35 results on '"PAUF"'
Search Results
2. PAUF Induces Migration of Human Pancreatic Cancer Cells Exclusively via the TLR4/MyD88/NF-κB Signaling Pathway.
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Youn, So Eun, Jiang, Fen, Won, Hye Yun, Hong, Da Eun, Kang, Tae Heung, Park, Yun-Yong, and Koh, Sang Seok
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PANCREATIC cancer , *CELLULAR signal transduction , *CELL membranes , *TOLL-like receptors , *CANCER cells , *CELL lines - Abstract
PAUF, a tumor-promoting protein secreted by cancer cells, exerts paracrine effects on immune cells through TLR4 receptors expressed on immune cell surfaces. This study aimed to investigate if PAUF elicits autocrine effects on pancreatic cancer (PC) cells through TLR4, a receptor that is overexpressed on PC cells. In this study, TLR4 expression was detected in PC cells only, but not normal pancreatic cells. The migration of TLR4 high-expressing PC cells (i.e., BxPC-3) was reduced by a selective TLR4 inhibitor, in a dose-dependent manner. Using TLR4 overexpressed and knockout PC cell lines, we observed direct PAUF-TLR4 binding on the PC cell surfaces, and that PAUF-induced cancer migration may be mediated exclusively through the TLR4 receptor. Further experiments showed that PAUF signaling was passed down through the TLR4/MyD88 pathway without the involvement of the TLR4/TRIF pathway. TLR4 knockout also downregulated PC membrane PD-L1 expression, which was not influenced by PAUF. To the best of our knowledge, TLR4 is the first receptor identified on cancer cells that mediates PAUF's migration-promoting effect. The results of this study enhanced our understanding of the mechanism of PAUF-induced tumor-promoting effects and suggests that TLR4 expression on cancer cells may be an important biomarker for anti-PAUF treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. PAUF as a Target for Treatment of High PAUF-Expressing Ovarian Cancer.
- Author
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Kim, Yeon Jeong, Jiang, Fen, Park, Jin, Jeong, Hyeon Hee, Baek, Ji Eun, Hong, Seung-Mo, Jeong, Seong-Yun, and Koh, Sang Seok
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OVARIAN cancer ,DOCETAXEL ,PANCREATIC tumors ,CANCER prognosis ,CELL lines ,TUMOR growth - Abstract
Pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in tumor growth, metastasis, and immune evasion in the pancreatic tumor microenvironment, and recent studies suggest an association between PAUF expression and poor prognosis in ovarian cancer patients. The current study aimed 1) to characterize the potential tumor-promoting role of PAUF in ovarian cancer, using in vitro and in vivo models, including a PAUF-knockout OVCAR-5 cell line, and 2) to explore the potential therapeutic effects of an anti-PAUF antibody for ovarian cancer. Recombinant PAUF significantly increased tumor metastatic capacity (migration, invasion, and adhesion) in all the ovarian cancer cell lines tested, except for the OVCAR-5 cell line which expresses PAUF at a much higher level than the other cells. PAUF-knockout in the OVCAR-5 cell line led to apparently delayed tumor growth in vitro and in vivo. Furthermore, the administration of an anti-PAUF antibody exhibited notable sensitizing and synchronizing effects on docetaxel in mice bearing the OVCAR-5 xenograft tumors. Taken together, this study shows that the expression level of PAUF is an independent factor determining malignant behaviors of ovarian cancer and, for the first time, it suggests that PAUF may be a promising therapeutic target for high PAUF-expressing ovarian cancer. [ABSTRACT FROM AUTHOR]
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- 2022
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4. PAUF as a Target for Treatment of High PAUF-Expressing Ovarian Cancer
- Author
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Yeon Jeong Kim, Fen Jiang, Jin Park, Hyeon Hee Jeong, Ji Eun Baek, Seung-Mo Hong, Seong-Yun Jeong, and Sang Seok Koh
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PAUF ,ovarian cancer ,molecular targeted therapy ,monoclonal antibody ,combination chemotherapy ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in tumor growth, metastasis, and immune evasion in the pancreatic tumor microenvironment, and recent studies suggest an association between PAUF expression and poor prognosis in ovarian cancer patients. The current study aimed 1) to characterize the potential tumor-promoting role of PAUF in ovarian cancer, using in vitro and in vivo models, including a PAUF-knockout OVCAR-5 cell line, and 2) to explore the potential therapeutic effects of an anti-PAUF antibody for ovarian cancer. Recombinant PAUF significantly increased tumor metastatic capacity (migration, invasion, and adhesion) in all the ovarian cancer cell lines tested, except for the OVCAR-5 cell line which expresses PAUF at a much higher level than the other cells. PAUF-knockout in the OVCAR-5 cell line led to apparently delayed tumor growth in vitro and in vivo. Furthermore, the administration of an anti-PAUF antibody exhibited notable sensitizing and synchronizing effects on docetaxel in mice bearing the OVCAR-5 xenograft tumors. Taken together, this study shows that the expression level of PAUF is an independent factor determining malignant behaviors of ovarian cancer and, for the first time, it suggests that PAUF may be a promising therapeutic target for high PAUF-expressing ovarian cancer.
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- 2022
- Full Text
- View/download PDF
5. PAUF Induces Migration of Human Pancreatic Cancer Cells Exclusively via the TLR4/MyD88/NF-κB Signaling Pathway
- Author
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So Eun Youn, Fen Jiang, Hye Yun Won, Da Eun Hong, Tae Heung Kang, Yun-Yong Park, and Sang Seok Koh
- Subjects
PAUF ,toll-like receptors ,TLR4 ,pancreatic cancer ,MyD88 ,NF-κB ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
PAUF, a tumor-promoting protein secreted by cancer cells, exerts paracrine effects on immune cells through TLR4 receptors expressed on immune cell surfaces. This study aimed to investigate if PAUF elicits autocrine effects on pancreatic cancer (PC) cells through TLR4, a receptor that is overexpressed on PC cells. In this study, TLR4 expression was detected in PC cells only, but not normal pancreatic cells. The migration of TLR4 high-expressing PC cells (i.e., BxPC-3) was reduced by a selective TLR4 inhibitor, in a dose-dependent manner. Using TLR4 overexpressed and knockout PC cell lines, we observed direct PAUF-TLR4 binding on the PC cell surfaces, and that PAUF-induced cancer migration may be mediated exclusively through the TLR4 receptor. Further experiments showed that PAUF signaling was passed down through the TLR4/MyD88 pathway without the involvement of the TLR4/TRIF pathway. TLR4 knockout also downregulated PC membrane PD-L1 expression, which was not influenced by PAUF. To the best of our knowledge, TLR4 is the first receptor identified on cancer cells that mediates PAUF’s migration-promoting effect. The results of this study enhanced our understanding of the mechanism of PAUF-induced tumor-promoting effects and suggests that TLR4 expression on cancer cells may be an important biomarker for anti-PAUF treatment.
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- 2022
- Full Text
- View/download PDF
6. Knockdown of pancreatic adenocarcinoma upregulated factor (PAUF) suppresses proliferation, migration, invasion, and cancer stem cell properties in lung cancer cells.
