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Wu H, Shang J, Bao Y, Liu H, Zhang H, Xiao Y, Li Y, Huang Z, Cheng X, Ma Z, Zhang W, Mo P, Wang D, Zhang M, Zhan Y. Identification of a novel prognostic marker ADGRG6 in pancreatic adenocarcinoma: multi-omics analysis and experimental validation. Front Immunol 2025; 16:1530789. [PMID: 40226617 PMCID: PMC11986822 DOI: 10.3389/fimmu.2025.1530789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/10/2025] [Indexed: 04/15/2025] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) ranks among the most lethal malignancies worldwide. Current treatment options have limited efficacy, underscoring the need for new therapeutic targets. Methods This study employed a multi-omics analytical framework to delve into the expression profiles and prognostic implications of ADGRG6 within the pan-cancer dataset of The Cancer Genome Atlas (TCGA) database, highlighting the prognostic value and potential carcinogenic role of ADGRG6 in PAAD, which was further validated using data from multiple PAAD cohorts in the Gene Expression Omnibus (GEO) database. To assess the role of ADGRG6 in the tumor microenvironment of PAAD, we evaluated immune infiltration using CIBERSORT, ssGSEA, xCell and Tracking Tumor Immunophenotype (TIP), and utilized single-cell sequencing data to explore cell-cell interactions. Further cellular and animal experiments, such as colony formation assay, transwell assay, western blot, real-time PCR, and tumor xenograft experiments, were used to investigate the effect of ADGRG6 on the proliferation, metastatic potential and immune marker expression of PAAD and the underlying mechanisms. Results ADGRG6 emerged as a potential prognostic biomarker and a therapeutic target for PAAD, which was further corroborated by data extracted from multiple PAAD cohorts archived in the GEO database. Single-cell sequencing and immune infiltration analyses predicted the positive correlation of ADGRG6 with the infiltration of immune cells and with the interaction between malignant cells and fibroblasts/macrophages within the PAAD microenvironment. In vitro cell assays demonstrated that ADGRG6 promoted the proliferation, metastatic potential and immune marker expression of PAAD cells by increasing protein level of mutated p53 (mutp53), which activated a spectrum of gain-of-functions to promote cancer progression via the EGFR, AMPK and NF-κB signaling cascades. Furthermore, subcutaneous xenograft experiments in mice demonstrated that ADGRG6 knockdown substantially suppressed the growth of engrafted PAAD tumors. Conclusions ADGRG6 may serve as a novel prognostic marker and a therapeutic targets for PAAD, playing a crucial role in the proliferation, metastasis, and immune marker regulation of PAAD through elevating protein level of mutated p53.
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Affiliation(s)
- Han Wu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University, Zhangzhou, Fujian, China
| | - Jin Shang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yuanyan Bao
- Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University, Zhangzhou, Fujian, China
| | - Huajie Liu
- Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University, Zhangzhou, Fujian, China
| | - Haoran Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yaosheng Xiao
- Department of Infectious Disease, Xiang’an Hospital Affiliated to Xiamen University, Xiamen, Fujian, China
| | - Yangtaobo Li
- Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University, Zhangzhou, Fujian, China
| | - Zhaozhang Huang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Xiaolei Cheng
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zixuan Ma
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Wenqing Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Pingli Mo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Science, Xiamen University, Xiamen, Fujian, China
| | - Daxuan Wang
- Provincial College of Clinical Medicine, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Mingqing Zhang
- Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University, Zhangzhou, Fujian, China
| | - Yanyan Zhan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Lopez-Blazquez C, Lacalle-Gonzalez C, Sanz-Criado L, Ochieng’ Otieno M, Garcia-Foncillas J, Martinez-Useros J. Iron-Dependent Cell Death: A New Treatment Approach against Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:14979. [PMID: 37834426 PMCID: PMC10573128 DOI: 10.3390/ijms241914979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell's antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.
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Affiliation(s)
- Carlos Lopez-Blazquez
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Carlos Lacalle-Gonzalez
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
| | - Lara Sanz-Criado
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Michael Ochieng’ Otieno
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Jesus Garcia-Foncillas
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
| | - Javier Martinez-Useros
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
- Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain
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Li XX, Li H, Jin LQ, Tan YB. Exploration and Validation of Pancreatic Cancer Hub Genes Based on Weighted Gene Co-Expression Network Analysis and Immune Infiltration Score Analysis. Pharmgenomics Pers Med 2023; 16:467-480. [PMID: 37252337 PMCID: PMC10216855 DOI: 10.2147/pgpm.s403116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 05/03/2023] [Indexed: 05/31/2023] Open
Abstract
Objective To find pancreatic cancer (PC)-related hub genes based on weighted gene co-expression network analysis (WGCNA) construction and immune infiltration score analysis and validate them immunohistochemically by clinical cases, to generate new concepts or therapeutic targets for the early diagnosis and treatment of PC. Material and Methods In this study, WGCNA and immune infiltration score were utilized to identify the relevant core modules of PC and the hub genes within these core modules. Results Using WGCNA analysis, data from PC and normal pancreas integrated with TCGA and GTEX were analyzed and brown modules were chosen from the six modules. Five hub genes, including DPYD, FXYD6, MAP6, FAM110B, and ANK2, were discovered to have differential survival significance via validation tests utilizing survival analysis curves and the GEPIA database. The DPYD gene was the only gene associated with PC survival side effects. Validation of the Human Protein Atlas (HPA) database and immunohistochemical testing of clinical samples showed positive results for DPYD expression in PC. Conclusion In this study, we identified DPYD, FXYD6, MAP6, FAM110B, and ANK2, as immune-related candidate markers for PC. Only the DPYD gene had a negative impact on the survival of PC patients. Through validation of the HPA database and immunohistochemical testing of clinical cases, we believe that the DPYD gene brings novel ideas and therapeutic targets in the diagnosis and treatment of PC.
