scholarly journals Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment

2019 ◽  
Vol 11 ◽  
pp. 175883591984123 ◽  
Author(s):  
Tessa Ya Sung Le Large ◽  
Btissame El Hassouni ◽  
Niccola Funel ◽  
Bart Kok ◽  
Sander R. Piersma ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Clinical Investigation ◽  
Predictive Biomarkers ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Resistant Cells

Background: Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers. Methods: The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated in vitro and in vivo. Cultured cells were analyzed by label-free proteomics. Differential proteins and phosphopeptides were evaluated by gene ontology and for their predictive or prognostic biomarker potential with immunohistochemistry of tissue microarrays. Results: Gemcitabine-resistant cells had increased potential to induce xenograft tumours ( p value < 0.001). Differential analyses showed that proteins associated with gemcitabine resistance are correlated with microtubule regulation. Indeed, gemcitabine-resistant cells displayed an increased sensitivity for paclitaxel in vitro ( p < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy in vivo. Microtubule-associated protein 2 (MAP2) was found to be highly upregulated ( p = 0.002, fold change = 10) and phosphorylated in these resistant cells. Expression of MAP2 was correlated with a poorer overall survival in patients treated with gemcitabine in the palliative ( p = 0.037) and adjuvant setting ( p = 0.014). Conclusions: These data show an explanation as to why the combination of gemcitabine with nab-paclitaxel is effective in PDAC patients. The identified gemcitabine-resistance marker, MAP2, emerged as a novel prognostic marker in PDAC patients treated with gemcitabine and warrants further clinical investigation.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Huiming Chen ◽  
Junfeng Zhao ◽  
Ningning Jiang ◽  
Zheng Wang ◽  
Chang Liu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Precancerous Lesions ◽  
Clinical Specimen ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

scholarly journals Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

2015 ◽  
Vol 49 (2) ◽  
pp. 147-154 ◽  
Author(s):  
Roberto Girelli ◽  
Simona Prejanò ◽  
Ivana Cataldo ◽  
Vincenzo Corbo ◽  
Lucia Martini ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Clinical Investigation ◽  
Tumour Response ◽  
Chemotherapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Safe Procedure ◽  
Reversible Electroporation

Abstract Background. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. Materials and methods. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Conclusions. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma, but has a potentiating effect on cytotoxicity of bleomycin in pancreatic tumour cell lines. Therefore, ECT could be considered as a valid alternative for the local control of non-resectable pancreatic cancer.

scholarly journals Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Guangbing Xiong ◽  
Chang Liu ◽  
Gang Yang ◽  
Mengyu Feng ◽  
Jianwei Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Reference Sequence ◽  
Gemcitabine Resistance ◽  
Cerna Network ◽  
Pancreatic Cancer Cells

Abstract Background Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. Methods Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. Results Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. Conclusion Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

scholarly journals Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 50 (3) ◽  
pp. 823-840 ◽  
Author(s):  
Dan-ming Wei ◽  
Yi-wu Dang ◽  
Zhen-bo Feng ◽  
Lu Liang ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Chorioallantoic Membrane ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Chick Chorioallantoic Membrane ◽  
Pancreatic Cancer Cells

Background/Aims: Accumulating evidence strongly suggests that microRNAs (miRNAs) modulate the expression of known tumor suppressor genes and oncogenes. In the present study, we found that the proliferation and invasion ability of pancreatic ductal adenocarcinoma (PDAC) cells were significantly suppressed by the overexpression of miR-23b-3p. In addition, there are miR-23b-3p binding sites in annexin A2 (ANXA2). Here, we investigated whether miR-23b-3p had an impact on the progression and metastasis of PDAC by targeting ANXA2. Methods: Cell proliferation, migration, and invasion, and cell cycle assays were performed to explore the effect of miR-23b-3p on various malignant phenotypes of pancreatic cancer cells. The size of tumors was observed following miR-23b-3p overexpression in an in vivo chick chorioallantoic membrane assay. Dual-luciferase reporter, quantitative real-time PCR, western blot, and immunohistochemical analyses were used to validate the relationship between miR-23b-3p and ANXA2 in vitro. Results: We observed that miR-23b-3p could bind specifically to the 3′ untranslated region of ANXA2 and inhibit its expression. MiR-23b-3p overexpression downregulated the expression of ANXA2 mRNA in PDAC cells and limited the size of tumors or even prevented tumor formation. In addition, there was a negative correlation between miR-23b-3p expression and ANXA2 protein expression in clinical specimens. Conclusion: MiR-23b-3p inhibits the development and progression of PDAC by regulating ANXA2 directly.

scholarly journals Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells

2020 ◽  
Vol 19 (10) ◽  
pp. 1649-1663
Author(s):  
Svenja Wiechmann ◽  
Elena Saupp ◽  
Daniela Schilling ◽  
Stephanie Heinzlmeir ◽  
Günter Schneider ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Actin Dynamics ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Intrinsic Radiosensitivity ◽  
Resistant Cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.

scholarly journals HAT1 Promotes Gemcitabine Resistance by Regulating the PVT1/EZH2 Complex in Pancreatic Cancer

