• BMB Reports
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• v.53 no.12
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• pp.658-663
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• 2020

The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2719-2724
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• 2015

Objective: The aim of this study was to investigate the clinical significance of annexin a1 (ANXA1) and provide molecular evidence to support that decreased ANXA1 expression could enhance cancer migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Immunohistochemistry of a tissue microarray with 162 surgically resected PDAC specimens was performed to examine the expression of ANXA1. We also investigated the relationship between ANXA1 expression and clinicopathological factors and prognosis of PDAC patients. We further studied the role of ANXA1 in PDAC cell proliferation, migration and invasion by cell proliferation assay, migration assay and matrigel invasion assay with reduced ANXA1 expression by RNAi. Western blotting was used to detect matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. We also detected MMP-9 enzyme activity by gelatin zymography. Results: Decreased expression of ANXA1 was significantly associated with poor differentiation, lymph node metastasis and advanced TNM stage of PDAC patients (p<0.05). Moreover, decreased expression of ANXA1 was correlated with poor survival (p<0.05). Furthermore, we found that ANXA1 knockdown inhibited cell proliferation, induced G1 phase cell cycle arrest, increased PDAC cell migration and invasion capacity compared with controls. In addition, Western blotting showed that ANXA1 knockdown increased the MMP-9 protein level and decreased TIMP-1 expression. Gelatin zymography showed that MMP-9 enzyme activity was also elevated. Conclusions: Negative ANXA1 expression is a most unfavorable prognostic factor for PDAC patients. ANXA1 knockdown inhibits cell proliferation by inducing G1 phase cell cycle arrest and increases migration and invasion of PDAC cells through up-regulating MMP-9 expression and activity, implying that ANXA1 may serve as a promising prognostic biomarker and therapeutic target for PDAC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.2971-2977
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• 2014

Background: Long non-coding RNAs (lncRNAs) have been recently observed in various human cancers. However, the role of lncRNAs in pancreatic duct adenocarcinoma (PDAC) remains unclarified. The aim of this study was to detect the expression of lncRNA MALAT1 in PDAC formalin-fixed, paraffin embedded (FFPE) tissues and to investigate the clinical significance of the MALAT1 level. Methods: The expression of MALAT1 was examined in 45 PDAC and 25 adjacent non-cancerous FFPE tissues, as well as in five PDAC cell lines and a normal pancreatic epithelium cell line HPDE6c-7, using qRT-PCR. The relationship between MALAT1 level and clinicopathological parameters of PDAC was analyzed with the Kaplan-Meier method and Cox proportional hazards model. Results: The relative level of MALAT1 was significantly higher in PDAC compared to the adjacent normal pancreatic tissues (p=0.009). When comparing the MALAT1 level in the cultured cell lines, remarkably higher expression of MALAT1 was found in aspc-1 PDAC cells compared with the immortal pancreatic duct epithelial cell line HPDE6c-7 (q=7.573, p<0.05). Furthermore, MALAT1 expression level showed significant correlation with tumor size (r=0.35, p=0.018), tumor stage (r=0.439, p=0.003) and depth of invasion (r=0.334, p=0.025). Kaplan-Meier analysis revealed that patients with higher MALAT1 expression had a poorer disease free survival (p=0.043). Additionally, multivariate analysis indicated that overexpression of MALAT1, as well as the tumor location and nerve invasion, was an independent predictor of disease-specific survival of PDAC. Conclusion: MALAT1 might be considered as a potential prognostic indicator and may be a target for diagnosis and gene therapy for PDAC.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2561-2567
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• 2015

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death worldwide. Our study aimed to reveal molecular mechanisms. Microarray data of GSE15471 (including 39 matching pairs of pancreatic tumor tissues and patient-matched normal tissues) was downloaded from Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in PDAC tissues compared with normal tissues by limma package in R language. Then GO and KEGG pathway enrichment analyses were conducted with online DAVID. In addition, principal component analysis was performed and a protein-protein interaction network was constructed to study relationships between the DEGs through database STRING. A total of 532 DEGs were identified in the 38 PDAC tissues compared with 33 normal tissues. The results of principal component analysis of the top 20 DEGs could differentiate the PDAC tissues from normal tissues directly. In the PPI network, 8 of the 20 DEGs were all key genes of the collagen family. Additionally, FN1 (fibronectin 1) was also a hub node in the network. The genes of the collagen family as well as FN1 were significantly enriched in complement and coagulation cascades, ECM-receptor interaction and focal adhesion pathways. Our results suggest that genes of collagen family and FN1 may play an important role in PDAC progression. Meanwhile, these DEGs and enriched pathways, such as complement and coagulation cascades, ECM-receptor interaction and focal adhesion may be important molecular mechanisms involved in the development and progression of PDAC.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.281-290
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• 2024

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4707-4712
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• 2012