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Affiliation(s)
- Xiao-Xi Li
- Dali University of Clinical Medicine School, Dali, Yunnan, 671000, People’s Republic of China
| | - Hong Li
- Department of Radiology, Affiliated Renhe Hospital of China Three Gorges University, Hubei, 443001, People’s Republic of China
| | - Li-Quan Jin
- Department of General Surgery, The First of Affiliated Hospital of Dali University, Dali, Yunnan, 671000, People’s Republic of China
| | - Yun-Bo Tan
- Dali University of Clinical Medicine School, Dali, Yunnan, 671000, People’s Republic of China
- Department of General Surgery, The First of Affiliated Hospital of Dali University, Dali, Yunnan, 671000, People’s Republic of China
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Li H, Wang H, Cui Y, Jiang W, Zhan H, Feng L, Gao M, Zhao K, Zhang L, Xie X, Zhao N, Li Y, Liu P. EZH2 regulates pancreatic cancer cells through E2F1, GLI1, CDK3, and Mcm4. Hereditas 2023; 160:23. [PMID: 37198697 DOI: 10.1186/s41065-023-00280-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 04/06/2023] [Indexed: 05/19/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most common malignant tumors in digestive tract. To explore the role of epigenetic factor EZH2 in the malignant proliferation of PC, so as to provide effective medical help in PC. Sixty paraffin sections of PC were collected and the expression of EZH2 in PC tissues was detected by immunohistochemical assay. Three normal pancreas tissue samples were used as controls. The regulation of EZH2 gene on proliferation and migration of normal pancreatic cell and PC cell were determined by MTS, colony forming, Ki-67 antibody, scratch and Transwell assays. Through differential gene annotation and differential gene signaling pathway analysis, differentially expressed genes related to cell proliferation were selected and verified by RT-qPCR. EZH2 is mainly expressed in the nuclei of pancreatic tumor cells, but not in normal pancreatic cells. The results of cell function experiments showed that EZH2 overexpression could enhance the proliferation and migration ability of PC cell BXPC-3. Cell proliferation ability increased by 38% compared to the control group. EZH2 knockdown resulted in reduced proliferation and migration ability of cells. Compared with control, proliferation ability of cells reduced by 16%-40%. The results of bioinformatics analysis of transcriptome data and RT-qPCR demonstrated that EZH2 could regulate the expression of E2F1, GLI1, CDK3 and Mcm4 in normal and PC cells. The results revealed that EZH2 might regulate the proliferation of normal pancreatic cell and PC cell through E2F1, GLI1, CDK3 and Mcm4.
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Affiliation(s)
- Hongfeng Li
- Department of Clinical Laboratory, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, 300120, China
| | - Hailong Wang
- Department of Oncology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, No. 354 Beima Road, Hongqiao District, Tianjin, 300120, China
| | - Yunlong Cui
- Department of Hepatobiliary Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Wenhua Jiang
- Department of Radiotherapy, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Hongjie Zhan
- Department of Gastric Cancer, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Lixia Feng
- Department of Nursing, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Konggang Hospital, Tianjin, 300300, China
| | - Mingyou Gao
- Department of Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Kuo Zhao
- Department of Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Limeng Zhang
- Department of Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Xiaojing Xie
- Department of Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Ning Zhao
- Department of Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Ying Li
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, No. 12 Health Road, Shijiazhuang, 050000, Hebei, China.
| | - Pengfei Liu
- Department of Oncology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, No. 354 Beima Road, Hongqiao District, Tianjin, 300120, China.
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Zhang J, Li J, Xiong Y, Li R. Circ_0000284 upregulates RHPN2 to facilitate pancreatic cancer proliferation, metastasis, and angiogenesis through sponging miR-1179. J Biochem Mol Toxicol 2023; 37:e23274. [PMID: 36536496 DOI: 10.1002/jbt.23274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 08/15/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Circular RNA (circRNA) has been confirmed to be a key regulator for pancreatic cancer (PC) progression, but the role of circ_0000284 in PC development remains unclear. METHODS Quantitative real-time PCR was used to measure the expression of circ_0000284, microRNA (miR)-1179, and rhophilin 2 (RHPN2). PC cell proliferation, metastasis, angiogenesis, and apoptosis were assessed by EdU assay, transwell assay, tube formation assay, and flow cytometry. Relative protein expression was determined by western blot analysis. The interaction between miR-1179 and circ_0000284 or RHPN2 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. RESULTS Circ_0000284 was significantly upregulated in PC tissues and cells, and its knockdown inhibited PC cell proliferation, migration, invasion, and angiogenesis while promoting apoptosis. MiR-1179 was downregulated in PC tissues and cells, and it could be sponged by circ_0000284. Moreover, the miR-1179 inhibitor reversed the regulation of circ_0000284 knockdown on PC cell progression. The highly expressed RHPN2 was found in PC tissues and cells, and it could be targeted by miR-1179. Also, circ_0000284 sponged miR-1179 to regulate RHPN2 expression. Overexpressed RHPN2 could reverse the regulation of circ_0000284 knockdown on PC cell progression. In addition, interference of circ_0000284 was discovered to repress PC tumor growth by regulating miR-1179/RHPN2.RHPN2. CONCLUSION To sum up, our data confirmed that circ_0000284 facilitated PC malignant progression depending on the regulation of miR-1179/RHPN2 axis, suggesting that circ_0000284 might be a potential target for PC treatment.
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Affiliation(s)
- Jian Zhang
- Department of Geratic Gastroenterological Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiangwei Li
- Department of Geratic Gastroenterological Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yongqiang Xiong
- Department of Geratic Gastroenterological Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ren Li
- Department of Geratic Gastroenterological Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Mi W, Zheng Z, Lu JD, Duan SQ, Zhang J, Zhang HQ, Ding YX, Yin J, Cao F, Zhang J, Li F. KLF16 promotes pancreatic adenocarcinoma cell proliferation and migration by positively regulating SMAD6. World J Gastrointest Oncol 2022; 14:2157-2169. [PMID: 36438710 PMCID: PMC9694270 DOI: 10.4251/wjgo.v14.i11.2157] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/10/2022] [Accepted: 10/18/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD) is a cancerous tumor with an extremely poor 5-year survival rate. The exploration of biomarkers for the diagnosis and treatment of PAAD is crucial in clinical practice. Krüppel-like factors (KLFs) are involved in a variety of biological functions in cells. According to multiple studies, KLF16 behave as an oncogene in prostate, breast and gastric cancers. However, no research has been done on the significance of KLF16 in PAAD.
AIM To explore the molecular mechanisms of KLF16 in PAAD.
METHODS KLF16 was identified in the tumor specimens and normal tissues by GEPIA database and verified by quantitative real-time PCR (qRT-PCR). Knockdown or exogenous expression of KLF16, combined with in vitro and in vivo assays, was performed to show the functional significance of KLF16. The molecular mechanism of KLF16 was demonstrated by qRT-PCR, western blotting, immunoprecipitation assay and flow cytometry.
RESULTS We showed that KLF16 was highly expressed in PAAD patients based on the GEPIA database. KLF16 silencing suppressed while KLF16 overexpression promoted the malignant function of PAAD cells. Based on RNA sequencing, we discovered that KLF16 potentiated the expression of SMAD6 in PAAD cells. SMAD6 transcript abundance was increased and positively correlated with KLF16 expression in PAAD samples. In addition, inhibiting SMAD6 was able to mitigate the effects of KLF16 overexpression on PAAD cell processes, suggesting the importance of SMAD6 in the development of KLF16-triggered PAAD.
CONCLUSION KLF16/SMAD6 axis might be explored as a therapeutic target for PAAD therapy.
