scholarly journals Role of integrin-linked kinase in regulating the protein stability of the MUC1-C oncoprotein in pancreatic cancer cells

Oncogenesis ◽  
2017 ◽  
Vol 6 (7) ◽  
pp. e359-e359 ◽  
Author(s):  
H-L Huang ◽  
H-Y Wu ◽  
P-C Chu ◽  
I-L Lai ◽  
P-H Huang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Stability ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Pancreatic Tumors ◽  
Alternative Mechanism ◽  
Pancreatic Cancer Cells ◽  
Integrin Linked Kinase

Abstract MUC1-C overexpression has been associated with the progression of pancreatic tumors by promoting the aggressive and metastatic phenotypes. As MUC1 is a STAT3 target gene, STAT3 plays a major role in regulating MUC1-C expression. In this study, we report an alternative mechanism by which integrin-linked kinase (ILK) post-transcriptionally modulates the expression of MUC1-C by maintaining its protein stability in pancreatic cancer cells. We found that ILK acts in concert with STAT3 to facilitate IL-6-mediated upregulation of MUC1-C; ILK depletion was equally effective as STAT3 depletion in abolishing IL-6-induced MUC1-C overexpression without disturbing the phosphorylation or cellular distribution of STAT3. Conversely, ectopic expression of constitutively active ILK increased MUC1-C expression, though this increase was not noted with kinase-dead ILK. This finding suggests the requirement of the kinase activity of ILK in regulating MUC1-C stability, which was confirmed by using the ILK kinase inhibitor T315. Furthermore, our data suggest the involvement of protein kinase C (PKC)δ in mediating the suppressive effect of ILK inhibition on MUC1-C repression. For example, co-immunoprecipitation analysis indicated that ILK depletion-mediated MUC1-C phosphorylation was accompanied by increased phosphorylation of PKCδ at the activation loop Thr-507 and increased binding of PKCδ to MUC1-C. Conversely, ILK overexpression resulted in decreased PKCδ phosphorylation. From a mechanistic perspective, the present finding, together with our recent report that ILK controls the expression of oncogenic KRAS through a regulatory loop, underscores the pivotal role of ILK in promoting pancreatic cancer progression.

scholarly journals MIB1 Upregulates IQGAP1 and Promotes Pancreatic Cancer Progression by inducing ST7 Degradation

2020 ◽  
Author(s):  
Tao Liu ◽  
Bin Zhang ◽  
xin jin ◽  
Xiang Cheng
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Western Blotting ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
The Relationship

Abstract BackgroundPancreatic cancer is a highly heterogeneous and has a poor prognosis. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient survival. Although the E3 ubiquitin ligase mind bomb 1 (MIB1) is involved in cancer cell proliferation and is often overexpressed in pancreatic cancer, the role of MIB1 in pancreatic cancer progression remains unclear.Methods The relationship of MIB1 with the clinicopathological features of pancreatic tumors was bioinformatically investigated in different datasets. The protein levels of MIB1 and ST7 were assessed by Western blotting and immunohistochemistry. The role of MIB1 and ST7 in pancreatic cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between MIB1 and ST7 was investigated by co-immunoprecipitation. The relationship between MIB1, ST7, and IQGAP1 levels was explored by Western blotting and quantitative real-time PCR.ResultsMIB1 expression was elevated in pancreatic cancer tissues, and its expression levels were associated with unfavorable prognosis. MIB1 overexpression enhanced pancreatic cancer proliferation and invasion in vitro and in vivo. We identified ST7 as a novel MIB1 target for proteasomal degradation. Further, we found that ST7 suppressed tumor growth by downregulating IQGAP1 in pancreatic cancer cells.ConclusionsThese data suggest that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation. ST7 suppresses tumor growth by downregulating IQGAP1 in pancreatic cancer cells. Therefore, the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may improve the survival of pancreatic cancer patients.

