scholarly journals The Vacuolar H+ ATPase α3 Subunit Negatively Regulates Migration and Invasion of Human Pancreatic Ductal Adenocarcinoma Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 465 ◽  
Author(s):  
Mette Flinck ◽  
Sofie Hagelund ◽  
Andrej Gorbatenko ◽  
Marc Severin ◽  
Elena Pedraz-Cuesta ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Detectable Effect ◽  
Autophagic Flux ◽  
Ph Homeostasis ◽  
Protein Levels ◽  
A Subunit ◽  
Α3 Subunit ◽  
Acid Extrusion

Increased metabolic acid production and upregulation of net acid extrusion render pH homeostasis profoundly dysregulated in many cancers. Plasma membrane activity of vacuolar H+ ATPases (V-ATPases) has been implicated in acid extrusion and invasiveness of some cancers, yet often on the basis of unspecific inhibitors. Serving as a membrane anchor directing V-ATPase localization, the a subunit of the V0 domain of the V-ATPase (ATP6V0a1-4) is particularly interesting in this regard. Here, we map the regulation and roles of ATP6V0a3 in migration, invasion, and growth in pancreatic ductal adenocarcinoma (PDAC) cells. a3 mRNA and protein levels were upregulated in PDAC cell lines compared to non-cancer pancreatic epithelial cells. Under control conditions, a3 localization was mainly endo-/lysosomal, and its knockdown had no detectable effect on pHi regulation after acid loading. V-ATPase inhibition, but not a3 knockdown, increased HIF-1α expression and decreased proliferation and autophagic flux under both starved and non-starved conditions, and spheroid growth of PDAC cells was also unaffected by a3 knockdown. Strikingly, a3 knockdown increased migration and transwell invasion of Panc-1 and BxPC-3 PDAC cells, and increased gelatin degradation in BxPC-3 cells yet decreased it in Panc-1 cells. We conclude that in these PDAC cells, a3 is upregulated and negatively regulates migration and invasion, likely in part via effects on extracellular matrix degradation.

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

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.

scholarly journals Modulation of FoxO1 Expression by miR-21 to Promote Growth of Pancreatic Ductal Adenocarcinoma

2015 ◽  
Vol 35 (1) ◽  
pp. 184-190 ◽  
Author(s):  
Weifeng Song ◽  
Qi Li ◽  
Lei Wang ◽  
Liwei Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Underlying Mechanism ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Primary Tumors ◽  
Protein Levels ◽  
Infusion System

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.

scholarly journals Low Serum miR-607 Level as a Potential Diagnostic and Prognostic Biomarker in Patients of Pancreatic Ductal Adenocarcinoma: A Preliminary Study

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dawei Jiang ◽  
Xiangfei Yuan ◽  
Jianqi Ni ◽  
Lan Shen ◽  
Min Cai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Prognostic Biomarker ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Roc Curve Analysis ◽  
Mesenchymal Transition ◽  
Low Serum ◽  
Better Than

Background. One of the microRNAs (miRNAs) known to be associated with cancer development is miR-607. The aim of this study is to investigate the clinical significance and diagnostic and prognostic value of miR-607 and to explore its potential role in pancreatic ductal adenocarcinoma (PDAC). Methods. The expression levels of miR-607 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miR-607 expression and clinical characteristics was analyzed by the Chi-square test. Overall survival (OS) and progression-free survival (PFS) were evaluated via the Kaplan–Meier method, and the association between miR-607 expression and OS was investigated by the Cox proportional hazard analysis. The diagnostic value was estimated via receiver operating characteristic (ROC) curve analysis. The effect of miR-607 overexpression on cell migration, invasion, and epithelial-mesenchymal transition (EMT) was determined by wound-healing, Transwell invasion, and Western blotting assays. Results. miR-607 levels were downregulated in PDAC tumor tissues compared with normal tissues. Also, low miR-607 levels were observed in serum samples from PDAC patients than that in healthy controls. The miR-607 level was found to be closely correlated with lymphatic metastasis and liver metastasis, perineural invasion, and OS and PFS, and the low miR-607 level was an independent prognostic factor for the poor OS of PDAC patients. Furthermore, the area under the curve (AUC) of serum miR-607 for discriminating PDAC patients was 0.785 with a sensitivity of 0.647 and a specificity of 0.772, which was better than those for CA19-9 (AUC: 0.702, sensitivity: 0.607, specificity: 0.736) and CEA (AUC: 0.648, sensitivity: 0.542, specificity: 0.670). The AUC (0.863), sensitivity (0.766), and specificity (0.831) of their combination in the diagnosis of PDAC were better than those for alone. Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability. Conclusions. Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients.

scholarly journals Robo2 Predicts a Better Prognosis and Inhibits Malignant Behavior in Vivo in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Cheng Ding ◽  
Yatong Li ◽  
Shunda Wang ◽  
Cheng Xing ◽  
Lixin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Pdac Cell ◽  
Pancreatic Cell