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Affiliation(s)
- Wei Mi
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhi Zheng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jiong-Di Lu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shu-Quan Duan
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou 014030, Inner Mongolia Autonomous Region, China
| | - Jie Zhang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Hai-Qiao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yi-Xuan Ding
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jie Yin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jun Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
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Cai D, Chen C, Su Y, Tan Y, Lin X, Xing R. LRG1 in pancreatic cancer cells promotes inflammatory factor synthesis and the angiogenesis of HUVECs by activating VEGFR signaling. J Gastrointest Oncol 2022; 13:400-412. [PMID: 35284128 PMCID: PMC8899736 DOI: 10.21037/jgo-21-910] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/30/2022] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND This study aimed to investigate the roles of leucine-rich alpha-2-glycoprotein 1 (LRG1) in regulating angiogenesis during pancreatic cancer (PC) pathogenesis. METHODS LRG1 expression in tissues was detected by qRT-PCR and immunohistochemistry. LRG1 in BxPC-3 and Capan-2 cells was knocked down or overexpressed. Cell viability and the migration and invasion abilities of cells were analyzed using the Cell Counting Kit-8 (CCK-8) assay and Transwell system, respectively. Interleukin-1 beta (IL-1β), IL-18, and vascular endothelial growth factor A (VEGFA) contents in cell culture were measured by ELISA, and the angiogenesis of HUVECs was assessed by the in vitro tube formation assay. In vitro LRG1 expression in BxPC-3 and Capan-2 cells was determined using immunofluorescence. RESULTS The results showed that LRG1 expression was significantly increased in pancreatic cancer tissues and cell lines. LRG1 knockdown inhibited the viability, migration, invasion, and IL-1β and IL-18 synthesis of BxPC-3 and Capan-2 cells. VEGFA synthesis in BxPC-3 and Capan-2 cells was also inhibited by LRG1 knockdown, which caused impaired tube formation of co-cultured HUVECs. LRG1 overexpression enhanced the viability, migration, and invasion of BxPC-3 and Capan-2 cells, also causing elevated tube formation of HUVECs and IL-1β and IL-18 synthesis in co-cultures of HUVECs and BxPC-3 or Capan-2 cells. Silencing of VEGF receptor (VEGFR) abrogated the enhanced tube formation and IL-1β and IL-18 synthesis in HUVECs co-cultured with BxPC-3 or Capan-2 cells overexpressing LRG1. CONCLUSIONS In conclusion, LRG1, which is highly expressed in pancreatic cancer cells, promotes inflammatory factor synthesis and the angiogenesis of HUVECs though activating the VEGFR signaling pathway.
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Affiliation(s)
- Duxiong Cai
- Department of Gastroenterology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Chunji Chen
- Department of Pathology, Hainan Provincial People’s Hospital, Haikou, China
| | - Yexiong Su
- Department of Gastroenterology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yan Tan
- Department of Gastroenterology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xuyue Lin
- Department of Gastroenterology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Rong Xing
- Department of Gastroenterology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
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8
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Jin G, Ruan Q, Shangguan F, Lan L. RUNX2 and LAMC2: promising pancreatic cancer biomarkers identified by an integrative data mining of pancreatic adenocarcinoma tissues. Aging (Albany NY) 2021; 13:22963-22984. [PMID: 34606473 PMCID: PMC8544338 DOI: 10.18632/aging.203589] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/18/2021] [Indexed: 01/25/2023]
Abstract
Pancreatic carcinoma (PC) is a severe disease associated with high mortality. Although strategies for cancer therapy have made great progress, outcomes of pancreatic carcinoma patients remain extremely poor. Therefore, it is urgent to find novel biomarkers and therapeutic targets. To identify biomarkers for early diagnosis and therapy, three mRNA microarray datasets and two miRNA datasets were selected, and combinative analysis was performed by GEO2R. Functional and pathway enrichment analysis were performed using DAVID database. MiRTarBase, miRWalk and Diana Tools were used to get key genes. TCGA, HPA and western blotting were used to verify diagnostic and prognostic value of key genes. By integrating mRNA and miRNA expression profiles, we identified 114 differentially expressed genes and 114 differentially expressed miRNAs, respectively. Then, three overlapping key genes, RUNX2, LAMC2 and FBXO32, were found. Their protein levels in pancreatic tissue from PC patients and normal people were analyzed by immunohistochemical staining and western blotting. RUNX2 showed a potential property to identify PC. Aberrant over-expression of LAMC2 was associated with poor prognosis of PC patients, tumor status and subtypes. In summary, our current study identified that RUNX2 and LAMC2 may be promising targets for early diagnosis and therapy of PC patients.
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Affiliation(s)
- Guihua Jin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Qingqing Ruan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Fugen Shangguan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Linhua Lan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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Mollinedo F, Gajate C. Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer. Cancers (Basel) 2021; 13:4173. [PMID: 34439330 PMCID: PMC8394177 DOI: 10.3390/cancers13164173] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/11/2021] [Accepted: 08/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy-the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells-including pancreatic cancer cells-and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.
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Affiliation(s)
- Faustino Mollinedo
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, C/Ramiro de Maeztu 9, E-28040 Madrid, Spain;
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10
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Hussain SM, Kansal RG, Alvarez MA, Hollingsworth TJ, Elahi A, Miranda-Carboni G, Hendrick LE, Pingili AK, Albritton LM, Dickson PV, Deneve JL, Yakoub D, Hayes DN, Kurosu M, Shibata D, Makowski L, Glazer ES. Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression. Cell Oncol (Dordr) 2021; 44:673-687. [PMID: 33694102 DOI: 10.1007/s13402-021-00594-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2021] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The transforming growth factor-beta (TGF-β) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-β signaling induces PDAC progression. METHODS We investigated the expression of non-SMAD-TGF-β signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-β, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-β receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, β-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model. RESULTS We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-β signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline β-catenin expression, TGF-β increased β-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p < 0.0001). In the mice, liver metastases contained more TAMs compared to the primary pancreatic tumors (p = 0.001), and TGF-β increased TAM PD-L1 expression (p < 0.05). CONCLUSIONS In PDAC, the non-SMAD-TGF-β signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-β ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-β paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.
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Affiliation(s)
- S Mazher Hussain
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Rita G Kansal
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Marcus A Alvarez
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - T J Hollingsworth
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Abul Elahi
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | | | - Leah E Hendrick
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | | | | | - Paxton V Dickson
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Jeremiah L Deneve
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Danny Yakoub
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - D Neil Hayes
- Department of Medicine, College of Medicine, Memphis, TN, USA
| | - Michio Kurosu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - David Shibata
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Liza Makowski
- Department of Medicine, College of Medicine, Memphis, TN, USA.,Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Evan S Glazer
- Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA.
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11
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Liu X, Yuan H, Zhou J, Wang Q, Qi X, Bernal C, Avella D, Kaifi JT, Kimchi ET, Timothy P, Cheng K, Miao Y, Jiang K, Li G. LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis. Front Cell Dev Biol 2021; 9:647387. [PMID: 33763427 PMCID: PMC7982467 DOI: 10.3389/fcell.2021.647387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/05/2021] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal human malignancies without effective treatment. In an effort to discover key genes and molecular pathways underlying PC growth, we have identified LIM domain only 7 (LMO7) as an under-investigated molecule, which highly expresses in primary and metastatic human and mouse PC with the potential of impacting PC tumorigenesis and metastasis. Using genetic methods with siRNA, shRNA, and CRISPR-Cas9, we have successfully generated stable mouse PC cells with LMO7 knockdown or knockout. Using these cells with loss of LMO7 function, we have demonstrated that intrinsic LMO7 defect significantly suppresses PC cell proliferation, anchorage-free colony formation, and mobility in vitro and slows orthotopic PC tumor growth and metastasis in vivo. Mechanistic studies demonstrated that loss of LMO7 function causes PC cell-cycle arrest and apoptosis. These data indicate that LMO7 functions as an independent and unrecognized druggable factor significantly impacting PC growth and metastasis, which could be harnessed for developing a new targeted therapy for PC.
