (NHE1). Human genome-wide gene expression analysis was performed to detect effects of Lys(8)-psi-Lys(9)NT(8-13) on BxPC-3 cells. Results indicated upregulation of genes involved in regulation of NHE1, hypoxic response and glycolysis in response to Lys(8)-psi-Lys(9)NT(8-13) even under normoxic conditions. Therefore, our findings suggest that growth factors like NT may be implicated in the early progression of pancreatic cancer by localized acidification and induction of an aerobic glycolytic phenotype with higher metastatic potential in small cell aggregates.