2020 ◽  
Author(s):  
Yan Sun ◽  
Jian Shen ◽  
Dianyun Ren ◽  
Yingke Zhou ◽  
Jingyuan Zhao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Statistical Significance ◽  
Gemcitabine Resistance ◽  
Development Of Resistance ◽  
Pancreatic Cancer Cells ◽  
Promising Therapeutic Target ◽  
The Relationship

Abstract Background: The poor prognosis of pancreatic cancer is primarily due to the development of resistance to therapies, including gemcitabine. PVT1 has been shown to interact with EZH2, promoting gemcitabine resistance in pancreatic cancer. Methods: In this study, we assessed the ability of PVT1/EZH2 targeting to reverse resistance to gemcitabine in pancreatic cancer cells. MTS assay, colony formation assay, and mouse xenotransplantation experiments were used to evaluate the anti-tumor effects of gemcitabine in HAT1 knockdown or overexpressing pancreatic cancer cells. The relationship between HAT1 and PVT1 in pancreatic cancer was determined by RNA sequencing, quantitative real-time PCR, and chromatin immunoprecipitation. Co-immunoprecipitation, pull-downs, western blotting, and immunohistochemistry were used to assess the relationship between HAT1 and EZH2 in pancreatic cancer. Chitosan (CS)-tripolyphosphate (TPP)-siHAT1 nanoparticles were developed to evaluate their effects on the anti-tumor potential of gemcitabine in pancreatic cancer. Student’s t-test, one-way analysis of variance (ANOVA), or two-way ANOVA was used to evaluate statistical significance. P-values <0.05 were considered statistically significant. All values were expressed as means ± SD. Results: Our results showed that the aberrant HAT1 expression promoted gemcitabine resistance in pancreatic cancer cells. We also found that HAT1 enhanced the binding of BRD4 to the PVT1 promoter, thereby promoting PVT1 transcription. Moreover, we found that HAT1 prevented EZH2 degradation by interfering with UBR4 binding to the N-terminal domain of EZH2, thus maintaining EZH2 protein stability. Finally, we showed that CS-TPP-siHAT1 nanoparticles augmented the anti-tumor effects of gemcitabine in pancreatic cancer cells in vitro and in vivo. Conclusions: Our findings suggest that by increasing the levels of the PVT1/EZH2 complex, HAT1 promotes gemcitabine resistance in pancreatic cancer. Therefore, HAT1 is a promising therapeutic target for pancreatic cancer.

scholarly journals Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuchong Zhao ◽  
Yun Wang ◽  
Wei Chen ◽  
Shuya Bai ◽  
Wang Peng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Early Metastasis ◽  
Pancreatic Cancer Cells ◽  
E Cadherin

Abstract Background Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference. Methods We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo. Results Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo. Conclusion Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.

scholarly journals Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

2021 ◽  
Vol 118 (10) ◽  
pp. e2003014118
Author(s):  
Pei-Yun Tsai ◽  
Min-Sik Lee ◽  
Unmesh Jadhav ◽  
Insia Naqvi ◽  
Shariq Madha ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Glutamine Synthetase ◽  
De Novo ◽  
Ductal Adenocarcinoma ◽  
Nutrient Deprivation ◽  
Open Chromatin ◽  
Nucleotide Synthesis ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.

scholarly journals STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer

2019 ◽  
Vol 133 (5) ◽  
pp. 645-663 ◽  
Author(s):  
Chao Liu ◽  
Jiaqi Shi ◽  
Qingwei Li ◽  
Zhiwei Li ◽  
Changjie Lou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Immunohistochemical Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Pancreatic Cancer Cells ◽  
Foxm1 Expression

Abstract Forkhead box protein M1 (FOXM1) was identified as an oncogenic transcription factor and master regulator of tumor progression and metastasis. FOXM1 expression often correlates with poor prognosis and chemotherapy resistance. In the present study, we investigated the association of FOXM1 expression and chemoresistance in pancreatic cancer. Elevated FOXM1 protein levels were associated with gemcitabine chemoresistance in patients with pancreatic cancer. In gemcitabine resistance cell line models of pancreatic cancer, FOXM1 expression increased, which induced gemcitabine chemoresistance in vitro. In pancreatic cancer cells treated with gemcitabine, FOXM1 affected nuclear factor κB (NF-κB) signaling activity. Immunohistochemical analysis demonstrated a negative association of FOXM1 expression and the level of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) in human pancreatic cancer tissues. Dual-luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that pSTAT1 directly binds to the FOXM1 promoter to down-regulate its transcription. Interferon γ (IFNγ) promoted gemcitabine-induced cell apoptosis and inhibited cell proliferation in vitro and in vivo by FOXM1 inhibition. These data suggested that FOXM1 enhances chemoresistance to gemcitabine in pancreatic cancer. IFNγ could be used to down-regulate the expression of FOXM1 through STAT1 phosphorylation, thereby increasing the sensitivity of pancreatic cancer cells to gemcitabine. These studies suggested the sensitization by IFNγ in pancreatic ductal adenocarcinoma (PDAC) chemotherapy, which requires further clinical studies.

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