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Liangchao Dong, Weiwei Li, and Xiaoli Zhang
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LUNG cancer , *CANCER stem cells , *CELL migration inhibition , *FOCAL adhesion kinase , *CANCER cells , *CANCER cell proliferation , *CELL migration - Abstract
Purpose: To investigate the role of pancreatic adenocarcinoma up-regulated factor (PAUF) in lung cancer. Method: Proliferation of lung cancer cell lines (A549 and H1299) was determined using MTS and Edu staining assays. Wound healing and transwell assays were performed to evaluate cell migration and invasion abilities. Lung cancer stem cell (CSC) marker expressions, including CD133, CD44, ALDH1, SOX2, and Oct4, were determined by western blot assay. Results: Knockdown of PAUF significantly inhibited A459 and H1299 cell proliferation (p < 0.01). The wound healing and transwell assay results indicated that depletion of PAUF markedly suppressed H1299 and A549 cell migration and invasion, compared with the control cells (p < 0.01). Knockdown of PAUF reduced distinct CSC marker expression, suggesting inhibition of CSC phenotypes, and reduced phosphorylated focal adhesion kinase (FAK), phosphorylated Src, and phosphorylated extracellular signal-regulated kinase (ERK), but not total FAK, Src, and ERK. These results suggested that knockdown of PAUF deactivated the FAK/Src/ERK signal pathway. Conclusion: Knockdown of PAUF inhibits lung cancer cell proliferation, migration, invasion, and CSC properties via deactivation of FAK/Src/ERK signal pathway. These results may provide a novel strategy for the development of lung cancer therapeutics. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Sorting secretory proteins.
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Parchure A and von Blume J
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- Protein Transport, Golgi Apparatus metabolism, Secretory Vesicles metabolism, trans-Golgi Network metabolism, Proteins metabolism
- Abstract
A receptor protein called TGN46 has an important role in sorting secretory proteins into vesicles going to different destinations inside cells., Competing Interests: AP, Jv No competing interests declared, (© 2023, Parchure and von Blume.)
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- 2023
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8. Genomic Network-Based Analysis Reveals Pancreatic Adenocarcinoma Up-Regulating Factor-Related Prognostic Markers in Cervical Carcinoma
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Jihye Kim, Joon-Yong Chung, Tae-Joong Kim, Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Chel Hun Choi, and Stephen M. Hewitt
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PAUF ,AGR2 ,BRD7 ,POM121 ,prognosis ,uterine cervical neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We previously showed that PAUF is involved in tumor development and metastases in cervical cancer. This study was conducted to discover novel molecular markers linked with PAUF in cervical cancer using genomic network analysis and to assess their prognostic value in cervical cancer. Three PAUF-related genes were identified using in-silico network-based analysis of the open genome datasets. To assess the expression of these genes and their relationship to the outcome of cervical cancer, immunohistochemical analysis was performed using cervical cancer TMA. The associations of the identified proteins with clinicopathologic characteristics and prognosis were examined. AGR2, BRD7, and POM121 were identified as interconnected with PAUF through in-silico network-based analysis. AGR2 (r = 0.213, p < 0.001) and POM121 (r = 0.135, p = 0.013) protein expression were positively correlated with PAUF. BRD7High and AGR2Low were significantly associated with favorable disease-free survival (DFS) (p = 0.009 and p < 0.001, respectively), and in combination with PAUFHigh, even more significantly favorable DFS observed (p < 0.001 for both). In multivariate analysis, AGR2High (HR = 3.16, p = 0.01) and BRD7High (HR = 0.5, p = 0.025) showed independent prognostic value for DFS. In a random survival forest (RSF) model, the combined clinical and molecular variable model predicted DFS with significantly improved power compared with that of the clinical variable model (C-index of 0.79 vs. 0.75, p < 0.001). In conclusion, AGR2 and BRD7 expression have prognostic significance in cervical cancer and provide opportunities for improved treatment options. Genomic network-based approaches using the cBioPortal may facilitate the discovery of additional biomarkers for the prognosis of cervical cancer and may provide new insights into the biology of cervical carcinogenesis.
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- 2018
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9. Genomic Network-Based Analysis Reveals Pancreatic Adenocarcinoma Up-Regulating Factor-Related Prognostic Markers in Cervical Carcinoma.
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Kim, Jihye, Chung, Joon-Yong, Kim, Tae-Joong, Lee, Jeong-Won, Kim, Byoung-Gie, Bae, Duk-Soo, Choi, Chel Hun, and Hewitt, Stephen M.
- Abstract
We previously showed that PAUF is involved in tumor development and metastases in cervical cancer. This study was conducted to discover novel molecular markers linked with PAUF in cervical cancer using genomic network analysis and to assess their prognostic value in cervical cancer. Three PAUF-related genes were identified using in-silico network-based analysis of the open genome datasets. To assess the expression of these genes and their relationship to the outcome of cervical cancer, immunohistochemical analysis was performed using cervical cancer TMA. The associations of the identified proteins with clinicopathologic characteristics and prognosis were examined. AGR2, BRD7, and POM121 were identified as interconnected with PAUF through in-silico network-based analysis. AGR2 (r = 0.213, p < 0.001) and POM121 (r = 0.135, p = 0.013) protein expression were positively correlated with PAUF. BRD7
High and AGR2Low were significantly associated with favorable disease-free survival (DFS) (p = 0.009 and p < 0.001, respectively), and in combination with PAUFHigh , even more significantly favorable DFS observed (p < 0.001 for both). In multivariate analysis, AGR2High (HR = 3.16, p = 0.01) and BRD7High (HR = 0.5, p = 0.025) showed independent prognostic value for DFS. In a random survival forest (RSF) model, the combined clinical and molecular variable model predicted DFS with significantly improved power compared with that of the clinical variable model (C-index of 0.79 vs. 0.75, p < 0.001). In conclusion, AGR2 and BRD7 expression have prognostic significance in cervical cancer and provide opportunities for improved treatment options. Genomic network-based approaches using the cBioPortal may facilitate the discovery of additional biomarkers for the prognosis of cervical cancer and may provide new insights into the biology of cervical carcinogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
10. DCPP1 is the mouse ortholog of human PAUF that possesses functional analogy in pancreatic cancer.
- Author
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Song, Hayne, Song, Jinhoi, Kim, Yeon Jeong, Jeong, Hyeon Hee, Min, Hye Jin, and Koh, Sang Seok
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ADENOCARCINOMA , *PANCREATIC duct , *CANCER invasiveness , *MOLECULAR mechanisms of immunosuppression , *CELL proliferation , *CELL migration , *CANCER - Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF) overexpressed in pancreatic ductal adenocarcinoma (PDAC) plays a major role in tumor progression and metastasis by autocrine and paracrine manners. However, underlying molecular mechanism of PAUF functioning in pancreatic cancer are not fully understood yet. The objective of this study was to evaluate the potential of demilune cell and parotid protein 1 (DCPP1) as a putative mouse ortholog of human PAUF by sequence alignment and functional studies. Overexpression of mouse DCPP1 in Chinese hamster ovary (CHO) cells or pancreatic cancer cells increased cell proliferation, migration, invasion, and adhesion ability in vitro . Treatment of human pancreatic cancer cells with recombinant mouse DCPP1 elevated cell growth, motility, invasiveness, and adhesiveness. Mouse DCPP1 exerted its function on pancreatic cancer cells by activating intracellular signaling pathways involved in aggressive cancer phenotype of human pancreatic cancer cells. Moreover, subcutaneous injection of mice with DCPP1-overexpressing CHO cells increased tumor sizes. Taken together, we conclude that mouse DCPP1 is a multifunctional promoter of tumor growth through functional activation of pancreatic cancer cells, suggesting it to be an ortholog of human PAUF. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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11. Pancreatic adenocarcinoma up-regulated factor has oncogenic functions in oral squamous cell carcinoma.
