Role In Development Of Pancreatic Cancer Research Articles

Correlating tissue and plasma‑specific piRNA changes to predict their possible role in pancreatic malignancy and chronic inflammation.

The aggressiveness of pancreatic ductal adenocarcinoma is primarily due to lack of effective early detection biomarkers. Circulating non-coding RNAs serve as diagnostic or prognostic biomarkers in multiple types of cancer. Comparison of their expression between diseased tissue and relevant body fluids such as saliva, urine, bile, pancreatic juice, blood etc. may reveal mechanistic involvement of common non-coding RNAs. piwi-interacting RNAs (piRNAs) are a class of non-coding RNAs. The aim of the present study was to investigate plasma and tumour tissue piRNA changes in patients with pancreatic cancer (PC) and explore the possible role in tumorigenesis and pancreatic inflammation. Sequencing of circulating plasma small RNAs from patients with PC and chronic pancreatitis (CP) was performed and differentially expressed piRNAs were compared with those in tissues. Subsequent search for target genes for those piRNAs was performed followed by pathway and cluster analysis. A total of 36 piRNAs were shown to be deregulated in pancreatic tumour tissue and alteration of 11 piRNAs was detected in plasma of patients with PC. piRNAs hsa-piR-23246, hsa-piR-32858 and hsa-piR-9137 may serve a key role in PC development as their expression was correlated in both plasma and tumour tissue. Key piRNA-target interactions interfering with key biological pathways were also characterized. A total of 19 deregulated piRNAs in plasma samples of patients with CP was identified; these targeted genes responsible for chronic inflammation. Therefore, the present study provides a comprehensive description of piRNA alteration in pancreatic malignancy and inflammation; these may be explored for biomarker potential in future.

Metagenomic analysis reveals altered gut virome and diagnostic potential in pancreatic cancer.

Pancreatic cancer (PC) is a highly aggressive malignancy with a poor prognosis, making early diagnosis crucial for improving patient outcomes. While the gut microbiome, including bacteria and viruses, is believed to be essential in cancer pathogenicity, the potential contribution of the gut virome to PC remains largely unexplored. In this study, we conducted a comparative analysis of the gut viral compositional and functional profiles between PC patients and healthy controls, based on fecal metagenomes from two publicly available data sets comprising a total of 101 patients and 82 healthy controls. Our results revealed a decreasing trend in the gut virome diversity of PC patients with disease severity. We identified significant alterations in the overall viral structure of PC patients, with a meta-analysis revealing 219 viral operational taxonomic units (vOTUs) showing significant differences in relative abundance between patients and healthy controls. Among these, 65 vOTUs were enriched in PC patients, and 154 were reduced. Host prediction revealed that PC-enriched vOTUs preferentially infected bacterial members of Veillonellaceae, Enterobacteriaceae, Fusobacteriaceae, and Streptococcaceae, while PC-reduced vOTUs were more likely to infect Ruminococcaceae, Lachnospiraceae, Clostridiaceae, Oscillospiraceae, and Peptostreptococcaceae. Furthermore, we constructed random forest models based on the PC-associated vOTUs, achieving an optimal average area under the curve (AUC) of up to 0.879 for distinguishing patients from controls. Through additional 10 public cohorts, we demonstrated the reproducibility and high specificity of these viral signatures. Our study suggests that the gut virome may play a role in PC development and could serve as a promising target for PC diagnosis and therapeutic intervention. Future studies should further explore the underlying mechanisms of gut virus-bacteria interactions and validate the diagnostic models in larger and more diverse populations.

Hsa_circ_0014784-induced YAP1 promoted the progression of pancreatic cancer by sponging miR-214-3p

