Restoration of miRNA‑148a in pancreatic cancer reduces invasion and metastasis by inhibiting the Wnt/β‑catenin signaling pathway via downregulating maternally expressed gene‑3

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

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2. Pathogenesis and Pathobiology in Pancreatic Cancer. -The Molecular Mechanisms of Carcinogenesis, and Invasion and Metastasis in Pancreatic Cancer-.

Nihon Naika Gakkai Zasshi ◽

10.2169/naika.101.7 ◽

2012 ◽

Vol 101 (1) ◽

pp. 7-16 ◽

Cited By ~ 2

Author(s):

Kennichi Satoh ◽

Tooru Shimosegawa

Keyword(s):

Pancreatic Cancer ◽

Molecular Mechanisms ◽

Invasion And Metastasis ◽

Mechanisms Of Carcinogenesis

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Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽

10.3390/biomedicines9070821 ◽

2021 ◽

Vol 9 (7) ◽

pp. 821

Author(s):

Wanglong Qiu ◽

Chia-Yu Kuo ◽

Yu Tian ◽

Gloria H. Su

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Critical Role ◽

Genetic Mutations ◽

Cancer Genetic ◽

Dual Roles ◽

Activin Signaling ◽

Physiological Processes ◽

Cancer Types ◽

Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

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Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner

Clinical Epigenetics ◽

10.1186/s13148-021-01016-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Hongzhen Li ◽

Chunyan Peng ◽

Chenhui Zhu ◽

Shuang Nie ◽

Xuetian Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nadph Oxidase ◽

Western Blot ◽

Cancer Progression ◽

Histone Methylation ◽

Invasion And Metastasis ◽

Independent Manner ◽

Nadph Oxidase 4

Abstract Background Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. Methods A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. Results We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. Conclusions This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

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Hypoxia-induced lncHILAR promotes renal cancer cell invasion and metastasis via ceRNA for the miR-613/206/1-1-3p/Jagged-1/Notch/CXCR4 signaling pathway

Molecular Therapy ◽

10.1016/j.ymthe.2021.05.020 ◽

2021 ◽

Author(s):

Guanghui Hu ◽

Junjie Ma ◽

Jin Zhang ◽

Yonghui Chen ◽

Huan Liu ◽

...

Keyword(s):

Signaling Pathway ◽

Cancer Cell ◽

Renal Cancer ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

Cxcr4 Signaling ◽

Renal Cancer Cell

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Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210201095613 ◽

2021 ◽

Vol 21 ◽

Author(s):

Huiming Chen ◽

Junfeng Zhao ◽

Ningning Jiang ◽

Zheng Wang ◽

Chang Liu

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Precancerous Lesions ◽

Clinical Specimen ◽

Ductal Adenocarcinoma ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

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