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Affiliation(s)
- Xinjian Liu
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Department of Pathogen Biology, Key Laboratory of Antibody Technique of National Health Commission of China, Nanjing Medical University, Nanjing, China
| | - Hao Yuan
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Zhou
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States
| | - Qiongling Wang
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States
| | - Xiaoqiang Qi
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States
| | - Catharine Bernal
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States
| | - Diego Avella
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, United States
| | - Jussuf T Kaifi
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, United States
| | - Eric T Kimchi
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, United States
| | - Parrett Timothy
- Department of Pathology and Anatomical Sciences, University of Missouri-Columbia, Columbia, MO, United States
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuirong Jiang
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guangfu Li
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, United States.,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
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12
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Giannis D, Moris D, Barbas AS. Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians. Cancers (Basel) 2021; 13:1071. [PMID: 33802340 PMCID: PMC7959127 DOI: 10.3390/cancers13051071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/13/2021] [Accepted: 02/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and is associated with aggressive tumor behavior and poor prognosis. Most patients with PDAC present with an advanced disease stage and treatment-resistant tumors. The lack of noninvasive tests for PDAC diagnosis and survival prediction mandates the identification of novel biomarkers. The early identification of high-risk patients and patients with PDAC is of utmost importance. In addition, the identification of molecules that are associated with tumor biology, aggressiveness, and metastatic potential is crucial to predict survival and to provide patients with personalized treatment regimens. In this review, we summarize the current literature and focus on newer biomarkers, which are continuously added to the armamentarium of PDAC screening, predictive tools, and prognostic tools.
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Affiliation(s)
- Dimitrios Giannis
- Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA;
| | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA;
| | - Andrew S. Barbas
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA;
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13
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Ferreira RG, Narvaez LEM, Espíndola KMM, Rosario ACRS, Lima WGN, Monteiro MC. Can Nimesulide Nanoparticles Be a Therapeutic Strategy for the Inhibition of the KRAS/PTEN Signaling Pathway in Pancreatic Cancer? Front Oncol 2021; 11:594917. [PMID: 34354940 PMCID: PMC8329661 DOI: 10.3389/fonc.2021.594917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is an aggressive, devastating disease due to its invasiveness, rapid progression, and resistance to surgical, pharmacological, chemotherapy, and radiotherapy treatments. The disease develops from PanINs lesions that progress through different stages. KRAS mutations are frequently observed in these lesions, accompanied by inactivation of PTEN, hyperactivation of the PI3K/AKT pathway, and chronic inflammation with overexpression of COX-2. Nimesulide is a selective COX-2 inhibitor that has shown anticancer effects in neoplastic pancreatic cells. This drug works by increasing the levels of PTEN expression and inhibiting proliferation and apoptosis. However, there is a need to improve nimesulide through its encapsulation by solid lipid nanoparticles to overcome problems related to the hepatotoxicity and bioavailability of the drug.
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Affiliation(s)
- Roseane Guimarães Ferreira
- Neuroscience and Cell Biology Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Luis Eduardo Mosquera Narvaez
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Kaio Murilo Monteiro Espíndola
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Amanda Caroline R. S. Rosario
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Wenddy Graziela N. Lima
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Marta Chagas Monteiro
- Neuroscience and Cell Biology Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
- *Correspondence: Marta Chagas Monteiro,
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14
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Zhang Q, Chen Z. lncRNA UASR1 sponges miR-107 in colorectal cancer to upregulate oncogenic CDK8 and promote cell proliferation. Oncol Lett 2020; 20:305. [PMID: 33093914 PMCID: PMC7573889 DOI: 10.3892/ol.2020.12168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/19/2020] [Indexed: 12/26/2022] Open
Abstract
lncRNA UASR1 (UASR1) has been characterized as an oncogenic lncRNA in breast cancer. UASR1 was predicted to interact with miR-107, which serves tumor suppressive roles mainly by targeting CDK8. The present study was performed to investigate the interactions among UASR1, miR-107 and CDK8 in colorectal cancer (CRC). A total of 62 patients with CRC, including 40 males and 22 females (age range, 38-67 years; mean age, 57.2±7.6 years) were enrolled at the Second Hospital of Shandong University between July 2012 and July 2014. The expression of UASR1 in tissues and cells were detected by reverse transcription-quantitative polymerase chain reaction. The interaction between UASR1 and miR-107 was investigated by performing dual luciferase activity assay, and the effects of overexpression of UASR1, miR-107 and CDK8 on the proliferation of CR4 cells were analyzed by performing cell proliferation analysis. It was observed that UASR1 is upregulated in CRC and its high expression levels predicted poor survival in patients with CRC. RNA-RNA interaction prediction demonstrated that UASR1 may interact with miR-107. In CRC cells, overexpression of UASR1 and miR-107 did not affect each other. However, the expression of CDK8, a target of miR-107, was upregulated following overexpression of UASR1. Notably, overexpression of UASR1 decreased the inhibitory effects of miR-107 on cell proliferation and the expression of CDK8. Therefore, UASR1 may sponge miR-107 to upregulate oncogenic CDK8, thereby promoting CRC cell proliferation.
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Affiliation(s)
- Qizhi Zhang
- Outpatient Department, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhaosheng Chen
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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15
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Zhang ZM, Wang JS, Zulfiqar H, Lv H, Dao FY, Lin H. Early Diagnosis of Pancreatic Ductal Adenocarcinoma by Combining Relative Expression Orderings With Machine-Learning Method. Front Cell Dev Biol 2020; 8:582864. [PMID: 33178697 PMCID: PMC7593596 DOI: 10.3389/fcell.2020.582864] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/15/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer deeply affecting human health. Diagnosing early-stage PDAC is the key point to PDAC patients' survival. However, the biomarkers for diagnosing early PDAC are inexact in most cases. Therefore, it is highly desirable to identify an effective PDAC diagnostic biomarker. In the current work, we designed a novel computational approach based on within-sample relative expression orderings (REOs). A feature selection technique called minimum redundancy maximum relevance was used to pick out optimal REOs. We then compared the performances of different classification algorithms for discriminating PDAC and its adjacent normal tissues from non-PDAC tissues. The support vector machine algorithm is the best one for identifying early PDAC diagnostic biomarker. At first, a signature composed of nine gene pairs was acquired from microarray gene expression data sets. These gene pairs could produce satisfactory classification accuracy up to 97.53% in fivefold cross-validation. Subsequently, two types of data from diverse platforms, namely, microarray and RNA-Seq, were used to validate this signature. For microarray data, all (100.00%) of 115 PDAC tissues and all (100.00%) of 31 PDAC adjacent normal tissues were correctly recognized as PDAC. In addition, 88.24% of 17 non-PDAC (normal or pancreatitis) tissues were correctly classified. For the RNA-Seq data, all (100.00%) of 177 PDAC tissues and all (100.00%) of 4 PDAC adjacent normal tissues were correctly recognized as PDAC. Validation results demonstrated that the signature had a good cross-platform effect for early detection of PDAC. This work developed a new robust signature that might be a promising biomarker for early PDAC diagnosis.