ABSTRACT Background Pancreatic cancer (PC) is one of the most common gastrointestinal tumors globally. Former investigations discovered that circular RNAs (circRNAs) play an important role in PC development. circRNAs belong to a new class of endogenous noncoding RNAs, which have been found to mediate the progression of diverse types of tumors. Nevertheless, the roles of circRNAs and the underlying regulatory mechanisms in PC remain unknown. Methods In this study, our team employed next-generation sequencing (NGS) to examine the abnormal circRNA expression in PC tissues. The circRNA expression in PC cell lines and tissues was detected. Then, regulatory mechanism and targets were examined with bioinformatics analysis, luciferase reporting analysis, Transwell migration, 5-ethynyl−2′-deoxyuridine, and CCK−8 analysis. An in vivo experiment was employed to elucidate hsa_circ_0014784 roles in PC tumor growth and metastasis. Results The results showcased abnormal circRNA expression in PC tissues. Our lab also found that hsa_circ_0014784 expression incremented in PC tissues and cell lines, implying that hsa_circ_0014784 functioned in PC progression. hsa_circ_0014784 downregulation inhibited PC proliferation and invasion in vivo and in vitro. The bioinformatics and luciferase report data validated that both miR−214-3p and YAP1 were hsa_circ_0014784 binding partners. The overexpression of YAP1 reversed the migration, proliferation, and epithelial – mesenchymal transition (EMT) of PC cells and the angiogenic differentiation of HUVECs after miR−214-3p overexpression. Conclusion Taken together, our study found that hsa_circ_0014784 downregulation decremented invasion, proliferation, EMT, and angiogenesis of PC by regulating miR−214-3p/YAP1 signaling.

KMT2D links TGF-β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The main methods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought a milestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potential molecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer.

Autoimmune conditions and pancreatic cancer risk in older American adults.

Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We conducted a population-based, nested case-control study to examine the associations between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n=80 074) were adults ≥66 years and diagnosed between 1992 and 2015. Controls (n=320 296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR=1.45; 95% CI: 1.14-1.84), Graves' disease (OR=1.18; 95% CI: 1.03-1.34), localized scleroderma (OR=1.27; 95% CI: 1.06-1.52), pernicious anemia (OR=1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR=1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR=1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR=1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR=1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values <.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development.

DNA Polymerase Theta Plays a Critical Role in Pancreatic Cancer Development and Metastasis.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. The occurrence of oncogenic KRAS mutations is considered a signature event in PDAC, leading to genomic instability. The aim of our study was to evaluate the impact of the oncogenic KRAS G12D mutation on the activity of the error-prone alt-EJ repair mechanism, and to investigate the potential role of Polθ in the development of pancreatic cancer. We found that oncogenic KRAS increases the expression of key alt-EJ proteins in a mouse and human PDAC model. Using TLR assay, we also found increased alt-EJ activity in mouse and human cell lines upon the expression of KRAS D12D. The inactivation/impairment of alt-EJ by polymerase theta (Polθ) depletion delays the development of pancreatic cancer and prolongs the survival of experimental mice, though it does not prevent the PDAC development, which leads to full-blown PDAC with disseminated metastasis. Our studies provide a high-value target as a novel therapeutic candidate for the treatment of pancreatic and other cancers.Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of effective treatment, despite decades of intensive research, will become the second leading cause of cancer-related deaths by 2030. Step-wise acquisition of mutations, due to genomic instability, is considered to drive the development of PDAC; the KRAS mutation occurs in 95 to 100% of human PDAC, and is already detectable in early premalignant lesions designated as pancreatic intraepithelial neoplasia (PanIN). This mutation is possibly the key event leading to genomic instability and PDAC development. Our study aimed to investigate the role of the error-prone DNA double-strand breaks (DSBs) repair pathway, alt-EJ, in the presence of the KRAS G12D mutation in pancreatic cancer development. Our findings show that oncogenic KRAS contributes to increasing the expression of Polθ, Lig3, and Mre11, key components of alt-EJ in both mouse and human PDAC models. We further confirm increased catalytic activity of alt-EJ in a mouse and human model of PDAC bearing the KRAS G12D mutation. Subsequently, we focused on estimating the impact of alt-EJ inactivation by polymerase theta (Polθ) deletion on pancreatic cancer development, and survival in genetically engineered mouse models (GEMMs) and cancer patients. Here, we show that even though Polθ deficiency does not fully prevent the development of pancreatic cancer, it significantly delays the onset of PanIN formation, prolongs the overall survival of experimental mice, and correlates with the overall survival of pancreatic cancer patients in the TCGA database. Our study clearly demonstrates the role of alt-EJ in the development of PDAC, and alt-EJ may be an attractive therapeutic target for pancreatic cancer patients.

WBSCR22 and TRMT112 synergistically suppress cell proliferation, invasion and tumorigenesis in pancreatic cancer via transcriptional regulation of ISG15.