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with an extremely poor prognosis and a high mortality rate. Genome-wide studies have shown that the SLIT/ROBO signaling pathway plays an important role in pancreatic tumor development and progression. However, the effect and mechanism of ROBO2 in the progression of pancreatic cancer remains largely unknown.MethodsIn this study, real-time polymerase chain reaction (RT-PCR) and western blot analyses were adopted to evaluate the expression level of ROBO2 and proteins in pancreatic cell lines. Cell migration and invasion and cell proliferation were conducted in AsPC-1 and MIA PaCa-2 cell lines. RNA sequencing and western blot were undertaken to explore the mechanisms and potential targeted molecules. ROBO2 expression in tumor tissues was evaluated by immunohistochemistry in 95 patients.ResultsROBO2 expression was downregulated in PDAC cell lines and tissue samples. A high level of ROBO2 was associated with good overall survival. Upregulation of ROBO2 inhibited PDAC cell proliferation, migration, and invasion, whereas the opposite results were found in the ROBO2 downregulation group. In addition, xenograft animal models further confirmed the effect of ROBO2 on proliferation. Finally, the RNA sequencing results indicated that ROBO2 facilitates anti-tumorigenicity partly via inhibiting ECM1 in PDAC. ConclusionsOur work suggests that ROBO2 inhibits tumor progression in PDAC and may serve as a predictive biomarker and therapeutic target in PDAC.

scholarly journals mir-218 modulates ARF6 expression and inhibits pancreatic ductal adenocarcinoma invasion

2020 ◽  
Author(s):  
Brenna A. Rheinheimer ◽  
Ronald L Heimark
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Target Genes ◽  
Target Prediction ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Matrix Degradation ◽  
Cancer Migration ◽  
Pancreatic Cancer Cells

AbstractBackgroundPancreatic ductal adenocarcinoma is an extremely malignant disease with the majority of patients having metastatic disease upon diagnosis. Recently, it was shown the SLIT2 plays a regulatory role in melanoma invasion through the control of invadopodia. Therefore, we sought to determine the mechanism behind miR-218 inhibition of pancreatic cancer invasion.Methodsmir-218 target genes were discovered using three miRNA target prediction websites. Modulation of mir-218 target ARF6 was determined by transfection with antagomirs and mimics to mir-218. Pancreatic cancer migration and invasion were measured using Boyden chamber assays. Invasion was further measured using matrix degradation assays.ResultsWe found that mir-218 modulates ARF6 RNA and protein expression in pancreatic cancer. mir-218 did not inhibit pancreatic cancer cell migration, but did inhibit invasion. mir-218 did not affect the formation of invadopodia in pancreatic cancer cells, but did inhibit the total area of matrix degradation caused by functional invadopodia.ConclusionsThis work suggests that miR-218 is a suppressor of pancreatic ductal adenocarcinoma invasion through a pathway that regulates invadopodia maturation.

scholarly journals Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 50 (3) ◽  
pp. 823-840 ◽  
Author(s):  
Dan-ming Wei ◽  
Yi-wu Dang ◽  
Zhen-bo Feng ◽  
Lu Liang ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Chorioallantoic Membrane ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Chick Chorioallantoic Membrane ◽  
Pancreatic Cancer Cells

Background/Aims: Accumulating evidence strongly suggests that microRNAs (miRNAs) modulate the expression of known tumor suppressor genes and oncogenes. In the present study, we found that the proliferation and invasion ability of pancreatic ductal adenocarcinoma (PDAC) cells were significantly suppressed by the overexpression of miR-23b-3p. In addition, there are miR-23b-3p binding sites in annexin A2 (ANXA2). Here, we investigated whether miR-23b-3p had an impact on the progression and metastasis of PDAC by targeting ANXA2. Methods: Cell proliferation, migration, and invasion, and cell cycle assays were performed to explore the effect of miR-23b-3p on various malignant phenotypes of pancreatic cancer cells. The size of tumors was observed following miR-23b-3p overexpression in an in vivo chick chorioallantoic membrane assay. Dual-luciferase reporter, quantitative real-time PCR, western blot, and immunohistochemical analyses were used to validate the relationship between miR-23b-3p and ANXA2 in vitro. Results: We observed that miR-23b-3p could bind specifically to the 3′ untranslated region of ANXA2 and inhibit its expression. MiR-23b-3p overexpression downregulated the expression of ANXA2 mRNA in PDAC cells and limited the size of tumors or even prevented tumor formation. In addition, there was a negative correlation between miR-23b-3p expression and ANXA2 protein expression in clinical specimens. Conclusion: MiR-23b-3p inhibits the development and progression of PDAC by regulating ANXA2 directly.

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