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Affiliation(s)
- Zi-Mei Zhang
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Jia-Shu Wang
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hasan Zulfiqar
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Lv
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Fu-Ying Dao
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Lin
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
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16
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Zhang Y, Xu G, Chen M, Wei Q, Zhou T, Chen Z, Shen M, Wang P. Stage IA Patients With Pancreatic Ductal Adenocarcinoma Cannot Benefit From Chemotherapy: A Propensity Score Matching Study. Front Oncol 2020; 10:1018. [PMID: 32766130 PMCID: PMC7379031 DOI: 10.3389/fonc.2020.01018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose: Adjuvant chemotherapy following resection is recommended by clinical practice guidelines for all patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the efficacy of adjuvant chemotherapy among the staging groups of the American Joint Committee on Cancer (AJCC) for PDAC. Patients and Methods: This retrospective cohort analysis was performed by the Surveillance Epidemiology and End Results (SEER) (2004–2015) database and multi-institutional dataset (2010–2018). Baseline clinicopathologic characteristics of PDAC patients, including age, gender, ethnicity, marital status, education level, county income level, county unemployed rate, insurance status, grade, stage, chemotherapy, and radiotherapy, were collected. Overall survival (OS) was analyzed using the Kaplan–Meier method. The SEER and multi-institutional data were adjusted with 1:1 ratio propensity score matching (PSM). Results: In total, 6,274 and 1,361 PDAC patients were included from the SEER database and multi-institutional dataset, respectively. Regardless of the count of resected lymph nodes, adjuvant chemotherapy prolonged the long-term OS time for stage IB, IIA, IIB, and III patients in both SEER and multi-institutional cohorts. Nevertheless, adjuvant chemotherapy did not provide additional clinical benefits even after a PSM adjustment for stage IA patients in both SEER and multi-institutional cohorts. Conclusion: Adjuvant chemotherapy improved the long-term survival of stage IB, IIA, IIB, and III PDAC patients; however, it demonstrated no survival benefit in stage IA PDAC patients. Thus, adjuvant chemotherapy should not be recommended for stage IA PDAC patients. These would significantly reduce the economic burden of society and improve the life quality of stage IA PDAC patients.
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Affiliation(s)
- Yuchao Zhang
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Gang Xu
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Maozhen Chen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Qian Wei
- Department of Breast Surgery, XuZhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, China
| | - Tengteng Zhou
- Department of Breast Surgery, Xuzhou Maternal and Child Health Hospital, Xuzhou, China
| | - Ziliang Chen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Mingyang Shen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Ping Wang
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
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17
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Wu QY, Yang CK, Rong LJ, Li JC, Lei LM. Investigation of the association between C-X-C motif chemokine receptor subunits and tumor infiltration levels and prognosis in patients with early-stage pancreatic ductal adenocarcinoma. Oncol Lett 2020; 20:16. [PMID: 32774489 PMCID: PMC7406880 DOI: 10.3892/ol.2020.11877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 04/01/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the highest morality rate due to postoperative local invasion and distant metastasis. Although C-X-C motif chemokine receptor (CXCR) subunits have been reported as prognostic indicators in gastric cancer, the prognostic value of CXCR subunits in PDAC remains poorly understood. In the present study, the expression levels and biological functions of CXCR subunits were investigated using multiple publicly accessible bioinformatic platforms and databases. Survival analysis was used to evaluate the prognostic value of CXCR subunits in 112 early-stage PDAC cases by setting the median expression levels as the cut-off values. A nomogram was constructed to combine CXCR subunit expression levels and clinical data for prognosis prediction. Moreover, the association between CXCR subunit expression levels and tumor infiltration levels were detected in PDAC. The expression levels of CXCR subunits were elevated in PDAC tumor tissues. In the multivariate Cox proportional risk regression model, high CXCR2, CXCR4 and CXCR6 expression levels in early-stage PDAC were associated with a more favorable prognosis. Further, it was demonstrated that the differential expression levels of CXCR subunits in PDAC for combined survival analysis could contribute to risk stratification. The nomogram model demonstrated the contribution of CXCR subunits and clinical features in the prognosis of PDAC. Gene Set Enrichment Analysis suggested that CXCR subunits serve a role in immunomodulatory functions. The expression levels and somatic copy number alterations of CXCR subunits were associated with tumor infiltration levels in PDAC. CXCR subunits were associated with prognosis in patients with early-stage PDAC and may be potential drug targets for the treatment of pancreatic cancer.
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Affiliation(s)
- Qiong-Yuan Wu
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R.China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530023, P.R.China
| | - Liang-Jun Rong
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R.China
| | - Jun-Chan Li
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R.China
| | - Long-Ming Lei
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R.China
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18
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Yang C, Liu Z, Zeng X, Wu Q, Liao X, Wang X, Han C, Yu T, Zhu G, Qin W, Peng T. Evaluation of the diagnostic ability of laminin gene family for pancreatic ductal adenocarcinoma. Aging (Albany NY) 2020; 11:3679-3703. [PMID: 31182680 PMCID: PMC6594799 DOI: 10.18632/aging.102007] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/29/2019] [Indexed: 12/21/2022]
Abstract
A poor outcome for pancreatic ductal adenocarcinoma (PDAC) patients is still a challenge worldwide. The aim of our study is to investigate the potential of key laminin subunits for being used both as a diagnostic and prognostic biomarker for PDAC patients. We evaluated the mRNA expression and prognostic value of laminin gene family in PDAC tissues using online public databases. Moreover, the relationship between key laminin subunits in PDAC blood cells and circulating tumor cells (CTCs) and the distinguishing ability of joint serum levels with carbohydrate antigen 19-9 (CA19-9) was analyzed. Two key differentially expressed subunits (LAMA3 and LAMC2) that are associated with prognosis of PDAC patients were found to show a potential for distinguishing between PDAC and non-tumor tissues. LAMA3 and LAMC2 expression were found to be positively related with CTC quantity in PDAC blood (R=0.628, p=0.029; R=0.776, p=0.003, respectively) using IgG chips. Furthermore, serum LAMC2 levels offered significant improvement over using CA19-9 alone for the discrimination of PDAC. Joint serum LAMC2 and CA19-9 levels increased the net benefit proportion in early stage/operational PDAC patients. Using integrated profiling, we identified LAMA3 and LAMC2 as potential therapeutic targets and prognostic markers for PDAC, for which further validation is warranted.