Pancreatic cancer (PC) is one of the most aggressive and devastating types of cancer owing to its poor prognosis and deadly characteristics. It is well established that aberrations in the expression of key regulatory genes, namely tumor suppressors and oncogenes, predispose patients to progression and metastasis of PC. Upregulation of Williams-Beuren syndrome chromosomal region 22 (WBSCR22) expression, a ribosomal biogenesis factor, has been reported in multiple types of human cancer. However, the role of WBSCR22 and its underlying mechanism in PC have not been well investigated. In the present study, the tumor suppressive role of WBSCR22 was reported in PC for the first time; the results indicated that WBSCR22 overexpression (OE) significantly suppressed cellular proliferation, migration, invasion and tumorigenesis in vivo and in vitro. RNA-sequencing analysis revealed that WBSCR22 negatively regulated the transcription of interferon-stimulated gene 15 (ISG15) downstream, which is a ubiquitin-like modifier protein involved in metabolic and proteasome degradation pathways, while the antitumor function of WBSCR22-OE could be rescued by ISG15 OE. In addition, the oncogenic role of ISG15 was further confirmed in PC; its upregulation promoted the proliferation, migration, invasion and tumorigenesis of PC. Furthermore, WBSCR22 and its cofactor tRNA methyltransferase activator subunit 11-2 (TRMT112) functioned synergistically in PC, and concurrent ectopic OE of WBSCR22 and TRMT112 further promoted the tumor suppressive potential of WBSCR22 in PC. Collectively, the findings indicated that WBSCR22 played an important role in PC development and that the WBSCR22/ISG15 axis may provide a novel therapeutic strategy for PC treatment.

Abstract PO-110: Targeting cathepsin B in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response

Abstract Background: Cathepsin B (CTSB) is a lysosomal cysteine protease which has been described to have a role in pancreatic cancer development. However, its significance in the tumor microenvironment has never been investigated. Pancreatic stellate cells (PSCs) are one of the main sources of Cancer Associated Fibroblasts (CAFs) in the pancreatic cancer microenvironment. Herein, we describe the effects of targeting CTSB in the pancreatic stellate cells (PSCs) in pancreatic cancer (PDAC). Methods: To specifically study the role of CTSB in PSCs, PSCs were isolated from C57BL/6J (WT) or CTSB -/- mice and were orthotopically injected with KPC cancer cells into the tail of pancreas of 6-week old female WT mice. Tumors were analyzed at endpoint using flow cytometry. To further study the dependence of effects of CTSB in PSCs on adaptive immune cells, WT or CTSB -/- PSCs were co-injected with KPC cells into Rag 1-/- mice or CD8+ T cell depleted mice (anti-CD8 mAb, 250ug/dose every 3 days). In vitro, WT or CTSB-/- PSCs were co-cultured with KPC across a transwell. CD8+ T cells, isolated from KPC tumor bearing mice, were exposed to conditioned media from this co-culture ex-vivo and their cytotoxicity was measured using calcein release assay. In another experiment, WT mice injected with KPC cancer cells were treated with vehicle control or the CTSB inhibitor, CA-074 methyl ester (10 mg/kg), through daily intraperitoneal injections. Results: Co-injections of WT PSC with KPC cells formed larger tumors as compared to KPC cancer cells alone, however, co-injection with CTSB-/- PSCs abrogated this tumor promoting effect. Flow cytometric analysis revealed increased infiltration of Ifn-γ secreting CD8+ T cells in the KPC+CB-/- PSC group as compared to KPC+WT PSC group. Tumor decreasing effect of CTSB-/- PSCs was lost when co-injections were performed in Rag 1-/- mice or CD8+ T cell depleted mice, indicating that this effect relies on a functional adaptive immune response, specifically CD8+ T cells. In vitro, co-culture of CTSB-/- PSCs with KPC led to reduced expression of inflammatory CAF (iCAF) markers like IL-6 and IL-11 when compared to co-culture of WT PSCs with KPC. CD8+ T cells exposed to conditioned media from CTSB-/- PSC co-culture showed increased cytotoxicity against KPC cells ex-vivo, as compared to those exposed to conditioned media from WT PSC co-culture. Finally, treatment with CA-074 was able to decrease orthotopic PDAC tumor growth with increased CD8+ T cell infiltration evident on flow cytometry. Conclusion: Targeting CTSB in the PSCs stimulates anti-tumor adaptive immune response against pancreatic cancer by inhibiting conversion of PSCs into the tumor-promoting iCAF phenotype. CTSB might emerge as a novel target for CAF-directed therapy in pancreatic cancer. Citation Format: Bharti Garg, Tejeshwar Jain, Utpreksha Vaish, Vikas Dudeja. Targeting cathepsin B in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-110.

AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells.

Risk factors of pancreatic cancer and their possible uses in diagnostics.