- Author
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Sasahira, Tomonori, Kurihara, Miyako, Nishiguchi, Yukiko, Nakashima, Chie, Kirita, Tadaaki, and Kuniyasu, Hiroki
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ORAL cancer risk factors , *PANCREATIC tumors , *ADENOCARCINOMA , *PROGNOSIS , *TUMOR risk factors , *DISEASE risk factors ,RISK of metastasis - Abstract
Aims Pancreatic adenocarcinoma up-regulated factor ( PAUF) is a novel secretory protein which promotes tumour progression, metastasis and poor prognosis in pancreatic, cervical and colorectal carcinoma. It is also associated with gemcitabine resistance in pancreatic cancer cells. However, the expression and function of PAUF in oral squamous cell carcinoma ( OSCC) remain unknown. Methods and results We performed an immunohistochemical analysis of PAUF in 222 clinicopathologically characterized cases of OSCC. We also investigated the growth, invasion, apoptosis induction and cisplatin resistance of OSCC cells under PAUF knockdown treatment. PAUF was localized in normal salivary glands. In OSCC, immunostaining for PAUF was found in 52 of 222 patients (23.4%), and correlated with nodal metastasis ( P < 0.0001) and poor prognosis ( P < 0.0001). Multivariate analysis using the Cox proportional hazards model identified that PAUF expression was an independent predictor of disease-free survival in OSCC ( P < 0.0001). The down-regulation of PAUF in OSCC cells suppressed cell growth and invasion and induced apoptosis and cisplatin sensitivity. Conclusions Our results suggest that PAUF has tumour-promoting functions in OSCC. It may thus be a useful diagnostic and therapeutic marker for OSCC. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Advanced nanoscopy tools to monitor intracellular membrane trafficking
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Pons Lanau, Roger, Universitat Politècnica de Catalunya. Institut de Ciències Fotòniques, Garcia-Parajo, Maria F., Campelo Aubarell, Felix, and García Parajo, María
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Fluorescence microscopy ,Single particle tracking ,Golgi ,CARTS ,Enginyeria de la telecomunicació::Telecomunicació òptica::Fotònica [Àrees temàtiques de la UPC] ,PAUF ,Microscòpia de fluorescència ,HILO - Abstract
Intracellular membrane trafficking function is to transport proteins and other macromolecules by membrane bound vesicles throughout the cell and it is key for maintaining homeostasis and responding to signaling processes. Novel super resolution microscopy techniques open now the door for studying membrane trafficking with unprecedented resolution. As a proof-of-concept, here a technique named single particle tracking (SPT) with highly inclined and laminated optical illumination is used to identify the movement of an specific type of intracellular carriers. The experimental procedure is optimized for SPT and its spatiotemporal resolution characterized. Thus validating the system and showing its potential for studying intracellular communication.
- Published
- 2021
13. Silencing pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer cells to gemcitabine.
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Gao, Chong-chong, Xu, Xiao-Lan, Li, Fei, Gong, Ben-gang, Liu, Shuang, Cui, Ye-qing, Sun, Hai-chen, Xu, Ping-yong, Zheng, Ya-min, and Jiang, Hua
- Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF) is a new oncogene that activates signaling pathways that play a critical role in resistance to gemcitabine. We thus speculated that PAUF also plays a role in resistance to gemcitabine of pancreatic cancer cells. We established BxPC-3 cell lines with stable PAUF knockdown (BxPC-3_shPAUF) and controls (BxPC-3_shCtrl) and evaluated sensitivity to gemcitabine in vitro by MTT and flow cytometry. We established a xenograft model of human pancreatic cancer to examine PAUF function in gemcitabine resistance in vivo. Gene chip microarrays were performed to identify differentially expressed genes in BxPC-3_shPAUF and BxPC-3_shCtrl cells. Silencing PAUF increased the sensitivity of BxPC-3 cells to gemcitabine in vitro and in vivo. PAUF-knockdown BxPC-3 cell lines treated with gemcitabine showed increased proliferation inhibition and apoptosis compared with controls. Gemcitabine exhibited a more pronounced effect on reduction of BxPC-3_shPAUF tumors than BxPC-3_shCtrl tumors. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assays confirmed a significantly higher apoptotic rate of BXPC-3_shPAUF tumors compared with BXPC-3_shCtrl tumors. Gene array showed that PAUF function in gemcitabine sensitivity might involve MRP2, MRP3, MDR1, PIK3R1, and NFkB2 genes. PAUF could be considered as a key molecular target for sensitizing pancreatic cancer cells to gemcitabine. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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14. Advanced nanoscopy tools to monitor intracellular membrane trafficking
- Author
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Universitat Politècnica de Catalunya. Institut de Ciències Fotòniques, Garcia-Parajo, Maria F., Campelo Aubarell, Felix, Pons Lanau, Roger, Universitat Politècnica de Catalunya. Institut de Ciències Fotòniques, Garcia-Parajo, Maria F., Campelo Aubarell, Felix, and Pons Lanau, Roger
- Abstract
Intracellular membrane trafficking function is to transport proteins and other macromolecules by membrane bound vesicles throughout the cell and it is key for maintaining homeostasis and responding to signaling processes. Novel super resolution microscopy techniques open now the door for studying membrane trafficking with unprecedented resolution. As a proof-of-concept, here a technique named single particle tracking (SPT) with highly inclined and laminated optical illumination is used to identify the movement of an specific type of intracellular carriers. The experimental procedure is optimized for SPT and its spatiotemporal resolution characterized. Thus validating the system and showing its potential for studying intracellular communication.
- Published
- 2021
15. Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients.
- Author
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Chel Hun Choi, Joon-Yong Chung, Ho-Seop Park, Minsik Jun, Yoo-Young Lee, Byung-Gie Kim, and Hewitt, Stephen M.
- Published
- 2015
- Full Text
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16. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling.
- Author
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Kaowinn, Sirichat, Cho, Il-Rae, Moon, Jeong, Jun, Seung Won, Kim, Chang Seok, Kang, Ho Young, Kim, Manbok, Koh, Sang Seok, and Chung, Young-Hwa
- Subjects
- *
ADENOCARCINOMA , *CANCER treatment , *CANCER patients , *PANCREATIC cancer , *CANCER cell growth regulation , *DRUG resistance in cancer cells , *PARVOVIRUS diseases , *INTERFERON alpha - Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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17. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis.
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Kim, Su Jin, Chang, Suhwan, Lee, Yangsoon, Kim, Na Young, Hwang, Yeonsil, Min, Hye Jin, Yoo, Kyung-Sook, Park, Eun Hye, Kim, Seokho, Chung, Young-Hwa, Park, Young Woo, and Koh, Sang Seok
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PANCREATIC cancer , *ENDOTHELIAL cells , *CANCER invasiveness , *METASTASIS , *ANTINEOPLASTIC agents , *PHARMACODYNAMICS , *MONOCLONAL antibodies - Abstract
Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31 + vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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18. Efficient targeting and tumor retardation effect of pancreatic adenocarcinoma up-regulated factor (PAUF)-specific RNA replacement in pancreatic cancer mouse model.
