circ-LDLRAD3 regulates cell proliferation, migration and invasion of pancreatic cancer by miR-876-3p/STAT3

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer

Frontiers in Medicine ◽

10.3389/fmed.2020.572494 ◽

2020 ◽

Vol 7 ◽

Author(s):

Yong Zeng ◽

Min Zou ◽

Yan Liu ◽

Keting Que ◽

Yunbing Wang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Cell Cycle Progression ◽

Pancreatic Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Cancer Cell Proliferation ◽

Cycle Progression ◽

Mesenchymal Transition

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.

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LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

Cellular Physiology and Biochemistry ◽

10.1159/000490167 ◽

2018 ◽

Vol 47 (3) ◽

pp. 1007-1024 ◽

Cited By ~ 6

Author(s):

Yi-Gang Qian ◽

Zhou Ye ◽

Hai-Yong Chen ◽

Zhen Lv ◽

Ai-Bin Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathway ◽

Microarray Data ◽

Cell Apoptosis ◽

Migration And Invasion ◽

Protein Levels ◽

Pancreatic Cancer Cells ◽

Significant Difference

Background/Aims: Pancreatic cancer is an aggressive malignancy as a result of highly metastatic potential. The current study was carried out to alter the expression of LINC01121 in pancreatic cancer, with the aim of elucidating its effects on the biological processes of cell proliferation, migration, invasion, and apoptosis. We hypothesized that both the GLP1R gene and cAMP/PKA signaling pathway participate in the aforementioned process. Methods: Microarray data (GSE14245, GSE27890 and GSE16515) and annotating probe files linked to pancreatic cancer were downloaded through the GEO database. The Multi Experiment Matrix (MEM) site was used to predict the target gene of lncRNA. Both pancreatic cancer tissues (n = 56) and paracancerous tissues (n = 45) were collected from patients diagnosed with pancreatic cancer. Immunohistochemistry was applied to identify the positive expression rate of GLP1R protein. Isolated pancreatic cancer cells and PANC-1 cells were independently classified into the blank, negative control (NC), LINC01121 vector, siRNA-LINC01121, siRNA-GLP1R and siRNA-LINC01121 + siRNA-GLP1R groups. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect the expressions of LINC01121, GLP1R, cAMP, PKA, CREB, Bcl-2, Bad and PCNA. Cell proliferation, migration, invasion, cycle progression, and apoptosis were examined by MTT assay, scratch test, Transwell assay and flow cytometry analyses of Annexin V-FITC/PI staining. Results: Observations were made indicating that LINC01121 was highly expressed, while low expressions of GLP1R in pancreatic cancer were detected based on microarray data, which was largely in consistent with the data collected of LINC01121 and GLP1R within the tissues. The target prediction program and luciferase activity analysis was testament to the notion suggesting that GLP1R was indeed a target of LINC01121. In contrast to the blank and NC groups, the LINC01121 vector group exhibited increased expressions of LINC01121; decreased mRNA and protein levels of GLP1R, Bad, cAMP, and PKA; increased protein levels of CREB, Bcl-2, PCNA, p-PKA and p-CREB; increased cell proliferation, migration and invasion; and decreased cell apoptosis. There was no significant difference detected among the blank, NC, and siRNA-LINC01121 + siRNA-GLP1R groups, except that decreased LINC01121 expression was determined in the siRNA-LINC01121 + siRNA-GLP1R group. Parallel data were observed in the pancreatic cancer cells and PANC-1 cells. Conclusion: The current study presents evidence indicating that LINC01121 might inhibit apoptosis while acting to promote proliferation, migration, and invasion of pancreatic cancer cells, supplementing the stance held that LINC01121 functions as a tumor promoter by means of its involvement in the process of translational repression of the GLP1R and inhibition of the cAMP/PKA signaling pathway.

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Broussoflavonol B from Broussonetia kazinoki Siebold Exerts Anti-Pancreatic Cancer Activity through Downregulating FoxM1

Molecules ◽

10.3390/molecules25102328 ◽

2020 ◽

Vol 25 (10) ◽

pp. 2328

Author(s):

Ji Hye Jeong ◽

Jae-Ha Ryu

Keyword(s):

Cell Cycle ◽

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Cellular Proliferation ◽

Cyclin B1 ◽

Human Pancreatic Cancer ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Cancer Activity

Pancreatic cancer has a high mortality rate due to poor rates of early diagnosis. One tumor suppressor gene in particular, p53, is frequently mutated in pancreatic cancer, and mutations in p53 can inactivate normal wild type p53 activity and increase expression of transcription factor forkhead box M1 (FoxM1). Overexpression of FoxM1 accelerates cellular proliferation and cancer progression. Therefore, inhibition of FoxM1 represents a therapeutic strategy for treating pancreatic cancer. Broussoflavonol B (BF-B), isolated from the stem bark of Broussonetia kazinoki Siebold has previously been shown to inhibit the growth of breast cancer cells. This study aimed to investigate whether BF-B exhibits anti-pancreatic cancer activity and if so, identify the underlying mechanism. BF-B reduced cell proliferation, induced cell cycle arrest, and inhibited cell migration and invasion of human pancreatic cancer PANC-1 cells (p53 mutated). Interestingly, BF-B down-regulated FoxM1 expression at both the mRNA and protein level. It also suppressed the expression of FoxM1 downstream target genes, such as cyclin D1, cyclin B1, and survivin. Cell cycle analysis showed that BF-B induced the arrest of G0/G1 phase. BF-B reduced the phosphorylation of extracellular signal-regulated kinase ½ (ERK½) and expression of ERK½ downstream effector c-Myc, which regulates cell proliferation. Furthermore, BF-B inhibited cell migration and invasion, which are downstream functional properties of FoxM1. These results suggested that BF-B could repress pancreatic cancer cell proliferation by inactivation of the ERK/c-Myc/FoxM1 signaling pathway. Broussoflavonol B from Broussonetia kazinoki Siebold may represent a novel chemo-therapeutic agent for pancreatic cancer.

