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Cell and Molecular Biology of Pancreatic Disorders
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Cell and Molecular Biology of Pancreatic Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 August 2018) | Viewed by 93681

Special Issue Editors

Prof. Dr. Jaya Padmanabhan

E-Mail Website
Guest Editor
1. Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA
2. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
Interests: calcium signaling; proteases in cancer; novel therapeutics in pancreatic cancer; cell cycle regulation; signal transduction; epithelial–mesenchymal transition; mechanisms of neurodegeneration; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Srikumar Chellappan

E-Mail Website
Guest Editor
H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Mail Code SRB3, Tampa, FL 33612, USA
Interests: molecular mechanisms that regulate cell proliferation; tumor progression; angiogenesis and metastasis; the role of nicotine in promoting growth and metastasis of tumors; cancer stem cells; mechanisms of drug resistance; novel drug targets
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues:

This Special Issue is a continuation of our 2016 Special Issue, "Pancreatic Disorders".

Elucidation of the molecular mechanisms underlying the initiation and progression of a disease enables the development of targeted therapies to inhibit or delay the disease progression. Pancreatic disorders are of varying nature, with pancreatic ductal adenocarcinoma being one of the most lethal cancers, with a dismal five-year survival rate of less than 6%. Due to a lack of non-invasive early detection methods, the cancer is detected at a late stage when it is aggressive and resistant to available therapies. Additionally, the tumor microenvironment—enriched with growth factors and cytokines—significantly supports the growth and metastasis of tumor, and hinders the therapeutic efficacy. Secreted factors can act at the autocrine or paracrine level to promote or suppress cell growth in the microenvironment. Identification of the signaling mechanisms is important for targeted drug development. Furthermore, the role of cancer stem cells or tumor initiating cells in the genesis and progression of pancreatic cancer is also not fully elucidated. This special thematic issue is expected to cover the molecular and cellular mechanisms associated with pancreatic ductal adenocarcinomas, as well as the contribution of pancreatitis to the genesis of this disease. Other relevant aspects like the contribution of microenvironmental factors, cancer stem cells, behavior correlates such as smoking, and role of environmental pollutants in genesis and progression as well as response to therapy will be covered in this issue. We expect that this Special Issue will provide the latest information on the underlying mechanisms and treatment strategies associated with pancreatic disorders, and would be of interest to scientists and clinicians working in this area.

Prof. Dr. Jaya Padmanabhan
Prof. Dr. Srikumar Chellappan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Pancreatitis
  • Pancreatic ductal adenocarcinoma
  • Pancreatic neuroendocrine tumors
  • Pancreatic intraepithelial neoplasia
  • Intraductal papillary mucinous neoplasms
  • Pancreatic cancer stem cells
  • Pancreatic stromal cells
  • Pancreatic microenvironment
  • Genetic changes
  • Transcription and translation
  • Cell metabolism
  • Intracellular and intercellular signaling
  • Genomics/Proteomics/Lipidomics
  • Inflammation
  • Metastasis

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Published Papers (16 papers)