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Affiliation(s)
- Chengkun Yang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xianmin Zeng
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Qiongyuan Wu
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi Province, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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19
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Damanakis AI, Gebauer F, Bruns CJ. [Molecular predictors for the course of disease and individualized therapy in pancreatic cancer]. Chirurg 2020; 91:642-649. [PMID: 32405728 DOI: 10.1007/s00104-020-01172-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The understanding of the development of pancreatic cancer has undergone considerable development over the last two decades. This is mainly due to the progress and use of methods for molecular biological analysis of pancreatic carcinomas. There is now a fundamental understanding with respect to the genetic drivers for the development of pancreatic cancer and the correlation with clinical data as well as the classification of different genetic characteristics of individual tumors even enables an estimation of the prognosis in some cases. The most common mutation in ductal adenocarcinoma, which if found in >90% of tumors, is the mutation of the KRAS oncogene. The other three, CDKN2A, p53 and SMAD4, are all tumor suppressor genes and are mutated in approximately 90%, 70% and 50% of carcinomas, respectively. In addition, genetic mutations predisposing to pancreatic cancer have been identified. Among the most important are BRCA2, p16/CDKN2A, STK11, PRSS1, PALP2, FANCC, FANCG and ATM. The classification of different subtypes and the knowledge of individual mutations (especially BRCA) can also be used to assess the response to treatment in individual cases. This applies to "conventional" combination chemotherapies (especially FOLFIRINOX) and also to targeted treatment approaches with tyrosine kinase inhibitors, PARP inhibitors and PD‑1 inhibitors. If knowledge about the course of the disease and decisions on individual therapies become established in everyday clinical practice in the future, this may also have a decisive impact on surgery as the most important pillar of curative treatment. This ranges from the increased achievement of secondary operability to the expansion of indications with respect to resection even in patients with metastases.
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Affiliation(s)
| | | | - C J Bruns
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Universitätsklinikum Köln (AöR), Kerpener Str. 62, 50937, Köln, Deutschland.
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Qin JJ, Cheng XD, Zhang J, Zhang WD. Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review. Cell Commun Signal 2019; 17:121. [PMID: 31511020 PMCID: PMC6740038 DOI: 10.1186/s12964-019-0435-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 09/02/2019] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.
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Affiliation(s)
- Jiang-Jiang Qin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China. .,Zhejiang Cancer Hospital, Hangzhou, 310022, China.
| | | | - Jia Zhang
- Shanxi Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Wei-Dong Zhang
- School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai, 200433, China. .,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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21
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Alvarez MA, Freitas JP, Mazher Hussain S, Glazer ES. TGF-β Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma. J Gastrointest Cancer 2019; 50:207-213. [PMID: 30891677 DOI: 10.1007/s12029-018-00195-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancerrelated mortality in the USA, and the overall incidence of the disease is increasing such that it is expected to be the third leading cause of cancer-related deaths in the next decade. Minimal improvements in therapy have not changed the overall mortality rate over the past decade for patients with PDAC. The purpose of this review is to identify new data regardign the role of Transforming growth factor beta (TGF-β) based therapeuics in patients with PDAC. METHODS The literature was searched for peer reviewed manuscripts regarding the use of TGF-β inhibitors in PDAC therapy and the mechanism in which TGF-β intracellular signaling effects patient survival. RESULTS TGF-β plays a vital, context-dependent role as both a tumor suppressor and promoter of PDAC. The downstream effects of this duality play a significant role in the immunologic response of the tumor microenvironment (TME), epithelial-mesenchymal transformation (EMT), and the development of metastatic disease. Immunologic pathways have been shown to be successful targets in the treatment of other diseases, though they have not been shown efficacious in PDAC. TGF-β-mediated EMT does play a critical role in PDAC progression in the development of metastases. The use of anti-TGF-β-based therapies in phase I and II clinical trials for metastatic PDAC demonstrate the importance of understanding the role of TGF-β in PDAC progression. CONCLUSION This review clarifies the recent literature investigating the role of anti-TGF-β-based therapy in PDAC and areas ripe for targeted investigations and therapies.
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Affiliation(s)
- Marcus A Alvarez
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Júlia Pedó Freitas
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - S Mazher Hussain
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Evan S Glazer
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA.
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22
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Madamsetty VS, Sharma A, Toma M, Samaniego S, Gallud A, Wang E, Pal K, Mukhopadhyay D, Fadeel B. Tumor selective uptake of drug-nanodiamond complexes improves therapeutic outcome in pancreatic cancer. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2019; 18:112-121. [PMID: 30849547 PMCID: PMC6588439 DOI: 10.1016/j.nano.2019.02.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/25/2018] [Accepted: 02/05/2019] [Indexed: 01/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths and novel treatment approaches are urgently needed. Here we show that poly(ethylene glycol)-functionalized nanodiamonds loaded with doxorubicin (ND-PEG-DOX) afforded a considerable improvement over free drug in an orthotopic pancreatic xenograft model. ND-PEG-DOX complexes were also superior to free DOX in 3-dimensional (3D) tumor spheroids of PDAC. ND-PEG showed no cytotoxicity towards macrophages, and histopathological analysis showed no abnormalities of major organs upon in vivo administration of ND-PEG-DOX. These results provide evidence that ND-mediated drug delivery may serve as a means of improving the therapeutic outcome in PDAC.
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Affiliation(s)
- Vijay S Madamsetty
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States
| | - Anil Sharma
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States
| | - Maria Toma
- Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Stefanie Samaniego
- Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Audrey Gallud
- Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Enfeng Wang
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States
| | - Krishnendu Pal
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Jacksonville, FL, United States.
| | - Bengt Fadeel
- Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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Malsy M, Graf B, Almstedt K. The active role of the transcription factor Sp1 in NFATc2-mediated gene regulation in pancreatic cancer. BMC BIOCHEMISTRY 2019; 20:2. [PMID: 30696421 PMCID: PMC6352339 DOI: 10.1186/s12858-019-0105-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 01/09/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Adenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body. The oncogenic potential of pancreatic cancer is mainly characterized by extremely rapid growth triggered by the activation of oncogenic signaling cascades, which suggests a change in the regulation of important transcription factors. Amongst others, NFAT transcription factors are assumed to play a central role in the carcinogenesis of pancreatic cancer. Recent research has shown the importance of the transcription factor Sp1 in the transcriptional activity of NFATc2 in pancreatic cancer. However, the role of the interaction between these two binding partners remains unclear. The current study investigated the role of Sp1 proteins in the expression of NFATc2 target genes and identified new target genes and their function in cells. A further objective was the domain of the Sp1 protein that mediates interaction with NFATc2. The involvement of Sp1 proteins in NFATc2 target genes was shown by means of a gene expression profile analysis, and the results were confirmed by quantitative RT-PCR. The functional impact of this interaction was shown in a thymidine incorporation assay. A second objective was the physical interaction between NFATc2 and different Sp1 deletion mutants that was investigated by means of immunoprecipitation. RESULTS In pancreatic cancer, the proto-oncogene c-Fos, the tumor necrosis factor TNF-alpha, and the adhesion molecule integrin beta-3 are target genes of the interaction between Sp1 and NFATc2. Loss of just one transcription factor inhibits oncogenic complex formation and expression of cell cycle-regulating genes, thus verifiably decreasing the carcinogenic effect. The current study also showed the interaction between the transcription factor NFATc2 and the N-terminal domain of Sp1 in pancreatic cancer cells. Sp1 increases the activity of NFATc2 in the NFAT-responsive promoter. CONCLUSIONS The regulation of gene promotors during transcription is a rather complex process because of the involvement of many proteins that - as transcription factors or co-factors - regulate promotor activity as required and control cell function. NFATc2 and Sp1 seem to play a key role in the progression of pancreatic cancer.