Pancreatic cancer (PC) is a form of malignancy of increasing incidence and poor prognosis, with an average of less than 10% of patients surviving 5 years after being diagnosed. The main reason for this unfavorable situation is the long asymptomatic course of the disease, and the absence of a simple screening method, typically leading to the late discovery of the disease. The development of the malignancy from the initial carcinogenesis into invasive pancreatic carcinoma takes approximately 10 years. However, the progression of pancreatic cancer from early into advanced stages can be, according to the latest studies, incredibly fast, just a few months. Early stages of pancreatic malignancy can be detected only by expensive, and sometimes invasive, diagnostic methods (CT, MRI, or EUS). Due to the current absence of a reliable non-invasive screening method, it is necessary to define a group of patients who have the highest risk of PC development, five to ten times higher risk compared to the regular population at a minimum. Risk factors combine in their effect; therefore, relative risks of PC development need to be summarized to obtain a total relative risk for each person. The main and non-influenceable risk factor in the development of PC is the increasing age. The other non-influenceable risk factor of PC is a genetic predisposition - family incidence of the disease can be detected in 4-16% of patients. Some specific genes and mutations, which can play a role in PC development have already been identified (for example mutation of the PRSS-1 gene). Among the influenceable risk factors of PC is primarily smoking; obesity can play a part in PC development as well. A higher risk of PC is observed in patients with chronic pancreatitis. Nowadays, the relationship between PC and diabetes mellitus (DM) is hotly discussed. In the case of long-standing DM, the risk of pancreatic cancer is two times higher compared to the healthy population. However, new-onset DM can be the first sign of still asymptomatic PC. These patients, with paraneoplastic DM caused by pancreatic cancer cells, represent approximately 1% of recently diagnosed patients. However, this group of patients is still too large for screening. Because of that, it is necessary to find specific criteria to distinguish classic DM from the paraneoplastic form. The application of these criteria can help with the better stratification of risk in patients with new-onset diabetes and hence, it can help to discover PC in its early stages.

Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells.

Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer. The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay. We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells. Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.

CYLD deficiency promotes pancreatic cancer development by causing mitotic defects

Successful treatment of pancreatic cancer, which has the highest mortality rate among all types of malignancies, has challenged oncologists for decades, and early detection would undoubtedly increase favorable patient outcomes. The identification of proteins involved in pancreatic cancer progression could lead to biomarkers for early detection of this disease. This study identifies one potential candidate, cylindromatosis (CYLD), a deubiquitinase and microtubule-binding protein that plays a suppressive role in pancreatic cancer development. In pancreatic cancer samples, downregulation of CYLD expression resulted from a loss in the copy number of the CYLD gene; additionally, reduced expression of CYLD negatively correlated with the clinicopathological parameters. Further study demonstrated that CYLD deficiency promoted colony formation in vitro and pancreatic cancer growth in vivo. Mechanistic studies revealed that CYLD is essential for spindle orientation and properly oriented cell division; CYLD deficiency resulted in a substantial increase in chromosome missegregation. Taken together, these data indicate a critical role for CYLD in suppressing pancreatic tumorigenesis, implicating its potential as a biomarker for early detection of pancreatic cancer and a prognostic indicator of patient outcomes.

Prospective metabolomics study identifies potential novel blood metabolites associated with pancreatic cancer risk.

Using a metabolomics approach, we systematically searched for circulating metabolite biomarkers for pancreatic cancer risk in a case-control study nested within two prospective Shanghai cohorts. Included in our study were 226 incident pancreatic cancer cases and their individually-matched controls. Untargeted mass spectrometry platforms were used to measure metabolites in blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess the associations of metabolites with pancreatic cancer risk. We identified 10 metabolites associated with pancreatic cancer, after accounting for multiple comparisons (the Benjamini-Hochberg false discovery rate <0.05). The majority of the identified metabolites were glycerophospholipids (ORs per SD increase: 0.44-2.32; p values: 7.2×10-4 to 1.0×10-6 ), six of which were associated with decreased risk and one with increased risk. Additionally, levels of coumarin (OR=1.96, p=3.7×10-6 ) and picolinic acid (OR=2.53, p=5.0×10-5 ) were positively associated with pancreatic cancer risk, while tetracosanoic acid was inversely associated with risk (OR=0.48, p=7.16×10-7 ). Four metabolites remained statistically significant after mutual adjustment. Our study provides novel evidence that the dysregulation of glycerophospholipids may play an important role in pancreatic cancer development.