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Research

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15 pages, 2532 KiB  
Article
Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System
by Emanuela Pessolano, Raffaella Belvedere, Valentina Bizzarro, Paola Franco, Iolanda De Marco, Amalia Porta, Alessandra Tosco, Luca Parente, Mauro Perretti and Antonello Petrella
Int. J. Mol. Sci. 2018, 19(12), 3878; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123878 - 04 Dec 2018
Cited by 55 | Viewed by 4909
Abstract
Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were [...] Read more.
Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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14 pages, 6450 KiB  
Article
Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine
by Michael H. Gerber, Patrick W. Underwood, Sarah M. Judge, Daniel Delitto, Andrea E. Delitto, Rachel L. Nosacka, Bayli B. DiVita, Ryan M. Thomas, Jennifer B. Permuth, Steven J. Hughes, Shannon M. Wallet, Andrew R. Judge and Jose G. Trevino
Int. J. Mol. Sci. 2018, 19(12), 3836; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123836 - 01 Dec 2018
Cited by 13 | Viewed by 4252
Abstract
Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. [...] Read more.
Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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13 pages, 2368 KiB  
Article
Sorafenib in Combination with Betulinic Acid Synergistically Induces Cell Cycle Arrest and Inhibits Clonogenic Activity in Pancreatic Ductal Adenocarcinoma Cells
by Justyna Kutkowska, Leon Strzadala and Andrzej Rapak
Int. J. Mol. Sci. 2018, 19(10), 3234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103234 - 19 Oct 2018
Cited by 15 | Viewed by 3188
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers in the world due to late diagnosis and poor response to available treatments. It is important to identify treatment strategies that will increase the efficacy and reduce the toxicity of the currently [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers in the world due to late diagnosis and poor response to available treatments. It is important to identify treatment strategies that will increase the efficacy and reduce the toxicity of the currently used therapeutics. In this study, the PDAC cell lines AsPC-1, BxPC-3, and Capan-1 were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of combined treatments on viability (MTS test), proliferation and apoptosis (annexin V staining), cell cycle arrest (PI staining), alterations in signaling pathways (Western blotting), and colony-forming ability. The combination of sorafenib with betulinic acid inhibited the viability and proliferation of PDAC cells without the induction of apoptosis. The antiproliferative effect, caused by G2 cell cycle arrest, was strongly associated with increased expression of p21 and decreased expression of c-Myc and cyclin D1, and was induced only by combined treatment. Additionally, decreased proliferation could also be associated with the inhibition of the P13K/Akt and MAPK signaling pathways. Importantly, combination treatment reduced the colony-forming ability of PDAC cells, as compared to both compounds alone. Collectively, we showed that combined treatment with low concentrations of sorafenib and betulinic acid had the capacity to inhibit proliferation and abolish clonogenic activity in PDAC cell lines. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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12 pages, 3761 KiB  
Article
Evaluation of Circulating MicroRNA Biomarkers in the Acute Pancreatic Injury Dog Model
by Han-Byul Lee, Hyun-Kyu Park, Hyun-Ji Choi, Sora Lee, Sang-Joon Lee, Ji-Young Lee, Eun-Ho Cho, Hyo-Jeong Han, Ju-Hyung Seok and Woo-Chan Son
Int. J. Mol. Sci. 2018, 19(10), 3048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103048 - 06 Oct 2018
Cited by 17 | Viewed by 3605
Abstract
This study aimed to evaluate the usefulness of four microRNAs (miRNAs) in an acute pancreatic injury dog model. Acute pancreatitis was induced by infusion of cerulein for 2 h (7.5 μg/kg/h). The levels of well-known miRNAs, microRNA-216a (miR-216a) and microRNA-375 (miR-375), and new [...] Read more.