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Affiliation(s)
- Manuela Malsy
- Department of Anesthesiology, University Medical Center, Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany
| | - Bernhard Graf
- Department of Anesthesiology, University Medical Center, Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany
| | - Katrin Almstedt
- Department of Obstetrics and Gynecology, University Hospital, Mainz, Mainz, Germany
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Chen ST, Kuo TC, Liao YY, Lin MC, Tien YW, Huang MC. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene 2018; 37:6041-6053. [PMID: 29993037 PMCID: PMC6237765 DOI: 10.1038/s41388-018-0403-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/28/2018] [Accepted: 06/14/2018] [Indexed: 12/18/2022]
Abstract
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.
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Affiliation(s)
- Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Yu Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital, Hsinchu, Hsinchu, Taiwan
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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25
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Liang D, Shi S, Liang C, Meng Q, Zhang B, Ni Q, Xu J, Yu X. Mismatch repair status as a beneficial predictor of fluorouracil-based adjuvant chemotherapy for pancreatic cancer. Surgery 2018; 163:1080-1089. [DOI: 10.1016/j.surg.2017.12.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 11/17/2017] [Accepted: 12/05/2017] [Indexed: 01/06/2023]
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Tanaka S. Precision medicine based on surgical oncology in the era of genome-scale analysis and genome editing technology. Ann Gastroenterol Surg 2018; 2:106-115. [PMID: 29863171 PMCID: PMC5881373 DOI: 10.1002/ags3.12059] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 12/21/2017] [Indexed: 12/25/2022] Open
Abstract
Accumulated evidence suggests that multiple molecular and cellular interactions promote cancer evolution in vivo. Surgical oncology is of growing significance to a comprehensive understanding of the malignant diseases for therapeutic application. We have analyzed more than 1000 clinical samples from surgically resected tissue to identify molecular biomarkers and therapeutic targets for advanced malignancies. Cancer stemness and mitotic instability were then determined as the essential predictors of aggressive phenotype with poor prognosis. Recently, whole genome/exome sequencing showed a mutational landscape underlying phenotype heterogeneity in caners. In addition, integrated genomic, epigenomic, transcriptomic, metabolic, proteomic and phenomic analyses elucidated several molecular subtypes that cluster in liver, pancreatic, biliary, esophageal and gastroenterological cancers. Identification of each molecular subtype is expected to realize the precise medicine targeting subtype-specific molecules; however, there are obstacle limitations to determine matching druggable targets or synthetic lethal interactions. Current breakthroughs in genome editing technology can provide us with unprecedented opportunity to recapitulate subtype-specific pathophysiology in vitro and in vivo. Given a great potential, on-demand editing system can design actionable strategy and revolutionize precision cancer medicine based on surgical oncology.
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Affiliation(s)
- Shinji Tanaka
- Department of Molecular OncologyTokyo Medical and Dental UniversityTokyoJapan
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27
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Vinogradova TV, Sverdlov ED. PDX1: A Unique Pancreatic Master Regulator Constantly Changes Its Functions during Embryonic Development and Progression of Pancreatic Cancer. BIOCHEMISTRY (MOSCOW) 2017; 82:887-893. [PMID: 28941456 DOI: 10.1134/s000629791708003x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Multifunctional activity of the PDX1 gene product is reviewed. The PDX1 protein is unique in that being expressed exclusively in the pancreas it exhibits various functional activities in this organ both during embryonic development and during induction and progression of pancreatic cancer. Hence, PDX1 belongs to the family of master regulators with multiple and often antagonistic functions.
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Affiliation(s)
- T V Vinogradova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
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28
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Hua YQ, Wang P, Zhu XY, Shen YH, Wang K, Shi WD, Lin JH, Meng ZQ, Chen Z, Chen H. Radiofrequency ablation for hepatic oligometastatic pancreatic cancer: An analysis of safety and efficacy. Pancreatology 2017; 17:967-973. [PMID: 29129384 DOI: 10.1016/j.pan.2017.08.072] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 08/17/2017] [Accepted: 08/30/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study was to evaluate the value of radiofrequency ablation (RFA) in the treatment of pancreatic cancer with synchronous liver oligometastasis. METHODS 102 patients diagnosed with pancreatic cancer with synchronous liver oligometastasis undergoing RFA were recruited in this retrospective study between January 2012 and December 2015. Clinical efficacy was evaluated by computed tomography or magnetic resonance imaging 1 month later. All patients were treated with RFA and systemic chemotherapy based on NCCN guideline. RESULTS The median follow-up was 21 months (range, 4.0-43.8 months). Of all patients, the 1-year survival rate was 47.1% and the median overall survival time was 11.40 months. Complete tumor ablation was achieved in 137 of 145 RFA sessions (94.5%), and in 244 of 254 tumors (96.1%). The incidence of common complications was 9.8%, and no severe complications were reported in any patient. Multivariate Cox regression analysis revealed that primary tumor in the head of the pancreas (HR = 1.868, 95% CI: 1.023-3.409; P = 0.042), maximum diameter of liver metastasis 3-5 cm (HR = 1.801, 95% CI: 1.081-3.001, P = 0.024) and neutrophil/lymphocyte ratio (NLR) ≥2.5 (HR = 1.716, 95% CI: 1.047-2.811; P = 0.032) were independent predictors of poorer survival. CONCLUSION RFA provides a minimally invasive and safe treatment for patients with pancreatic cancer with liver oligometastases. The clinical efficiency of RFA for hepatic oligometastatic pancreatic cancer was easily affected by the following factors: primary tumor location, maximum diameter of liver metastasis and NLR. These factors could be helpful for treatment decision and clinical trial design.
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Affiliation(s)
- Yong-Qiang Hua
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Peng Wang
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China
| | - Xiao-Yan Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Ye-Hua Shen
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China
| | - Kun Wang
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Wei-Dong Shi
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China
| | - Jun-Hua Lin
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Zhi-Qiang Meng
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China
| | - Zhen Chen
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Hao Chen
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China.