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Kim, Yun-Hee, Moon, Ju Young, Kim, Eun-Ok, Lee, Sang-Jin, Kang, Se Hun, Kim, Seok Ki, Heo, Kyun, Lee, Yusun, Kim, Hana, Kim, Kyung-Tae, Kim, Daehong, Song, Min Sun, Lee, Seoung-Wook, Lee, Yangsoon, Koh, Sang Seok, and Kim, In-Hoo
- Subjects
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PANCREATIC cancer treatment , *TARGETED drug delivery , *DRUG efficacy , *LABORATORY mice , *GENE replacement , *TUMOR proteins , *CANCER invasiveness - Abstract
Abstract: The soluble protein pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in pancreatic tumor progression and has begun to attract attention as a therapeutic target for pancreatic cancer. We herein present PAUF RNA-targeting gene therapy strategies with both targeting and therapeutic function using trans-splicing ribozyme (TSR) in pancreatic cancer. We developed adenoviral PAUF-targeting TSR (Rz) containing a PAUF-specific internal guide sequence (IGS) determined by library screening. This Rz harbors suicide gene, herpes simplex virus thymidine kinase (HSV-tk) or firefly luciferase (Luc) as a transgene for 3′ exon replacement of PAUF RNAs. Ad-Rz-TK, Rz harboring the HSV-tk, showed significant inhibition of tumor growth in vivo as well as PAUF-dependent cell death in vitro via a successful trans-splicing reaction. Selective induction of Rz-controlled transgene in PAUF-expressing pancreatic cancer was confirmed through noninvasive in vivo imaging; a luminescence signal from Rz harboring Luc (Ad-Rz-Luc) was detectable only in pancreatic tumor sites, not in normal mice. In addition, a [125I] FIAU signal reflecting thymidine kinase expression through SPECT and ex vivo biodistribution was co-localized with the tumor sites when we treated with Ad-Rz-TK in orthotopic xenograft model. Taken together, these results imply that PAUF-targeting TSR can contribute to successful targeted gene therapy for pancreatic cancer. [Copyright &y& Elsevier]
- Published
- 2014
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19. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin
- Author
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Cho, Il-Rae, Koh, Sang Seok, Malilas, Waraporn, Srisuttee, Ratakorn, Moon, Jeong, Choi, Young-Whan, Horio, Yoshiyuki, Oh, Sangtaek, and Chung, Young-Hwa
- Subjects
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PANCREATIC cancer treatment , *SIRTUINS , *CANCER cell proliferation , *ONCOGENES , *CATENINS , *RESVERATROL , *CYCLINS - Abstract
Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of β-catenin, we postulated that β-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target β-catenin in a colon cancer model, suppresses β-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of β-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced β-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of β-catenin. Treatment with MG132, a proteasomal inhibitor, restored β-catenin protein levels, suggesting that SIRT1-mediated degradation of β-catenin requires proteasomal activity. It was reported that inhibition of GSK-3β or Siah-1 stabilizes β-catenin in colon cancer cells, but suppression of GSK-3β or Siah-1 using siRNA in the presence of resveratrol instead diminished β-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3β and Siah-1 are not involved in SIRT1-mediated degradation of β-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target molecule of β-catenin. These results suggest that SIRT1 activation may be a therapeutic strategy for treatment of pancreatic cancer cells that express PAUF via the down-regulation of β-catenin. [Copyright &y& Elsevier]
- Published
- 2012
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20. An RNA aptamer that specifically binds pancreatic adenocarcinoma up-regulated factor inhibits migration and growth of pancreatic cancer cells
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Kim, Yun-Hee, Sung, Ho Jin, Kim, Sukyoung, Kim, Eun-Ok, Lee, Ji Won, Moon, Ju Young, Choi, Kyungho, Jung, Ji-Eun, Lee, Yangsoon, Koh, Sang Seok, Rhee, Sue Goo, Heo, Kyun, and Kim, In-Hoo
- Subjects
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NUCLEIC acids , *ADENOCARCINOMA , *PANCREATIC cancer , *CELL migration , *TUMOR growth , *CANCER cells , *ANTINEOPLASTIC agents - Abstract
Abstract: Previously, we reported that a novel secretory protein, pancreatic adenocarcinoma up-regulated factor (PAUF), which is highly expressed in pancreatic cancer and mediates the growth and metastasis of pancreatic cancer cells. In this study, we generated and characterized a 2′-fluoropyrimidine modified RNA aptamer (P12FR2) directed against human PAUF. P12FR2 binds specifically to human PAUF with an estimated apparent KD of 77nM. P12FR2 aptamer inhibits PAUF-induced migration of PANC-1, human pancreatic cancer cells, in a wound healing assay. Moreover, intraperitoneal injection of P12FR2 decreased tumor growth by about 60% in an in vivo xenograft model with CFPAC-1 pancreatic cancer cells, without causing a loss of weight in the treated mice. Taken together, we propose here that PAUF-specific RNA aptamer, P12FR2, has the potential to be effective in the therapy of human pancreatic cancer. [Copyright &y& Elsevier]
- Published
- 2011
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21. PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression.
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Lee, Y., Kim, S. J., Park, H. D., Park, E. H., Huang, S. M., Jeon, S. B., Kim, J.-M., Lim, D.-S., and Koh, S. S.
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PANCREATIC cancer genetics , *METASTASIS , *TUMOR suppressor proteins , *CANCER invasiveness , *CELLULAR pathology , *CANCER cells - Abstract
Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
22. Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells
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Soo Been Park, Jae Hee Cho, Hee Man Kim, Kim Sun A, and Si Young Song
- Subjects
cancer stem cells ,0301 basic medicine ,medicine.medical_specialty ,pancreatic cancer ,medicine.disease_cause ,Gastroenterology ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,SOX2 ,Cancer stem cell ,Pancreatic cancer ,Internal medicine ,medicine ,business.industry ,MRP5 ,Cancer ,medicine.disease ,Gemcitabine ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,RRM2 ,Cancer research ,Adenocarcinoma ,PAUF ,Carcinogenesis ,business ,Research Paper ,medicine.drug - Abstract
// Jae Hee Cho 1, 2, * , Sun A. Kim 1, * , Soo Been Park 1 , Hee Man Kim 3 and Si Young Song 1, 4 1 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea 4 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Si Young Song, email: sysong@yuhs.ac Keywords: cancer stem cells, PAUF, pancreatic cancer, MRP5, RRM2 Received: March 03, 2017 Accepted: June 23, 2017 Published: July 22, 2017 ABSTRACT Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44 + CD24 + ESA + pancreatic CSCs. PAUF knockdown (shPAUF) CFPAC-1 diminished the number of spheres and decreased stemness genes and CSC surface markers (CD133, c-MET and ALDH1). In addition, siPAUF CFPAC-1 decreased the mRNA expression of multidrug resistant protein 5 (MRP5) and ribonucleotide reductase M2 (RRM2) and were more vulnerable to gemcitabine and 5-FU than negative control (p
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- 2017
23. Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer
- Author
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Ji Eun Baek, Yeon Jeong Kim, Song Cheol Kim, Seongyea Jo, Jinhoi Song, Dong-Uk Kim, Kwang-Pyo Lee, Yun-Yong Park, Jinsil Kim, Siyoung Yang, Jaemin Lee, Sang Seok Koh, Ki-Sun Kwon, Eun-Soo Kwon, Seokho Kim, Hee Jun Cho, Tae Heung Kang, and Suhwan Chang
- Subjects
0301 basic medicine ,medicine.medical_treatment ,MDSC ,pancreatic cancer ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pancreatic cancer ,Cell Line, Tumor ,Lectins ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Tumor microenvironment ,business.industry ,Myeloid-Derived Suppressor Cells ,Cancer ,Membrane Proteins ,Immunotherapy ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Myeloid-derived Suppressor Cell ,Adenocarcinoma ,Intercellular Signaling Peptides and Proteins ,Tumor Escape ,Carcinogenesis ,business ,PAUF ,Research Paper ,Carcinoma, Pancreatic Ductal - Abstract
// Jinhoi Song 1, 2, * , Jaemin Lee 1, * , Jinsil Kim 1, * , Seongyea Jo 1 , Yeon Jeong Kim 3 , Ji Eun Baek 3 , Eun-Soo Kwon 1 , Kwang-Pyo Lee 1 , Siyoung Yang 1 , Ki-Sun Kwon 1 , Dong-Uk Kim 1 , Tae Heung Kang 4 , Yun-Yong Park 5 , Suhwan Chang 6 , Hee Jun Cho 7 , Song Cheol Kim 8 , Sang Seok Koh 3 , Seokho Kim 1 1 Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea 3 Department of Biological Sciences, Dong-A University, Busan, Republic of Korea 4 Department of Immunology, School of Medicine, Konkuk University, Seoul, Republic of Korea 5 Department of Biomedical Sciences and Physiology, University of Ulsan College of Medicine, Seoul, Republic of Korea 6 Departments of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 7 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 8 Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Song-Cheol Kim, email: drksc@amc.seoul.kr Sang Seok Koh, email: sskoh@dau.ac.kr Seokho Kim, email: kims@kribb.re.kr Keywords: MDSC, PAUF, pancreatic cancer, tumor microenvironment Received: November 30, 2015 Accepted: May 28, 2016 Published: June 17, 2016 ABSTRACT Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.