This study aimed to evaluate the usefulness of four microRNAs (miRNAs) in an acute pancreatic injury dog model. Acute pancreatitis was induced by infusion of cerulein for 2 h (7.5 μg/kg/h). The levels of well-known miRNAs, microRNA-216a (miR-216a) and microRNA-375 (miR-375), and new candidates microRNA-551b (miR-551b), and microRNA-7 (miR-7), were measured at 0, 0.5, 1, 2, 6, 12, and 24 h with serum amylase and lipase, and histopathological examination was performed. Among the four miRNAs, miR-216a and miR-375, and serum enzymes were significantly increased by cerulein treatment. The expression levels of miRNAs and serum enzymes peaked at 2–6 h with a similar pattern; however, the overall increases in miR-216a and miR-375 levels were much higher than those of the serum enzyme biomarkers. Increased levels of miR-216a and miR-375 were most highly correlated to the degree of individual histopathological injuries of the pancreas, and showed much greater dynamic response than serum enzyme biomarkers. Twenty-four-hour time-course analysis in this study revealed time-dependent changes of miRNA expression levels, from initial increase to decrease by predose level in acute pancreatitis. Our findings demonstrate that, in dogs, miR-216a and miR-375 have the potential to sensitively detect pancreatitis and reflect well the degree of pancreatic injury, whereas miR-551b and miR-7 do not. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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14 pages, 3449 KiB  
Article
A Novel Monoclonal Antibody Targets Mucin1 and Attenuates Growth in Pancreatic Cancer Model
by Guang Wu, Sony Maharjan, Dongbum Kim, Jung Nam Kim, Byoung Kwon Park, Heeju Koh, Kyungduk Moon, Younghee Lee and Hyung-Joo Kwon
Int. J. Mol. Sci. 2018, 19(7), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19072004 - 09 Jul 2018
Cited by 32 | Viewed by 6242
Abstract
Mucin1 (MUC1) is a highly glycosylated transmembrane protein that plays a crucial role in the lubrication and protection of normal epithelial cells. However, MUC1 has emerged as a potential target for cancer therapy because it is overexpressed and functions in several types of [...] Read more.
Mucin1 (MUC1) is a highly glycosylated transmembrane protein that plays a crucial role in the lubrication and protection of normal epithelial cells. However, MUC1 has emerged as a potential target for cancer therapy because it is overexpressed and functions in several types of cancers. Recently, we produced a monoclonal antibody (the anti-hMUC1 antibody) specific to the extracellular region of the MUC1 subunit MUC1-C to evaluate the utility of using anti-MUC1 antibodies in pancreatic cancer models. The anti-hMUC1 antibody recognized the MUC1-C protein in pancreatic cancer cells. Based on immunostaining and confocal image analyses, the anti-hMUC1 antibody initially bound to the cell membrane then was internalized in cancer cells that express MUC1. The anti-hMUC1 antibody suppressed epidermal growth factor (EGF)-mediated extracellular signal–regulated kinase (ERK) phosphorylation and cyclin D1 expression. When the anti-hMUC1 antibody was injected into a xenograft mouse model and traced using an in vivo imaging system, we observed that the anti-hMUC1 antibody was localized to MUC1-expressing pancreatic tumors. Importantly, the anti-hMUC1 monoclonal antibody suppressed pancreatic tumor growth in mice. According to immunohistochemistry analysis using a pancreatic cancer tissue array and the anti-hMUC1 antibody, MUC1 was highly expressed in human pancreatic cancer tissues compared to normal tissues. Therefore, we conclude that the anti-hMUC1 antibody specifically targets MUC1 and suppresses its function in pancreatic cancer in vitro and in vivo and can be further developed as a promising targeted therapy to treat pancreatic cancer. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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15 pages, 5137 KiB  
Article
miR-196a Is Able to Restore the Aggressive Phenotype of Annexin A1 Knock-Out in Pancreatic Cancer Cells by CRISPR/Cas9 Genome Editing
by Raffaella Belvedere, Pasquale Saggese, Emanuela Pessolano, Domenico Memoli, Valentina Bizzarro, Francesca Rizzo, Luca Parente, Alessandro Weisz and Antonello Petrella
Int. J. Mol. Sci. 2018, 19(7), 1967; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19071967 - 06 Jul 2018
Cited by 28 | Viewed by 4246
Abstract
Annexin A1 (ANXA1) is a Ca2+-binding protein that is involved in pancreatic cancer (PC) progression. It is able to mediate cytoskeletal organization maintaining a malignant phenotype. Our previous studies showed that ANXA1 Knock-Out (KO) MIA PaCa-2 cells partially lost their migratory [...] Read more.