Long non‑coding RNA PVT1 promotes epithelial‑mesenchymal transition via the TGF‑β/Smad pathway in pancreatic cancer cells.

Recent studies have revealed that overexpression of long non‑coding RNA (lncRNA) PVT1 is correlated with several types of cancer. However, its role in pancreatic cancer development remains to be clarified. In the present study, we found that PVT1 promoted the growth and the epithelial‑mesenchymal transition (EMT) of pancreatic cancer cells. We first determined that PVT1 was upregulated in pancreatic cancer tissues compared with adjacent normal tissues. Knockdown of PVT1 inhibited viability, adhesion, migration and invasion. Furthermore, PVT1 knockdown reduced the expression of mesenchymal markers including Snail, Slug, β‑catenin, N‑cadherin and vimentin, while it increased epithelial marker expression of E‑cadherin. Finally, knockdown of PVT1 inhibited the TGF‑β/Smad signaling, including p‑Smad2/3 and TGF‑β1 but enhanced the expression of Smad4. In contrast, overexpression of PVT1 reversed the process. These findings revealed that PVT1 acts as an oncogene in pancreatic cancer, possibly through the regulation of EMT via the TGF‑β/Smad pathway and PVT1 may serve as a potential target for diagnostics and therapeutics in pancreatic cancer.

Integrative analysis of gene expression profiles reveals specific signaling pathways associated with pancreatic duct adenocarcinoma

BackgroundPancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database.MethodsPathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1.ResultsThe KEGG signaling pathway called “pathway in cancer” may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro.ConclusionsAnalysis integrating existing microarray datasets allowed identification of the “pathway in cancer” as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer.

Upregulation of ABC transporters involved in cholesterol homeostasis may play role in pancreatic cancer development and progression

Upregulation of ABC transporters involved in cholesterol homeostasis may play role in pancreatic cancer development and progression

Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy.

Chemokine networks regulate a variety of cellular, physiological, and immune processes. These normal functions can become appropriated by cancer cells to facilitate a more hospitable niche for aberrant cells by enhancing growth, proliferation, and metastasis. This is especially true in pancreatic cancer, where chemokine signaling is a vital component in the development of the supportive tumor microenvironment and the signaling between the cancer cells and surrounding stromal cells. Although expression patterns vary among cancer types, the chemokine receptor CXCR4 has been implicated in nearly every major malignancy and plays a prominent role in pancreatic cancer development and progression. This receptor, in conjunction with its primary chemokine ligand CXCL12, promotes pancreatic cancer development, invasion, and metastasis through the management of the tumor microenvironment via complex crosstalk with other pathways. Thus, CXCR4 likely contributes to the poor prognoses observed in patients afflicted with this malignancy. Recent exploration of combination therapies with CXCR4 antagonists have demonstrated improved outcomes, and abolishing the contribution of this pathway may prove crucial to effectively treat pancreatic cancer at both the primary tumor and metastases.

Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a “passive bystander”, stroma may play a role as a “partner in crime” in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease.

KRAS, BRAF, and PIK3CA mutations, and patient prognosis in 126 pancreatic cancers: pyrosequencing technology and literature review.

The oncogenic hallmarks of pancreatic cancer (PC), such as the KRAS, BRAF, and PIK3CA mutations, have been widely investigated. However, almost all of the previous studies were limited by small sample sizes. In addition, previous data on the KRAS mutation and clinical outcomes in PC remain inconclusive. To clarify these data, we examined the mutation status of 126 PC patients and its relationship to clinical outcome. The frequencies of KRAS, BRAF, and PIK3CA mutations were determined from a non-biased database of 126 resected PCs and a high-throughput pyrosequencing assay. KRAS mutations were detected in 109 (86.5%) of the 126 cases; the most common mutation was c.34G>T (p.G12C), which was present in 80 tumors, followed by c.35G>T (p.G12V) in 52 tumors. The KRAS mutation was not associated with any clinical or pathological features (p>0.05 in all cases). In addition, the KRAS mutation was unrelated to overall survival (log rank p=0.21) and cancer-specific survival (log rank p=0.27). Importantly, the influence of KRAS mutation on patient outcome was not modified by any of the clinical or pathological variables (p for all interactions >0.05). Only one PIK3CA mutation (0.8%) was detected on exon 9 RS3 (c.1633G>A, p.E545K). The BRAF mutation was not detected in PC. KRAS mutations appear to be unrelated to clinical outcome in PC. BRAF and PIK3CA mutations were extremely rare in PC, suggesting that they play a limited role in PC development.