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- 2016
24. Genomic Network-Based Analysis Reveals Pancreatic Adenocarcinoma Up-Regulating Factor-Related Prognostic Markers in Cervical Carcinoma
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Chel Hun Choi, Jeong-Won Lee, Duk-Soo Bae, Stephen M. Hewitt, Byoung-Gie Kim, Joon-Yong Chung, Jihye Kim, and Tae-Joong Kim
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,AGR2 ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,uterine cervical neoplasms ,Internal medicine ,Cervical carcinoma ,medicine ,POM121 ,Gene ,Original Research ,Cervical cancer ,business.industry ,Treatment options ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Immunohistochemistry ,prognosis ,PAUF ,business ,BRD7 - Abstract
We previously showed that PAUF is involved in tumor development and metastases in cervical cancer. This study was conducted to discover novel molecular markers linked with PAUF in cervical cancer using genomic network analysis and to assess their prognostic value in cervical cancer. Three PAUF-related genes were identified using in-silico network-based analysis of the open genome datasets. To assess the expression of these genes and their relationship to the outcome of cervical cancer, immunohistochemical analysis was performed using cervical cancer TMA. The associations of the identified proteins with clinicopathologic characteristics and prognosis were examined. AGR2, BRD7, and POM121 were identified as interconnected with PAUF through in-silico network-based analysis. AGR2 (r = 0.213, p < 0.001) and POM121 (r = 0.135, p = 0.013) protein expression were positively correlated with PAUF. BRD7High and AGR2Low were significantly associated with favorable disease-free survival (DFS) (p = 0.009 and p < 0.001, respectively), and in combination with PAUFHigh, even more significantly favorable DFS observed (p < 0.001 for both). In multivariate analysis, AGR2High (HR = 3.16, p = 0.01) and BRD7High (HR = 0.5, p = 0.025) showed independent prognostic value for DFS. In a random survival forest (RSF) model, the combined clinical and molecular variable model predicted DFS with significantly improved power compared with that of the clinical variable model (C-index of 0.79 vs. 0.75, p < 0.001). In conclusion, AGR2 and BRD7 expression have prognostic significance in cervical cancer and provide opportunities for improved treatment options. Genomic network-based approaches using the cBioPortal may facilitate the discovery of additional biomarkers for the prognosis of cervical cancer and may provide new insights into the biology of cervical carcinogenesis.
- Published
- 2018
25. Nuevos biomarcadores y dianas terapúticas en cancer colorectal metastásico
- Author
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Casal, J. Ignacio, Ministerio de Economía y Competitividad (España), Escudero-Paniagua, B., Casal, J. Ignacio, Ministerio de Economía y Competitividad (España), and Escudero-Paniagua, B.
- Abstract
[EN] Colorectal cancer (CRC) is the fourth most worldwide deadly cancer due to the metastatic development of the disease. For this reason, efforts are focused on the prediction and treatment of CRC metastases. Metastatic tumor cells undergo a series of alterations, for example in their capacity of adhesion and invasion, which allow them to colonize, survive and proliferate in distal organs. At present, molecular mechanisms and proteins responsible for hepatic and pulmonary colonization of colon tumor cells are not known. Recently, our laboratory has identified CDH17 and IL13R2, and the molecular mechanisms through which they function, for hepatic colonization of CCR cells. To search for biomarkers associated with diseases such as cancer, "omic" techniques are used to identify, quantify and characterize thousands of genes and/or proteins in complex biological samples. Our laboratory has used these techniques, such as protein microarrays or quantitative proteomics, identifying a total of 43 tumor associated antigens, including FGFR4 and PIM1, which could function as CRC biomarkers. These advances are of great importance, since few proteins have been described as CRC biomarkers. Goals: In this context, the work developed in this Doctoral Thesis has attempted to advance in the knowledge of the mechanisms involved in CRC metastasis, with the final aim of finding new metastasis biomarkers and therapeutic targets for this disease. Results and Discussion: Using quantitative proteomics tools, we have characterized the altered mechanisms in CRC metastasis, discovering that the alterations in metastatic cells with respect to tumor cells are broader than previously described, and encompass processes such as lipid and glycoproteins metabolism, sub-cellular protein localization and mitochondrial organization, among others. On the other hand, we have identified a number of potential metastatic CRC biomarkers, whose overexpression is associated with poorer survival, including PLOD, LOXL1 is an extracellular matrix protein, necessary for lung colonization of breast cancer cells. In this work we observe that LOXL1 is overexpressed in the secretoma of highly metastatic CCR cells KM12L4, which in particular, metastasize to the lung. We have observed that LOXL1 is involved in the pro-metastatic processes of cell adhesion and invasion, and found, thanks to the study of its interactome, that it can participate, at least in CRC, in other biological processes such as the Wnt canonical signaling pathway and regulation of intra- and extra-cellular transport. In conclusion, we started the study of the relationship between LOXL1 and CRC, discovering that LOXL1, like in breast cancer, participates in cell adhesion and invasion, and may be a determinant for lung colonization of KM12L4 cells. On the other hand, we have analyzed for the first time the role in CRC of PAUF, a poorly known protein, upregulated in pancreatic cancer, where it participates in processes of cell adhesion, migration and invasion. We identified PAUF as a protein whose expression decreases in the primary colon tumor to subsequently increase in liver metastasis of CRC, and corroborated its effect on cell adhesion and invasion. We observed that PAUF is located in the nucleus and cytosol, distributed in a very similar way to APC. In addition, its silencing causes increase in nuclear size, displacement of the cell cycle profile, errors in mitosis, decreased cell proliferation, as well as great chromosomal instability, suggesting its participation in the mitotic checkpoint. The analysis of its interactome corroborated this function, identifying numerous proteins belonging to the mitotic checkpoint, among which was APC. APC expression decreases after silencing of PAUF, and is accompanied by a decrease in E-cadherin expression, and an increase in nuclear -catenin, suggesting that loss of PAUF could promote the epithelial-mesenchymal transition and tumor progression. Finally, we have observed th, [ES] El cáncer colorrectal (CCR) es el cuarto cáncer más mortal a nivel mundial, debido al desarrollo metastásico de la enfermedad. Por esta razón, parte de los esfuerzos se focalizan en la predicción y el tratamiento de la metástasis de CCR. Las células tumorales metastásicas sufren una serie de alteraciones, por ejemplo en su capacidad de adhesión e invasión, que les permiten colonizar, sobrevivir y proliferar en órganos distales. Actualmente, no se conocen con exactitud los mecanismos moleculares ni las proteínas responsables de la colonización hepática y pulmonar de las células tumorales de colon. Recientemente, nuestro laboratorio identificó a CDH17 e IL13R2, y los mecanismos moleculares a través de los cuales son necesarias para la colonización hepática de las células de CCR. Para la búsqueda de biomarcadores asociados a enfermedades como el cáncer, se utilizan técnicas ómicas , que permiten identificar, cuantificar