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Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1388-4 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 10

Author(s):

Shan Lei ◽

Zhiwei He ◽

Tengxiang Chen ◽

Xingjun Guo ◽

Zhirui Zeng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Migration And Invasion ◽

Potential Biomarker

Abstract Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

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Estrogen-Related Receptor-α Promotes Pancreatic Cancer Progression by Enhancing the Transcription of PAI1 and Activating the MEK/ERK Signaling Pathway

10.21203/rs.3.rs-33052/v1 ◽

2020 ◽

Author(s):

Shi-lei Liu ◽

Xiang-song Wu ◽

Feng-nan Li ◽

Wen-yan Yao ◽

Zi-you Wu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Rna Sequencing ◽

Chromatin Immunoprecipitation ◽

Erk Signaling ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Erk Pathway ◽

Reporter Assays ◽

Estrogen Related Receptor

Abstract Background: Estrogen-related receptor alpha (ERRα), an orphan nuclear receptor, was reported to be highly associated with the progression and tumorigenesis of several human malignancies. However, the biological role and underlying molecular mechanisms of ERRα in pancreatic cancer (PC) remain unknown.Methods: The expression of ERRα in PC tissues was determined by qRT-PCR and immunohistochemistry. A series of in vitro and in vivo assays were performed to investigate the function of ERRα and Plasminogen activator inhibitor 1 (PAI1) in tumorigenesis in PC cells. The relationship between ERRα and PAI1 was identified by RNA sequencing, Chromatin immunoprecipitation and dual-luciferase reporter assays. The effects of ERRα on the MEK/ERK signaling pathway were determined by western blotting and rescue assays using ERK inhibitor GDC-0994.Results: ERRα was significantly overexpressed in PC tissues and cell lines. Its high expression was correlated with tumor size, distant metastasis, TNM stage, tumor differentiation and poor prognosis of PC. Subsequent functional assays showed that ERRα promoted PC cell proliferation, tumor growth, as well as migration and invasion via activating the epithelial-mesenchymal transition. In addition, knockdown of ERRα induced apoptosis and G0/G1 cell cycle arrest in PC cells. PAI1 was identified by RNA sequencing, knockdown of which could suppress the cell proliferation, migration and invasion that promoted by ERRα overexpression. Further mechanistic investigation using chromatin immunoprecipitation and dual-luciferase reporter assays revealed that ERRα could bind to the PAI1 promoter region and transcriptionally enhance PAI1 expression. Moreover, our data indicated that ERRα played its oncogenic role in PC via activating the MEK/ERK pathway.Conclusions: Our study demonstrates that ERRα promotes PC progression by enhancing the transcription of PAI1 and activation of the MEK/ERK pathway, pointing to ERRα as a novel diagnostic and therapeutic target for PC.

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CircRNA_000864 Upregulates B-cell Translocation Gene 2 Expression and Represses Migration and Invasion in Pancreatic Cancer Cells by Binding to miR-361-3p

Frontiers in Oncology ◽

10.3389/fonc.2020.547942 ◽

2020 ◽

Vol 10 ◽

Author(s):

Linsheng Huang ◽

Junxiang Han ◽

Huifan Yu ◽

Jialing Liu ◽

Lili Gui ◽

...

Keyword(s):

Cell Cycle ◽

Pancreatic Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Expression Patterns ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Pancreatic Cancer Cells ◽

Gene Assay ◽

Cancer Tissues

BackgroundPancreatic cancer is a fatal disease with a very poor prognosis due to its characteristic insidious symptoms, early metastasis, and chemoresistance. Circular RNAs (circRNAs) are involved in the development of pancreatic cancer.AimHence, the aim of this study is to elucidate the mechanism of circRNA_000864 in regulating BTG2 expression in pancreatic cancer by binding to miR-361-3p.MethodsCircRNA_000864, miR-361-3p, and BTG2 expression patterns in the pancreatic cancer tissues were detected by RT-qPCR. Correlation among circRNA_000864, miR-361-3p, and BTG2 was evaluated by RNA-pull down assay, RNA Immunoprecipitation assay, and dual-luciferase reporter gene assay. After ectopic expression and depletion experiments, 5-ethynyl-2′-deoxyuridine assay, Transwell assay, and flow cytometry were employed to assess the cell proliferation, migration and invasion, cell cycle, and apoptosis. Xenotransplantation of nude mice was conducted to detect the effects of circRNA_000864, miR-361-3p, and BTG2 on tumor growth.ResultsCircRNA_000864 and BTG2 were poorly expressed, and miR-361-3p was highly expressed in the pancreatic cancer tissues. CircRNA_000864 bound to miR-361-3p could target BTG2. Cell proliferation, migration, and invasion were inhibited, and the cell cycle arrest and apoptosis were stimulated after overexpression of circRNA_000864 or BTG2 or downregulation of miR-361-3p. Overexpression of circRNA_000864 or downregulation of miR-361-3p also decreased the tumor growth in vivo.ConclusionsConjointly, our findings elicited that the overexpression of circRNA_000864 could promote BTG2 expression to inhibit pancreatic cancer development by binding to miR-361-3p, which represents an appealing therapeutic target for the treatment of pancreatic cancer.

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