Shanghai Key Laboratory of Pancreatic Diseases Research

Shanghai, China

Shanghai Key Laboratory of Pancreatic Diseases Research

Shanghai, China

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Cui J.,Shanghai Key Laboratory of Pancreatic Diseases Research | Cui J.,Shanghai JiaoTong University | Shi M.,Shanghai JiaoTong University | Xie D.,Shanghai Key Laboratory of Pancreatic Diseases Research | And 3 more authors.
Clinical Cancer Research | Year: 2014

Purpose: The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism. Experimental Design: The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens. Results: We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both themRNAand protein level and elevated LDHactivity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1-LDHA signaling increased the pancreatic cancer cell growth and metastasis. Conclusions: Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression. © 2014 American Association for Cancer Research.


Song W.,Shanghai JiaoTong University | Song W.,Shanghai Key Laboratory of Pancreatic Diseases Research | Li Q.,Shanghai JiaoTong University | Li Q.,Shanghai Key Laboratory of Pancreatic Diseases Research | And 2 more authors.
Cellular Physiology and Biochemistry | Year: 2015

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC. © 2015 S. Karger AG, Basel.


Song W.,Shanghai JiaoTong University | Song W.,Shanghai Key Laboratory of Pancreatic Diseases Research | Wang L.,Shanghai JiaoTong University | Li Q.,Shanghai JiaoTong University | Li Q.,Shanghai Key Laboratory of Pancreatic Diseases Research
Tumor Biology | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant primary tumors in humans, with extremely high lethality. Although great efforts have been made to understand the molecular regulation of the tumorigenesis of PDAC, our current knowledge remains very limited. Previous work has shown a possible involvement of miR-21 in the growth of PDAC, whereas the underlying mechanism has not been clarified. Here, we show significant higher levels of miR-21 in PDAC, compared to the adjacent normal pancreatic tissue. Moreover, overexpression of miR-21 in PDAC cells increased cell growth, whereas inhibition of miR-21 decreased cell growth. Furthermore, miR-21 was found to inhibit nuclear retention of FoxO1 to augment the growth of PDAC cells. Thus, miR-21/FoxO1 axis appears to be a novel therapeutic target for inhibiting the growth of PDAC. © 2015, International Society of Oncology and BioMarkers (ISOBM).


Song W.-F.,Shanghai JiaoTong University | Song W.-F.,Shanghai Key Laboratory of Pancreatic Diseases Research | Wang L.,Shanghai JiaoTong University | Wang L.,Shanghai Key Laboratory of Pancreatic Diseases Research | And 5 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2013

Background and Aims: MicroRNA-21 (miR-21) is reported to be overexpressed and to contribute to proliferation, apoptosis and gemcitabine resistance in pancreatic ductal adenocarcinomas (PDACs). The aims of this study were to explore regulation of miR-21 expression by epigenetic change and its impact on chemoresistance and malignant properties of of pancreatic cancer. Materials and methods: We retrospectively collected 41 cases of advanced pancreatic cancer patients who were sensitive or resistant to gemcitabine and assessed levels of serum circulating miR-21 for correlation with cytotoxic activity. Histone acetylation in the miR-21 promoter was also studied in gemcitabine-sensitive and gemcitabine-resistant PDAC cells. Gemcitabine-resistant HPAC and PANC-1 cells were transfected with pre-miR-21 precursors (pre-miR-21) and antisense oligonucleotides (anti-miR-21), and were treated with TSA. Finally, invasion and metastasis assays were performed and alteration in mir-21, PTEN, AKT and pAKT level was evaluated in these cells. Results: Serum miR-21 levels were increased in gemcitabine-resistant PDAC patients compared with gemcitabine-sensitive subjects. The miR-21 levels were increased in 6 PDAC cells treated with gemcitabine significantly, associated with 50% inhibitory concentrations (IC50s). Histone acetylation levels at miR-21 promoter were increased in PDAC cells after treatment with gemcitabine. Enhanced invasion and metastasis, increased miR-21 expression, decreased PTEN, elevated pAKT level were demonstrated in gemcitabine-resistant HPAC and PANC-1 cells. Pre-miR-21 transfection or TSA treatment further increased invasion and metastasis ability, decreased PTEN, and elevated pAKT levels in these two lines. In contrast, anti-miR-21 transfection could reverse invasion and metastasis, and PTEN and pAKT expressions induced by gemcitabine. Conclusions: MiR-21 upregulation induced by histone acetylation in the promoter zone is associated with chemoresistance to gemcitabine and enhanced malignant potential in pancreatic cancer cells.

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