y caracterizar miles de genes o proteínas en muestras biológicas complejas. Nuestro laboratorio ha utilizado estas técnicas, como microarrays de proteínas o proteómica cuantitativa, identificando un total de 43 antígenos asociados a tumor, entre los que se encontraban FGFR4 y PIM1, que podrían funcionar como biomarcadores de CCR. Estos avances son de gran importancia, ya que pocas proteínas se han descrito como biomarcadores de esta enfermedad. Objetivos: En este contexto, el trabajo desarrollado en esta Tesis Doctoral ha pretendido avanzar en el conocimiento de los mecanismos implicados en la metástasis de CCR, con el fin último de encontrar nuevos biomarcadores y dianas terapéuticas de la metástasis de esta enfermedad. Resultados y discusión: Mediante la utilización de herramientas de proteómica cuantitativa, hemos caracterizado los mecanismos alterados en la metástasis de CCR, observando que las alteraciones en las células metastásicas respecto de las células tumorales son más amplias de lo descrito hasta ahora, y abarcan procesos como metaboli, Dentro de las proteínas identificadas como proteínas desreguladas en la metástasis de CCR se encontraban LOXL1 y PAUF. LOXL1 es una proteína de matriz extracelular, necesaria para la colonización pulmonar de células de cáncer de mama. En este trabajo observamos que LOXL1 se sobre-expresa en el secretoma de células altamente metastásicas de CCR KM12L4, que particularmente, metastatizan a pulmón. Observamos que LOXL1 está involucrada en los procesos pro-metastásicos de adhesión e invasión celular, y encontramos, gracias al estudio de su interactoma, que puede participar, al menos en CCR, en otros procesos biológicos como la vía de señalización canónica de Wnt o la regulación del transporte intra- y extra-celular. En definitiva, iniciamos el estudio de la relación existente entre LOXL1 y CCR observando que LOXL1, al igual que sucede en cáncer de mama, participa en adhesión e invasión celular, pudiendo ser determinante para la colonización pulmonar de las células KM12L4. Por otro lado, caracterizamos por primera vez el papel en CCR de PAUF, una proteína poco conocida, regulada al alza en cáncer de páncreas, donde participa en procesos de adhesión, migración e invasión celular. Identificamos a PAUF como una proteína cuya expresión disminuye en el tumor primario de colon para posteriormente aumentar en la metástasis hepática de CCR, y corroboramos su efecto sobre adhesión e invasión celular. Observamos que PAUF se localiza en el núcleo y en el citosol, distribuyéndose de manera muy similar a APC. Además, su silenciamiento provoca aumento del tamaño nuclear, desplazamiento del perfil de ciclo celular, errores en las mitosis, diminución de la proliferación celular, así como gran inestabilidad cromosómica, sugiriendo su participación en el checkpoint mitótico. El análisis de su interactoma corroboró esta función, identificándose numerosas proteínas pertenecientes al checkpoint mitótico, entre las que se encontraba APC. La expresión de APC disminuye después del silenciamiento
- Published
- 2017
26. Nuevos biomarcadores y dianas terapúticas en cancer colorectal metastásico
- Author
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Escudero-Paniagua, B., Casal, J. Ignacio, and Ministerio de Economía y Competitividad (España)
- Subjects
Biomarcadores ,Proteómica ,LOXL1 ,Cáncer colorrectal ,Metástasis ,PAUF - Abstract
277 p.-80 fig.-9 tab.-anexos., [EN] Colorectal cancer (CRC) is the fourth most worldwide deadly cancer due to the metastatic development of the disease. For this reason, efforts are focused on the prediction and treatment of CRC metastases. Metastatic tumor cells undergo a series of alterations, for example in their capacity of adhesion and invasion, which allow them to colonize, survive and proliferate in distal organs. At present, molecular mechanisms and proteins responsible for hepatic and pulmonary colonization of colon tumor cells are not known. Recently, our laboratory has identified CDH17 and IL13R2, and the molecular mechanisms through which they function, for hepatic colonization of CCR cells. To search for biomarkers associated with diseases such as cancer, "omic" techniques are used to identify, quantify and characterize thousands of genes and/or proteins in complex biological samples. Our laboratory has used these techniques, such as protein microarrays or quantitative proteomics, identifying a total of 43 tumor associated antigens, including FGFR4 and PIM1, which could function as CRC biomarkers. These advances are of great importance, since few proteins have been described as CRC biomarkers. Goals: In this context, the work developed in this Doctoral Thesis has attempted to advance in the knowledge of the mechanisms involved in CRC metastasis, with the final aim of finding new metastasis biomarkers and therapeutic targets for this disease. Results and Discussion: Using quantitative proteomics tools, we have characterized the altered mechanisms in CRC metastasis, discovering that the alterations in metastatic cells with respect to tumor cells are broader than previously described, and encompass processes such as lipid and glycoproteins metabolism, sub-cellular protein localization and mitochondrial organization, among others. On the other hand, we have identified a number of potential metastatic CRC biomarkers, whose overexpression is associated with poorer survival, including PLOD1, a protein never before related to cancer, and QSOX1, whose involvement in metastasis of cancer has begun to be studied. Within the proteins identified as deregulated proteins in CRC metastasis were LOXL1 and PAUF., LOXL1 is an extracellular matrix protein, necessary for lung colonization of breast cancer cells. In this work we observe that LOXL1 is overexpressed in the secretoma of highly metastatic CCR cells KM12L4, which in particular, metastasize to the lung. We have observed that LOXL1 is involved in the pro-metastatic processes of cell adhesion and invasion, and found, thanks to the study of its interactome, that it can participate, at least in CRC, in other biological processes such as the Wnt canonical signaling pathway and regulation of intra- and extra-cellular transport. In conclusion, we started the study of the relationship between LOXL1 and CRC, discovering that LOXL1, like in breast cancer, participates in cell adhesion and invasion, and may be a determinant for lung colonization of KM12L4 cells. On the other hand, we have analyzed for the first time the role in CRC of PAUF, a poorly known protein, upregulated in pancreatic cancer, where it participates in processes of cell adhesion, migration and invasion. We identified PAUF as a protein whose expression decreases in the primary colon tumor to subsequently increase in liver metastasis of CRC, and corroborated its effect on cell adhesion and invasion. We observed that PAUF is located in the nucleus and cytosol, distributed in a very similar way to APC. In addition, its silencing causes increase in nuclear size, displacement of the cell cycle profile, errors in mitosis, decreased cell proliferation, as well as great chromosomal instability, suggesting its participation in the mitotic checkpoint. The analysis of its interactome corroborated this function, identifying numerous proteins belonging to the mitotic checkpoint, among which was APC. APC expression decreases after silencing of PAUF, and is accompanied by a decrease in E-cadherin expression, and an increase in nuclear -catenin, suggesting that loss of PAUF could promote the epithelial-mesenchymal transition and tumor progression. Finally, we have observed that the silencing of PAUF sensitizes APC-deficient CCR cells to treatment with certain types of drugs, such as taxol. In short, we characterized PAUF as a mitotic checkpoint protein, important for the maintenance of chromosomal stability in CRC, and whose silencing, combined