Annexin A1 is a 37-kDa calcium- and phospholipid-binding protein of the annexin superfamily considered to play an important role in tumorigenesis. However, associations with clinicopathological features in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be fully defined. We therefore investigated the prognostic value of annexin A1 protein as a PDAC biomarker in 83 tumor and matched non-cancerous tissues or normal pancreas tissues. Expression was analyzed using real-time RT-PCR, Western blotting and immunohistochemistry. In non-tumor tissue, myoepithelial cells showed no or weak expression of annexin A1 while expression was strong and sometimes even located in the nuclei of endothelial cells in tumor tissue. High expression was significantly associated with advanced stage (P <0.05) and a worse overall survival (P <0.05). These results provide new insights to better understand the role of annexin A1 in PDAC survival, and might be relevant to prediction of prognosis and development of more effective therapeutic strategies aimed at improving survival.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9921-9926
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• 2014

To investigate the value of expression of annexin A2, microvessel density (MVD) and CD105 in pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent normal tissues, immunohistochemical staining was used. The positive expression rate of Annexin A2 and the MVD in pancreatic ductal adenocarcinoma tissues was higher than that in in adjacent normal tissues (p<0.005). Expression of Annexin A2 and MVD correlated with histological grade (p<0.05). MVD of cancers in TNM stage IIb was higher than that in TNM stageI~IIa (p<0.026). Cancerous tissues with Annexin A2 staining grade 3+ had lower MVD than the tissues with the other Annexin A2 staining grade (p<0.05). Patients with high MVD had worse prognosis. However, our study did not confirm Annexin A2 was an independent risk factor for patients with PDAC. We confirmed MVD labeled by CD105 was an independent risk factor for patients with PDAC and had moderate predictive value of prognosis.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.2
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• pp.661-666
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• 2015

Background: Postoperative carbohydrate antigen 19-9 (CA19-9) is an independent predictor of survival for pancreatic ductal adenocarcinoma (PDAC), and more powerful than preoperative CA19-9. However, making decisions just dependent on postoperative CA19-9 may result in necessary treatments not being performed. Materials and Methods: A total of 178 patients with resected PDAC were eligible for this retrospective study, classified into two corresponding subgroups according to postoperative CA19-9. Prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses. Results: Postoperative CA19-9, preoperative CA125 and lymph node status were independent predictors. Better predictive performances for overall survival (OS) and recurrence-free survival (RFS) were achieved by postoperative CA19-9 compared to preoperative CA125 and lymph node status. Particularly, preoperative CA125 was associated with poor OS (p<0.001 for the normalized CA19-9 patients, p=0.012 for the elevated) and RFS (p=0.005 for the normalized, p=0.004 for the elevated). Moreover, preoperative CA125 levels related with survival in double-negative patients. Conclusions: Normalization of CA19-9 is not tantamount to be cured. Preoperative CA125 is a critical predictor for PDAC patients, especially in double-negative patients.

• Journal of Digestive Cancer Reports
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• v.9 no.1
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• pp.8-18
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• 2021

Although many guidelines for pancreatic cystic neoplasms focus on the management of intraductal papillary mucinous neoplasm of the pancreas (IPMN) at the highest oncological risk, there are many issues that surgeons need to consider at the time to plan the surgical procedures based on characteristics of IPMN subtypes, such as multiplicity of branch duct-IPMN (BD-IPMN) and intraductal spreading of main duct-IPMN (MD-IPMN). For multifocal BD-IPMN, partial pancreatectomy would be selected to remove BD-IPMN with predictors of malignancy, while the other lesions without risk factors can be left, although total pancreatectomy might be considered if the patients have a strong family history of pancreatic cancer. Partial pancreatectomy would be also adequate procedure for MD-IPMN if negative surgical margin for high-grade dysplasia or invasive carcinoma were achieved. It has become to be well-known that patients with BD-IPMN are at increased risk for developing not only IPMN-associated pancreatic ductal adenocarcinoma (PDAC) but also PDAC independent from the IPMN. Hence, the detection of a concomitant PDAC is also an important focus for strategies after resection of BD-IPMNs. Our recent analysis of patients after partial pancreatectomy for MD-IPMN with negative surgical margin identified an unexpected recurrence pattern, which we called "monoclonal skip" recurrence. MD-IPMN seems to be disseminated in the pancreatic ductal systems and MD-IPMN with identical genetic background was detected in the remnant pancreas even in a long time after index surgery. We proposed strategies of postoperative surveillance based on characteristics and natural history of each morphological subtype.

• Journal of Digestive Cancer Research
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• v.5 no.2
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• pp.91-96
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• 2017

Background: To evaluate whether DM affects the SUVmax of metastatic lesions on ¹⁸F-FDG PET/CT and whether the SUVmax can influence the prognosis of metastatic PDAC patients. Methods: We conducted a retrospective study of 86 patients with metastatic PDAC who underwent PET/CT before treatment. The SUVmax of primary and metastatic lesions and the ratios of the SUVmax were measured. Long-term survival was evaluated using clinical parameters. Results: The mean SUVmax of primary lesion was lower in the DM group than in the non-DM group (4.74 vs. 5.96, p=0.009). The SUVmax for all metastatic lesions, except those in the lung, were lower in the DM group than in the non-DM group, and these differences were statistically significant in the lymph nodes and peritoneum. In the 35 patients with hepatic metastasis, higher ratios of the liver SUVmax significantly correlated with shorter OS (HR, 2.625; p=0.013). Conclusion: DM can influence the lower SUVmax of metastatic lesions as well as primary lesions. The SUVmax ratio of hepatic metastasis could influence on prognosis in metastatic PDAC patients.