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Malsy M, Graf B, Almstedt K. Interaction between NFATc2 and the transcription factor Sp1 in pancreatic carcinoma cells PaTu 8988t. BMC Mol Biol 2017; 18:20. [PMID: 28774282 PMCID: PMC5543739 DOI: 10.1186/s12867-017-0097-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 07/20/2017] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Nuclear factors of activated T-cells (NFATs) have been mainly characterized in the context of immune response regulation because, as transcription factors, they have the ability to induce gene transcription. NFAT proteins are found in several types of tumors, for instance, pancreatic carcinoma. The role of NFATs in carcinogenesis is regulating central genes in cell differentiation and cell growth. NFAT proteins are primarily located in cytoplasm and only transported to the cell nucleus after activation. Here, they interact with other transcription factors cooperating with NFAT proteins, thus influencing the selection and regulation of NFAT-controlled genes. To identify and characterize possible interaction partners of the transcription factor NFATc2 in pancreatic carcinoma cells PaTu 8988t. METHODS NFATc2 expression and the mode of action of Ionomycin in the pancreatic tumor cell lines PaTu 8988t were shown with Western blotting and immunofluorescence tests. Potential partner proteins were verified by means of immunoprecipitation and binding partners, their physical interactions with DNA pull-down assays, siRNA technologies, and GST pull-down assays. Functional evidence was complemented by reporter-promoter analyses. RESULTS NFATc2 and Sp1 are co-localized in cell nuclei and physically interact at the NFAT target sequence termed NFAT-responsive promotor construct. Sp1 increases the functional activity of its binding partner NFATc2. This interaction is facilitated by Ionomycin in the early stimulation phase (up to 60 min). CONCLUSIONS Oncological therapy concepts are becoming more and more specific, aiming at the efficient modulation of specific signal and transcription pathways. The oncogenic transcription partner Sp1 is important for the transcriptional and functional activity of NFATc2 in pancreatic carcinoma. The binding partners interact in cells. Further studies are necessary to identify the underlying mechanisms and establish future therapeutic options for treating this aggressive type of tumor.
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Affiliation(s)
- Manuela Malsy
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
| | - Bernhard Graf
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
| | - Katrin Almstedt
- Department of Obstetrics and Gynecology, University Hospital Mainz, Mainz, Germany
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Lin G, Chen CK, Yin F, Yang C, Tian J, Chen T, Xu G, He C, Lin MCM, Wang J, Lu F, Wang X, Yong KT. Biodegradable nanoparticles as siRNA carriers for in vivo gene silencing and pancreatic cancer therapy. J Mater Chem B 2017; 5:3327-3337. [DOI: 10.1039/c6tb03116a] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biodegradable charged polyester-based vectors (BCPVs) were utilized for efficiently delivering mutatedK-Ras-targeting siRNA and successfully inhibiting tumor growth in a pancreatic xenograft modelin vivo.
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31
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Furuyama T, Tanaka S, Shimada S, Akiyama Y, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Fukamachi H, Arii S, Kawaguchi Y, Tanabe M. Proteasome activity is required for the initiation of precancerous pancreatic lesions. Sci Rep 2016; 6:27044. [PMID: 27244456 PMCID: PMC4886684 DOI: 10.1038/srep27044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 05/12/2016] [Indexed: 12/14/2022] Open
Abstract
Proteasome activity is significantly increased in advanced cancers, but its role in cancer initiation is not clear, due to difficulties in monitoring this process in vivo. We established a line of transgenic mice that carried the ZsGreen-degron(ODC) (Gdeg) proteasome reporter to monitor the proteasome activity. In combination with Pdx-1-Cre;LSL-Kras(G12D) model, proteasome activity was investigated in the initiation of precancerous pancreatic lesions (PanINs). Normal pancreatic acini in Gdeg mice had low proteasome activity. By contrast, proteasome activity was increased in the PanIN lesions that developed in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice. Caerulein administration to Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice induced constitutive elevation of proteasome activity in pancreatic tissues and accelerated PanIN formation. The proteasome inhibitor markedly reduced PanIN formation in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice (P = 0.001), whereas it had no effect on PanIN lesions that had already formed. These observations indicated the significance of proteasome activity in the initiation of PanIN but not the maintenance per se. In addition, the expressions of pERK and its downstream factors including cyclin D1, NF-κB, and Cox2 were decreased after proteasome inhibition in PanINs. Our studies showed activation of proteasome is required specifically for the initiation of PanIN. The roles of proteasome in the early stages of pancreatic carcinogenesis warrant further investigation.
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Affiliation(s)
- Takaki Furuyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Satoshi Matsumura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Mitsunori
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Arihiro Aihara
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanori Ochiai
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroshi Fukamachi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeki Arii
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshiya Kawaguchi
- Department of Clinical Application, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Gharibi A, Adamian Y, Kelber JA. Cellular and molecular aspects of pancreatic cancer. Acta Histochem 2016; 118:305-16. [PMID: 26868366 PMCID: PMC5654315 DOI: 10.1016/j.acthis.2016.01.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/28/2016] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that affects nearly 50,000 patients each year. The overall 5-year survival rate for this malignancy remains the lowest of any cancer at around 7% due to limited diagnostic methods, disease aggressiveness and a lack of targeted therapeutic interventions. This review highlights the successes achieved over the past several decades as well as the significant cellular and molecular hurdles that remain in combatting this deadly disease at a translational level.
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Affiliation(s)
- A Gharibi
- Developmental Oncogene Laboratory, Department of Biology, California State University Northridge, Northridge, CA 91330, USA
| | - Y Adamian
- Developmental Oncogene Laboratory, Department of Biology, California State University Northridge, Northridge, CA 91330, USA
| | - J A Kelber
- Developmental Oncogene Laboratory, Department of Biology, California State University Northridge, Northridge, CA 91330, USA.
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Grapsa D, Saif MW, Syrigos K. Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go? World J Gastrointest Oncol 2015; 7:172-177. [PMID: 26483872 PMCID: PMC4606172 DOI: 10.4251/wjgo.v7.i10.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic adenocarcinoma (usually referred to as pancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field.
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Tanaka S. Cancer stem cells as therapeutic targets of hepato-biliary-pancreatic cancers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:531-537. [PMID: 25874410 DOI: 10.1002/jhbp.248] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 03/12/2015] [Indexed: 12/12/2022]
Abstract
Heterogeneity is one of the essential hallmarks of malignancies. Within bulk cancer cells, a striking variability differs in biological characteristics including the proliferation rate, cell-cell interaction, metastatic tendency and even sensitivity to anticancer therapies. Such diversity makes the investigation and treatment of the cancers complicated. Increasing evidence suggests this plasticity of cancers is a result of self-renewing and differentiation of a small subpopulation of cancer cells with stem-like properties, called cancer stem cells (CSCs). More importantly, CSCs are believed to be responsible for the resistance to conventional therapies and metastatic abilities in clinical practice. This review summarizes the molecular pathogenesis of hepato-biliary-pancreatic CSCs on the basis of the recent studies, and promising strategy of novel therapy targeting the signal transduction pathways or potentially epigenetic addictions of CSCs.
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Affiliation(s)
- Shinji Tanaka
- Department of Molecular Oncology, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan.
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