with the use of different drugs, could be a good strategy to follow for the treatment of patients with CRC. Conclusions: In this Doctoral Thesis we have expanded the knowledge of the altered mechanisms in the CRC metastasis, as well as identifying a series of proteins as potential biomarkers of this disease. In addition, we have analysed for the first time the role of LOXL1 and PAUF in CRC., [ES] El cáncer colorrectal (CCR) es el cuarto cáncer más mortal a nivel mundial, debido al desarrollo metastásico de la enfermedad. Por esta razón, parte de los esfuerzos se focalizan en la predicción y el tratamiento de la metástasis de CCR. Las células tumorales metastásicas sufren una serie de alteraciones, por ejemplo en su capacidad de adhesión e invasión, que les permiten colonizar, sobrevivir y proliferar en órganos distales. Actualmente, no se conocen con exactitud los mecanismos moleculares ni las proteínas responsables de la colonización hepática y pulmonar de las células tumorales de colon. Recientemente, nuestro laboratorio identificó a CDH17 e IL13R2, y los mecanismos moleculares a través de los cuales son necesarias para la colonización hepática de las células de CCR. Para la búsqueda de biomarcadores asociados a enfermedades como el cáncer, se utilizan técnicas ómicas , que permiten identificar, cuantificar y caracterizar miles de genes o proteínas en muestras biológicas complejas. Nuestro laboratorio ha utilizado estas técnicas, como microarrays de proteínas o proteómica cuantitativa, identificando un total de 43 antígenos asociados a tumor, entre los que se encontraban FGFR4 y PIM1, que podrían funcionar como biomarcadores de CCR. Estos avances son de gran importancia, ya que pocas proteínas se han descrito como biomarcadores de esta enfermedad. Objetivos: En este contexto, el trabajo desarrollado en esta Tesis Doctoral ha pretendido avanzar en el conocimiento de los mecanismos implicados en la metástasis de CCR, con el fin último de encontrar nuevos biomarcadores y dianas terapéuticas de la metástasis de esta enfermedad. Resultados y discusión: Mediante la utilización de herramientas de proteómica cuantitativa, hemos caracterizado los mecanismos alterados en la metástasis de CCR, observando que las alteraciones en las células metastásicas respecto de las células tumorales son más amplias de lo descrito hasta ahora, y abarcan procesos como metabolismo de lípidos y glicoproteínas, localización proteica sub-celular y organización mitocondrial, entre otros. Por otro lado, hemos identificado una serie de potenciales biomarcadores de la metástasis de CCR, cuya sobreexpresión se relaciona con peor supervivencia a la enfermedad, destacando PLOD1, una proteína nunca antes relacionada con cáncer, y QSOX1, proteína cuya implicación en la metástasis del cáncer se ha empezado a estudiar., Dentro de las proteínas identificadas como proteínas desreguladas en la metástasis de CCR se encontraban LOXL1 y PAUF. LOXL1 es una proteína de matriz extracelular, necesaria para la colonización pulmonar de células de cáncer de mama. En este trabajo observamos que LOXL1 se sobre-expresa en el secretoma de células altamente metastásicas de CCR KM12L4, que particularmente, metastatizan a pulmón. Observamos que LOXL1 está involucrada en los procesos pro-metastásicos de adhesión e invasión celular, y encontramos, gracias al estudio de su interactoma, que puede participar, al menos en CCR, en otros procesos biológicos como la vía de señalización canónica de Wnt o la regulación del transporte intra- y extra-celular. En definitiva, iniciamos el estudio de la relación existente entre LOXL1 y CCR observando que LOXL1, al igual que sucede en cáncer de mama, participa en adhesión e invasión celular, pudiendo ser determinante para la colonización pulmonar de las células KM12L4. Por otro lado, caracterizamos por primera vez el papel en CCR de PAUF, una proteína poco conocida, regulada al alza en cáncer de páncreas, donde participa en procesos de adhesión, migración e invasión celular. Identificamos a PAUF como una proteína cuya expresión disminuye en el tumor primario de colon para posteriormente aumentar en la metástasis hepática de CCR, y corroboramos su efecto sobre adhesión e invasión celular. Observamos que PAUF se localiza en el núcleo y en el citosol, distribuyéndose de manera muy similar a APC. Además, su silenciamiento provoca aumento del tamaño nuclear, desplazamiento del perfil de ciclo celular, errores en las mitosis, diminución de la proliferación celular, así como gran inestabilidad cromosómica, sugiriendo su participación en el checkpoint mitótico. El análisis de su interactoma corroboró esta función, identificándose numerosas proteínas pertenecientes al checkpoint mitótico, entre las que se encontraba APC. La expresión de APC disminuye después del silenciamiento de PAUF y se acompaña de una disminución de la expresión de E-cadherina y de un aumento de -catenina nuclear, sugiriendo que la pérdida de PAUF podría promover la transición epitelio-mesénquima y la progresión tumoral de CCR. Por último, observamos que el silenciamiento de PAUF sensibiliza a células de CCR deficientes en APC al tratamiento con determinados tipos de drogas, como por ejemplo, el taxol. En definitiva, caracterizamos a PAUF como una proteína del checkpoint mitótico, importante para el mantenimiento de la estabilidad cromosómica en CCR, y cuyo silenciamiento, combinado con el uso de diferentes drogas, podría ser una buena estrategia a seguir para el tratamiento de pacientes con CCR. Conclusiones: En esta Tesis Doctoral hemos ampliado el conocimiento de los mecanismos alterados en la metástasis de CCR, identificando, además, una serie de proteínas como potenciales biomarcadores de la enfermedad. Además, hemos caracterizado por primera vez el papel de LOXL1 y PAUF en CCR., Esta Tesis Doctoral ha sido financiada por el Ministerio de Economía con los proyectos BIO2015-66489-R y MINECO. RTC-2014-1518-1. ; beca FPI del Ministerio de Economía y Competitividad y una beca de la Sociedad Española de Proteómica (Seprot) para una estancia breve de 3 meses en la Universidad Libre de Ámsterdam (Países Bajos).
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- 2017
27. Pancreatic adenocarcinoma upregulated factor, a novel endothelial activator, promotes angiogenesis and vascular permeability
- Author
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Kim, S J, Lee, Y, Kim, N Y, Hwang, Y, Hwang, B, Min, J-K, and Koh, S S
- Published
- 2013
- Full Text
- View/download PDF
28. Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4
- Author
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Seokho Kim, Hee Dong Han, Benjamin Yang, Yeong Min Park, Je-Jung Lee, Hyun-Ju Lee, Seung Hyun Lee, Young Seob Kim, Sang Seok Koh, In Duk Jung, T-C Wu, Jaemin Lee, and Tae Heung Kang
- Subjects
medicine.medical_treatment ,Papillomavirus E7 Proteins ,Biology ,Adenocarcinoma ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Monocytes ,Mice ,Adjuvants, Immunologic ,Pancreatic cancer ,Cell Line, Tumor ,Lectins ,medicine ,Animals ,Humans ,dendritic cells ,TLR4 ,Mice, Knockout ,Immunogenicity ,Cancer ,NF-kappa B p50 Subunit ,Dendritic cell ,medicine.disease ,Flow Cytometry ,3. Good health ,Up-Regulation ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Toll-Like Receptor 4 ,Oncology ,adjuvants ,Immunology ,Intercellular Signaling Peptides and Proteins ,Female ,Peptides ,PAUF ,Adjuvant ,Immunologic Memory ,CD8 ,Signal Transduction ,Research Paper - Abstract
Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants.
- Published
- 2015
29. Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation
- Author
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Park, H D, Lee, Y, Oh, Y K, Jung, J G, Park, Y W, Myung, K, Kim, K-H, Koh, S S, and Lim, D-S
- Published
- 2011
- Full Text
- View/download PDF
30. Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells.