Annexin A1 (ANXA1) is a Ca2+-binding protein that is involved in pancreatic cancer (PC) progression. It is able to mediate cytoskeletal organization maintaining a malignant phenotype. Our previous studies showed that ANXA1 Knock-Out (KO) MIA PaCa-2 cells partially lost their migratory and invasive capabilities and also the metastatization process appeared affected in vivo. Here, we investigated the microRNA (miRNA) profile in ANXA1 KO cells finding that the modification in miRNA expression suggests the significant involvement of ANXA1 in PC development. In this study, we focused on miR-196a which appeared down modulated in absence of ANXA1. This miRNA is a well known oncogenic factor in several tumour models and it is able to trigger the agents of the epithelial to mesenchymal transition (EMT), like ANXA1. Our results show that the reintroduction in ANXA1 KO cells of miR-196a through the mimic sequence restored the early aggressive phenotype of MIA PaCa-2. Then, ANXA1 seems to support the expression of miR-196a and its role. On the other hand, this miRNA is able to mediate cytoskeletal dynamics and other protein functions promoting PC cell migration and invasion. This work describes the correlation between ANXA1 and specific miRNA sequences, particularly miR-196a. These results could lead to further information on ANXA1 intracellular role in PC, explaining other aspects that are apart from its tumorigenic behaviour. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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13 pages, 4037 KiB  
Article
Probing the Effect of Physiological Concentrations of IL-6 on Insulin Secretion by INS-1 832/3 Insulinoma Cells under Diabetic-Like Conditions
by Jonathan Barlow, Steven Carter and Thomas P. J. Solomon
Int. J. Mol. Sci. 2018, 19(7), 1924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19071924 - 30 Jun 2018
Cited by 6 | Viewed by 4871
Abstract
Exercise improves insulin secretion by pancreatic beta cells (β-cells) in patients with type 2 diabetes, but molecular mechanisms of this effect are yet to be determined. Given that contracting skeletal muscle causes a spike in circulating interleukin-6 (IL-6) levels during exercise, muscle-derived IL-6 [...] Read more.
Exercise improves insulin secretion by pancreatic beta cells (β-cells) in patients with type 2 diabetes, but molecular mechanisms of this effect are yet to be determined. Given that contracting skeletal muscle causes a spike in circulating interleukin-6 (IL-6) levels during exercise, muscle-derived IL-6 is a possible endocrine signal associated with skeletal muscle to β-cell crosstalk. Evidence to support a role of IL-6 in regulating the health and function of β-cells is currently inconsistent and studies investigating the role of IL-6 on the function of β-cells exposed to type 2 diabetic-like conditions are limited and often confounded by supraphysiological IL-6 concentrations. The purpose of this study is to explore the extent by which an exercise-relevant concentration of IL-6 influences the function of pancreatic β-cells exposed to type 2 diabetic-like conditions. Using insulin-secreting INS-1 832/3 cells as an experimental β-cell model, we show that 1-h IL-6 (10 pg/mL) has no effect on insulin secretion under normal conditions and does not restore the loss of insulin secretion caused by elevated glucose ± palmitate or IL-1β. Moreover, treatment of INS-1 832/3 cells to medium collected from C2C12 myotubes conditioned with electrical pulse stimulation does not alter insulin secretion despite significant increases in IL-6. Since insulin secretory defects caused by diabetic-like conditions are neither improved nor worsened by exposure to physiological IL-6 levels, we conclude that the beneficial effect of exercise on β-cell function is unlikely to be driven by muscle-derived IL-6. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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13 pages, 3009 KiB  
Article
Does the Automatic Measurement of Interleukin 6 Allow for Prediction of Complications during the First 48 h of Acute Pancreatitis?
by Witold Kolber, Paulina Dumnicka, Małgorzata Maraj, Beata Kuśnierz-Cabala, Piotr Ceranowicz, Michał Pędziwiatr, Barbara Maziarz, Małgorzata Mazur-Laskowska, Marek Kuźniewski, Mateusz Sporek and Jerzy Walocha
Int. J. Mol. Sci. 2018, 19(6), 1820; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061820 - 20 Jun 2018
Cited by 18 | Viewed by 4887
Abstract
Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, [...] Read more.
Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, which reduces mortality. Serum interleukin-6 (IL-6) has been proposed as a biomarker to assist early diagnosis of SAP, however, most data come from studies utilizing IL-6 measurements with ELISA. Our aim was to verify the diagnostic usefulness of IL-6 for the prediction of SAP, organ failure, and need for intensive care in the course of AP using a fully automated assay. The study included 95 adult patients with AP of various severity (29 mild, 58 moderately-severe, 8 severe) admitted to a hospital within 24 h from the onset of symptoms. Serum IL-6 was measured using electochemiluminescence immunoassay in samples collected on admission and on the next day of hospital stay. On both days, patients with SAP presented the highest IL-6 levels. IL-6 correlated positively with other inflammatory markers (white blood cell and neutrophil counts, C-reactive protein, procalcitonin), the markers of renal injury (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and the markers of endothelial dysfunction (angiopoietin-2, soluble fms-like tyrosine kinase-1). IL-6 on admission significantly predicted SAP, vital organ failure, and the need for intensive care or death, with areas under the receiver operating curve between 0.75 and 0.78, not significantly different from multi-variable prognostic scores. The fully automated assay allows for fast and repeatable measurements of serum IL-6, enabling wider clinical use of this valuable biomarker. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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15 pages, 4116 KiB  
Article
Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression
by Lian-Yu Chen, Chien-Shan Cheng, Chao Qu, Peng Wang, Hao Chen, Zhi-Qiang Meng and Zhen Chen
Int. J. Mol. Sci. 2018, 19(6), 1768; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061768 - 14 Jun 2018
Cited by 29 | Viewed by 4302
Abstract
Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and [...] Read more.
Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and function of CBX3 in PAAD. Methods: Data of transcriptomic and protein expression of CBX3 in PAAD were collected from different databases and analyzed. The in vitro and in vivo role of CBX3 in PAAD was examined. Results: CBX3 was overexpressed in human PAAD tissues, which was associated with poor prognosis of overall and disease-free survival of the patients. Overexpression of CBX3 induced the in vitro proliferation, anchorage-free growth, migration and invasion of the PAAD cells, and led to in vivo growth of orthotoptic PAAD tumors in mice. GO and KEGG pathway analysis, as well as experimental observation showed that CBX3 may be associated with cell cycle transition of PAAD cells, and cyclin-dependent kinase 1 (CDK1) and proliferating cell nuclear antigen (PCNA) may mediate the tumor-promoting action of CBX3. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. Conclusion: Our findings suggest the tumor-promoting role of CBX3 in PAAD to be targeted by novel therapeutic strategies. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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13 pages, 15755 KiB  
Article
Knocking down Insulin Receptor in Pancreatic Beta Cell lines with Lentiviral-Small Hairpin RNA Reduces Glucose-Stimulated Insulin Secretion via Decreasing the Gene Expression of Insulin, GLUT2 and Pdx1
by Jie Wang, Wenyi Gu and Chen Chen
Int. J. Mol. Sci. 2018, 19(4), 985; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19040985 - 26 Mar 2018
Cited by 16 | Viewed by 6291
Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterized by beta cell dysfunction and insulin resistance in fat, muscle and liver cells. Recent studies have shown that the development of insulin resistance in pancreatic beta cell lines may contribute to beta cell dysfunction [...] Read more.
Type 2 diabetes (T2D) is a metabolic disorder characterized by beta cell dysfunction and insulin resistance in fat, muscle and liver cells. Recent studies have shown that the development of insulin resistance in pancreatic beta cell lines may contribute to beta cell dysfunction in T2D. However, there still is a lack of detailed investigations regarding the mechanisms by which insulin deficiency may contribute in diabetes. In this study, we firstly established a stable insulin receptor knockdown cell line in pancreatic beta cells INS-1 (InsRβKD cells) using anti InsRβ small hairpin RNA (InsRβ-shRNA) encoded by lentiviral vectors. The resultant InsRβKD cells demonstrated a significantly reduced expression of InsRβ as determined by real-time PCR and Western blotting analyses. Upon removing glucose from the medium, these cells exhibited a significant decrease in insulin gene expression and protein secretion in response to 20 mM glucose stimulation. In accordance with this insulin reduction, the glucose uptake efficiency as indicated by a 3[H]-2-deoxy-d-glucose assay also decreased. Furthermore, InsRβKD cells showed a dramatic decrease in glucose transporter 2 (GLUT2, encoded by SLC2A2) and pancreatic duodenal homeobox (Pdx1) mRNA expression compared to the controls. These data collectively suggest that pancreatic beta cell insulin resistance contributes to the development of beta cell dysfunction by impairing pancreatic beta cell glucose sensation through the Pdx1- GLUT2 pathway. InsRβKD cells provide a good model to further investigate the mechanism of β-cell dysfunction in T2D. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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Review

