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CD147 Silencing Inhibits Lactate Transport and Reduces Malignant Potential of pancreatic cancer cells in in-vivo and in-vitro Models
  1. Wilhelm Schneiderhan (wilhelm.schneiderhan{at}klinik.uni-regensburg.de)
  1. University Hospital of Regensburg, Germany
    1. Max Scheler (max.scheler{at}web.de)
    1. University Hospital of Ulm, Germany
      1. Karl-Heinz Holzmann (karl-heinz.holzmann{at}uni-ulm.de)
      1. University Hospital of Ulm, Germany
        1. Martin Marx (martin.marx{at}uni-ulm.de)
        1. University of Ulm, Germany
          1. Jürgen E Gschwend (juergen.gschwend{at}lrz.tu-muenchen.de)
          1. TU Munich, Germany
            1. Malte Buchholz (malte.buchholz{at}med.uni-marburg.de)
            1. University of Marburg, Germany
              1. Thomas M Gress (gress{at}med.uni-marburg.de)
              1. University Hospital of Marburg, Germany
                1. Guido Adler (guido.adler{at}uniklinik-ulm.de)
                1. University Hospital of Ulm, Germany
                  1. Thomas Seufferlein (thomas.seufferlein{at}medizin.uni-halle.de)
                  1. University Hospital of Halle, Germany
                    1. Franz Oswald (franz.oswald{at}uni-ulm.de)
                    1. University Hospital of Ulm, Germany

                      Abstract

                      Background: CD147 (Basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDAC), that is associated to poor prognosis in many malignancies. The role of CD147 in pancreatic cancer, however, remains elusive.

                      Methods and results: Silencing of CD147 by RNAi reduced proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for function and expression of monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time RT-PCR as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg-effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in a increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer-cell growth in a dose dependant fashion. In vivo, knock down of CD147 in MiaPaCa2 by inducible short hairpin RNA (shRNA) mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM-assay) and inhibited tumorigenicity in a xenograft model in nude-mice.

                      Conclusion: The function of CD147 as an ancillary protein that it is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression to the malignant potential of pancreatic cancer cells exhibiting the Warburg-effect.

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