- Author
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Cho JH, Kim SA, Park SB, Kim HM, and Song SY
- Abstract
Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44
+ CD24+ ESA+ pancreatic CSCs. PAUF knockdown (shPAUF) CFPAC-1 diminished the number of spheres and decreased stemness genes and CSC surface markers (CD133, c-MET and ALDH1). In addition, siPAUF CFPAC-1 decreased the mRNA expression of multidrug resistant protein 5 (MRP5) and ribonucleotide reductase M2 (RRM2) and were more vulnerable to gemcitabine and 5-FU than negative control (p<0.05). In conclusion, PAUF was increased in pancreatic CSCs and the suppression of PAUF enhances chemotherapeutic response to gemcitabine and 5FU by decreasing MRP5 and RRM2 in pancreatic cancer cells., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest.- Published
- 2017
- Full Text
- View/download PDF
31. Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer.
- Author
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Song J, Lee J, Kim J, Jo S, Kim YJ, Baek JE, Kwon ES, Lee KP, Yang S, Kwon KS, Kim DU, Kang TH, Park YY, Chang S, Cho HJ, Kim SC, Koh SS, and Kim S
- Subjects
- Animals, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Humans, Intercellular Signaling Peptides and Proteins, Lectins metabolism, Membrane Proteins immunology, Membrane Proteins metabolism, Mice, Pancreatic Neoplasms metabolism, Tumor Microenvironment immunology, Carcinoma, Pancreatic Ductal immunology, Lectins immunology, Myeloid-Derived Suppressor Cells immunology, Pancreatic Neoplasms immunology, Tumor Escape immunology
- Abstract
Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
32. Silencing pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer cells to gemcitabine.
- Author
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Gao CC, Xu XL, Li F, Gong BG, Liu S, Cui YQ, Sun HC, Xu PY, Zheng YM, and Jiang H
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Animals, Antimetabolites, Antineoplastic pharmacology, Apoptosis drug effects, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Cell Proliferation drug effects, Deoxycytidine pharmacology, Flow Cytometry, Humans, Immunoenzyme Techniques, Intercellular Signaling Peptides and Proteins, Lectins genetics, Lectins metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, RNA, Messenger genetics, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Gemcitabine, Adenocarcinoma pathology, Deoxycytidine analogs & derivatives, Gene Expression Regulation, Neoplastic drug effects, Gene Silencing, Lectins antagonists & inhibitors, Pancreatic Neoplasms pathology
- Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF) is a new oncogene that activates signaling pathways that play a critical role in resistance to gemcitabine. We thus speculated that PAUF also plays a role in resistance to gemcitabine of pancreatic cancer cells. We established BxPC-3 cell lines with stable PAUF knockdown (BxPC-3_shPAUF) and controls (BxPC-3_shCtrl) and evaluated sensitivity to gemcitabine in vitro by MTT and flow cytometry. We established a xenograft model of human pancreatic cancer to examine PAUF function in gemcitabine resistance in vivo. Gene chip microarrays were performed to identify differentially expressed genes in BxPC-3_shPAUF and BxPC-3_shCtrl cells. Silencing PAUF increased the sensitivity of BxPC-3 cells to gemcitabine in vitro and in vivo. PAUF-knockdown BxPC-3 cell lines treated with gemcitabine showed increased proliferation inhibition and apoptosis compared with controls. Gemcitabine exhibited a more pronounced effect on reduction of BxPC-3_shPAUF tumors than BxPC-3_shCtrl tumors. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assays confirmed a significantly higher apoptotic rate of BXPC-3_shPAUF tumors compared with BXPC-3_shCtrl tumors. Gene array showed that PAUF function in gemcitabine sensitivity might involve MRP2, MRP3, MDR1, PIK3R1, and NFkB2 genes. PAUF could be considered as a key molecular target for sensitizing pancreatic cancer cells to gemcitabine.
- Published
- 2016
- Full Text
- View/download PDF
33. Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4.
- Author
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Kang TH, Kim YS, Kim S, Yang B, Lee JJ, Lee HJ, Lee J, Jung ID, Han HD, Lee SH, Koh SS, Wu TC, and Park YM
- Subjects
- Adjuvants, Immunologic chemistry, Animals, CD8-Positive T-Lymphocytes cytology, Cancer Vaccines chemistry, Cell Line, Tumor, Dendritic Cells cytology, Female, Flow Cytometry, Humans, Immunologic Memory, Intercellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes cytology, Papillomavirus E7 Proteins metabolism, Peptides chemistry, Signal Transduction, Up-Regulation, Adenocarcinoma metabolism, Dendritic Cells metabolism, Lectins biosynthesis, Lectins metabolism, NF-kappa B p50 Subunit metabolism, Pancreatic Neoplasms metabolism, Toll-Like Receptor 4 metabolism
- Abstract
Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants.
- Published
- 2015
- Full Text
- View/download PDF
34. Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients.
- Author
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Choi CH, Chung JY, Park HS, Jun M, Lee YY, Kim BG, and Hewitt SM
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Cell Line, Tumor, Cell Nucleus metabolism, Female, Humans, Middle Aged, Pancreatic Neoplasms complications, Pancreatic Neoplasms pathology, Prognosis, Up-Regulation, Uterine Cervical Neoplasms complications, Uterine Cervical Neoplasms pathology, Pancreatic Neoplasms, Adenocarcinoma diagnosis, Gene Expression Regulation, Neoplastic physiology, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms mortality, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms mortality
- Abstract
Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma., (Published by Elsevier Inc.)
- Published
- 2015
- Full Text
- View/download PDF
35. Association of pancreatic adenocarcinoma up-regulated factor expression in ovarian mucinous adenocarcinoma with poor prognosis.
- Author
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Kim SK, Song SY, Kim S, Cho NH, Yim GW, Kim SW, Kim YT, and Nam EJ
- Subjects
- Adult, Cystadenocarcinoma, Mucinous metabolism, Cystadenocarcinoma, Mucinous mortality, Cystadenoma, Mucinous metabolism, Cystadenoma, Mucinous mortality, Cystadenoma, Mucinous pathology, Female, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Kaplan-Meier Estimate, Lectins analysis, Middle Aged, Ovarian Neoplasms metabolism, Ovarian Neoplasms mortality, Prognosis, Proportional Hazards Models, Biomarkers, Tumor analysis, Cystadenocarcinoma, Mucinous pathology, Lectins biosynthesis, Ovarian Neoplasms pathology
- Abstract
Pancreatic adenocarcinoma up-regulated factor (PAUF) expression is elevated in both ovarian tumors and pancreatic adenocarcinoma. However, PAUF expression in ovarian tumors according to histologic subtype and grade has not been investigated. In this study, we examined various clinicopathologic features of 24 patients with mucinous cystadenoma (MCA), 36 with mucinous borderline tumors (MBTs), and 46 with mucinous adenocarcinomas (MACs) according to PAUF expression status assessed using immunohistochemistry. We found that MACs more frequently stained positive for PAUF than did MCAs and MBTs (P < 0.0001). Although there was no significant differences with respect to other clinicopathologic characteristics of MACs according to PAUF expression status, patients with PAUF-weakly positive and PAUF-strongly positive MACs tended to have a shorter overall survival (OS) than those with PAUF-negative MAC, determined using a Kaplan-Meier analysis (P = 0.1885). After adjusting for various clinicopathologic parameters, PAUF positivity of MACs was a significant predictive factor for disease-free survival (DFS) (negative vs. weakly positive: P = 0.045, hazard ratio [HR] = 57.406, 95% confidence interval [CI]: 1.090-3022.596; and negative vs. strongly positive: P = 0.034, HR = 97.890, 95% CI: 1.412-6785.925). In conclusion, PAUF was more frequently expressed in MAC than in its benign and borderline counterparts, and was associated with a poor OS and DFS in MAC patients. Therefore, we suggest that PAUF may be a practical biomarker for histopathological categorization and a prognostic marker for patients with an ovarian mucinous tumor.
- Published
- 2014
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