CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models
- W Schneiderhan1,
- M Scheler2,
- K-H Holzmann3,
- M Marx4,
- J E Gschwend5,
- M Bucholz6,
- T M Gress6,
- T Seufferlein7,
- G Adler2,
- F Oswald2
- 1Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, Regensburg, Germany
- 2Clinic for Internal Medicine I, University Hospital of Ulm, Ulm, Germany
- 3ZKF, University Hospital of Ulm, Ulm, Germany
- 4Institute for Transfusion Medicine, University Hospital of Ulm, Ulm, Germany
- 5Department of Urology, Hospital of the Technical University Munich, Rechts der Isar Medical Center, München, Germany
- 6Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University Hospital of Marburg, Marburg, Germany
- 7Clinic for Internal Medicin I, University Hospital Halle-Wittenberg, Halle, Germany
- Correspondence to Dr W Schneiderhan, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, Franz-Josef-Strauss Allee 11, D-93053 Regensburg, Germany; wilhelm.schneiderhan{at}klinik.uni-regensburg.de
- Received 1 March 2009
- Accepted 12 May 2009
- Published Online First 7 June 2009
Abstract
Background: CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The role of CD147 in pancreatic cancer, however, remains elusive.
Methods and Results: Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (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 an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice.
Conclusion : The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.
Footnotes
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Funding This work was supported in part by DFG grant SFB518 (A7) to WS, SFB518 (A18) to FO, SFB 518 (B3) to TS, and by grants from the EU (FP6P, Project 018771) and LOEWE-Center “Tumor and Inflammation” Marburg project A4 to TG and MB.
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Competing interests None.
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Provenance and Peer review Not commissioned; externally peer reviewed.
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‣ Additional methods and figures are published online only at http://gut.bmj.com/content/vol58/issue10