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12 pages, 224 KiB  
Review
Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer
by Shravanti Macherla, Shachar Laks, Abdul Rafeh Naqash, Anushi Bulumulle, Emmanuel Zervos and Mahvish Muzaffar
Int. J. Mol. Sci. 2018, 19(11), 3505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113505 - 07 Nov 2018
Cited by 63 | Viewed by 5467
Abstract
Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with [...] Read more.
Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it’s obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
19 pages, 651 KiB  
Review
Gene Therapy for Pancreatic Diseases: Current Status
by Kenya Kamimura, Takeshi Yokoo and Shuji Terai
Int. J. Mol. Sci. 2018, 19(11), 3415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113415 - 31 Oct 2018
Cited by 11 | Viewed by 5108
Abstract
The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. [...] Read more.
The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. While various therapeutic methodologies have been established to date, however, the improvement of conventional treatments and establishment of novel therapies are essential to improve the efficacy. For example, conventional therapeutic options, including chemotherapy, are not effective against pancreatic cancer, and despite improvements in the last decade, the mortality rate has not declined and is estimated to become the second cause of cancer-related deaths by 2030. Therefore, continuous efforts focus on the development of novel therapeutic options. In this review, we will summarize the progress toward the development of gene therapies for pancreatic diseases, with an emphasis on recent preclinical studies and clinical trials. We aim to identify new areas for improvement of the current methodologies and new strategies that will lead to safe and effective gene therapeutic approaches in pancreatic diseases. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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18 pages, 270 KiB  
Review
Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance
by Priscilla Cascetta, Alessandro Cavaliere, Geny Piro, Lorena Torroni, Raffaela Santoro, Giampaolo Tortora, Davide Melisi and Carmine Carbone
Int. J. Mol. Sci. 2018, 19(11), 3331; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113331 - 25 Oct 2018
Cited by 30 | Viewed by 5611
Abstract
Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and [...] Read more.
Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20–40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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28 pages, 1019 KiB  
Review
The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma
by Balbina García-Reyes, Anna-Laura Kretz, Jan-Philipp Ruff, Silvia Von Karstedt, Andreas Hillenbrand, Uwe Knippschild, Doris Henne-Bruns and Johannes Lemke
Int. J. Mol. Sci. 2018, 19(10), 3219; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103219 - 18 Oct 2018
Cited by 58 | Viewed by 18811
Abstract
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer [...] Read more.
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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13 pages, 1452 KiB  
Review
Mesenchymal Stem Cells as New Therapeutic Approach for Diabetes and Pancreatic Disorders
by Arianna Scuteri and Marianna Monfrini
Int. J. Mol. Sci. 2018, 19(9), 2783; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092783 - 16 Sep 2018
Cited by 20 | Viewed by 5192
Abstract
Diabetes is a worldwide disease which actually includes different disorders related to glucose metabolism. According to different epidemiological studies, patients affected by diabetes present a higher risk to develop both acute and chronic pancreatitis, clinical situations which, in turn, increase the risk to [...] Read more.
Diabetes is a worldwide disease which actually includes different disorders related to glucose metabolism. According to different epidemiological studies, patients affected by diabetes present a higher risk to develop both acute and chronic pancreatitis, clinical situations which, in turn, increase the risk to develop pancreatic cancer. Current therapies are able to adjust insulin levels according to blood glucose peak, but they only partly reach the goal to abrogate the consequent inflammatory milieu responsible for diabetes-related diseases. In recent years, many studies have investigated the possible use of adult mesenchymal stem cells (MSCs) as alternative therapeutic treatment for diabetes, with promising results due to the manifold properties of these cells. In this review we will critically analyze the many different uses of MSCs for both diabetes treatment and for the reduction of diabetes-related disease development, focusing on their putative molecular mechanisms. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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17 pages, 954 KiB  
Review
New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review
by Nuria Garcia-Carbonero, Weiyao Li, Marticela Cabeza-Morales, Javier Martinez-Useros and Jesus Garcia-Foncillas
Int. J. Mol. Sci. 2018, 19(9), 2468; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092468 - 21 Aug 2018
Cited by 22 | Viewed by 5449
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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