scholarly journals Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells

2017 ◽  
Vol 8 (7) ◽  
pp. e2924-e2924 ◽  
Author(s):  
Yuran Gao ◽  
Zhicheng Zhang ◽  
Kai Li ◽  
Liying Gong ◽  
Qingzhu Yang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Pancreatic Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Sense Strand ◽  
The Impact

AbstractThe acquisition of epithelial–mesenchymal transition (EMT) and/or existence of a sub-population of cancer stem-like cells (CSC) are associated with malignant behavior and chemoresistance. To identify which factor could promote EMT and CSC formation and uncover the mechanistic role of such factor is important for novel and targeted therapies. In the present study, we found that the long intergenic non-coding RNA linc-DYNC2H1-4 was upregulated in pancreatic cancer cell line BxPC-3-Gem with acquired gemcitabine resistance. Knockdown of linc-DYNC2H1-4 decreased the invasive behavior of BxPC-3-Gem cells while ectopic expression of linc-DYNC2H1-4 promoted the acquisition of EMT and stemness of the parental sensitive cells. Linc-DYNC2H1-4 upregulated ZEB1, the EMT key player, which led to upregulation and downregulation of its targets vimentin and E-cadherin respectively, as well as enhanced the expressions of CSC makers Lin28, Nanog, Sox2 and Oct4. Linc-DYNC2H1-4 is mainly located in the cytosol. Mechanically, it could sponge miR-145 that targetsZEB1,Lin28,Nanog,Sox2,Oct4to restore these EMT and CSC-associated genes expressions. We proved thatMMP3, the nearby gene of linc-DYNC2H1-4 in the sense strand, was also a target of miR-145. Downregulation ofMMP3by miR-145 was reverted by linc-DYNC2H1-4, indicating that competing with miR-145 is one of the mechanisms for linc-DYNC2H1-4 to regulateMMP3. In summary, our results explore the important role of linc-DYNC2H1-4 in the acquisition of EMT and CSC, and the impact it has on gemcitabine resistance in pancreatic cancer cells.

Curcumin Inhibits Pancreatic Cancer Progression via Down-Regulation of miR-21-5p

2020 ◽  
Vol 18 (3) ◽  
pp. 236-240
Author(s):  
Li Junjian ◽  
Xu Qigang ◽  
Tao Chonglin
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
B Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Promote Cell Proliferation ◽  
Pancreatic Cancer Cells

In this study, we investigated the role of curcumin in pancreatic cancer through the regulation of miR-21-5p. We first evaluated the expression of miR-21-5p in pancreatic cancer cells (ASPC-1) treated with different concentrations of curcumin. The results showed that curcumin effectively inhibited the expression of miR-21-5p in ASPC-1 cells in a dose-dependent manner. B cell translocation gene 2 was identified as a target gene of miR-21-5p. MiR-21-5p mimics could promote cell proliferation, migration, and invasion of ASPC-1, as well as decrease the expression of B cell translocation gene 2. Curcumin treatment inhibited cell proliferation, migration and invasion of ASPC-1, as well as increased the expression of B cell translocation gene 2. MiR-21-5p could reverse the inhibitory activities of curcumin on ASPC-1 cell proliferation, migration, and invasion. In conclusion, curcumin is capable of inhibiting the proliferation, migration and invasion of pancreatic cancer cells via down-regulating miR-21-5p-mediated B cell translocation gene 2.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

The Role of Oxygen-Derived Free Radicals and Nitric Oxide in Cytokine-Induced Antiproliferation of Pancreatic Cancer Cells

Pancreas ◽  
2002 ◽  
Vol 24 (2) ◽  
pp. 161-168 ◽  
Author(s):  
William J. Thomas ◽  
Deborah L. Thomas ◽  
Joseph A. Knezetic ◽  
Thomas E. Adrian
Keyword(s):  
Nitric Oxide ◽  
Pancreatic Cancer ◽  
Free Radicals ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Oxygen Derived Free Radicals
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