Ubiquitin specific peptidase 5 enhances STAT3 signaling and promotes migration and invasion in Pancreatic Cancer

Abstract Signal transducing adaptor molecule 2 (STAM2) is a phosphotyrosine protein, which regulates receptor signaling and trafficking of mammalian cells. However, its role in gastric cancer (GC) remains undiscovered. In this study, we aimed to investigate the functions of STAM2 in GC. The mRNA and protein expression levels of STAM2 were measured by quantitative real-time PCR, western blot analysis, and immunohistochemistry. STAM2 was stably silenced in AGS and HGC-27 cells using small interfering RNA. The function of STAM2 in GC cells was further investigated by CCK-8 assay, EdU incorporation assay, flow cytometry, and scratch wound healing and Boyden chamber assays. Additionally, we conducted biological pathway enrichment analysis and rescue assays to explore the effects of STAM2 on JAK/STAT signaling pathway. Our results showed that STAM2 is remarkably highly expressed in GC tissues and cells, and overexpressed STAM2 is correlated with tumor size, advanced tumor node metastasis stage, and poor prognosis. In addition, STAM2 knockdown could significantly inhibit proliferation, block cell cycle, and restrain migration and invasion capabilities of GC cells. Mechanistically, we found that STAM2 knockdown effectively decreased the expressions of MMP2 and MMP9 and the phosphorylation levels of JAK2 and STAT3. Taken together, this study revealed that STAM2 knockdown could suppress malignant process by targeting the JAK2/STAT3 signaling pathway in GC.

Download Full-text

Su1863 Tenascin C in Cancer Stroma Induces Migration and Invasion of Pancreatic Cancer Cells by Interaction With Fibronectin

Gastroenterology ◽

10.1016/s0016-5085(14)61753-4 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-488

Author(s):

Hideyuki Yoshitomi ◽

Hiroaki Shimizu ◽

Masayuki Ohtsuka ◽

Atsushi Kato ◽

Katsunori Furukawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Migration And Invasion ◽

Tenascin C ◽

Cancer Stroma ◽

Pancreatic Cancer Cells

Download Full-text

Sinapic acid inhibits pancreatic cancer proliferation, migration, and invasion via downregulation of the AKT /Gsk‐3β signal pathway

Drug Development Research ◽

10.1002/ddr.21904 ◽

2021 ◽

Author(s):

Zhiwei Huang ◽

Hao Chen ◽

Peng Tan ◽

Meizhou Huang ◽

Hao Shi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Sinapic Acid ◽

Signal Pathway ◽

Migration And Invasion ◽

Cancer Proliferation ◽

Gsk 3Β

Download Full-text

OSU-A9 inhibits pancreatic cancer cell lines by modulating p38-JAK-STAT3 signaling

Oncotarget ◽

10.18632/oncotarget.16450 ◽

2017 ◽

Vol 8 (17) ◽

pp. 29233-29246 ◽

Cited By ~ 4

Author(s):

Wan-Chi Tsai ◽

Li-Yuan Bai ◽

Yi-Jin Chen ◽

Po-Chen Chu ◽

Ya-Wen Hsu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Cancer Cell Lines ◽

Stat3 Signaling

Download Full-text

The Disruption of the β-Catenin/TCF-1/STAT3 Signaling Axis by 4-Acetylantroquinonol B Inhibits the Tumorigenesis and Cancer Stem-Cell-Like Properties of Glioblastoma Cells, In Vitro and In Vivo

Cancers ◽

10.3390/cancers10120491 ◽

2018 ◽

Vol 10 (12) ◽

pp. 491 ◽

Cited By ~ 12

Author(s):

Heng-Wei Liu ◽

Yu-Kai Su ◽

Oluwaseun Bamodu ◽

Dueng-Yuan Hueng ◽

Wei-Hwa Lee ◽

...

Keyword(s):

Poor Prognosis ◽

Migration And Invasion ◽

Rank Test ◽

Lower Grade ◽

Aberrant Expression ◽

Stat3 Signaling ◽

Log Rank Test ◽

Signaling Axis

Background: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). Experimental approach: Herein, we investigated the effect of 4-Acetylantroquinonol B (4-AAQB), a bioactive isolate of Antrodia cinnamomea, on GBM cell viability, oncogenic, and CSCs-like activities. Results: We observed that aberrant expression of catenin is characteristic of GBM, compared to other glioma types (p = 0.0001, log-rank test = 475.2), and correlates with poor prognosis of GBM patients. Lower grade glioma and glioblastoma patients (n = 1152) with low catenin expression had 25% and 21.5% better overall survival than those with high catenin expression at the 5 and 10-year time-points, respectively (p = 3.57e-11, log-rank test = 43.8). Immunohistochemistry demonstrated that compared with adjacent non-tumor brain tissue, primary and recurrent GBM exhibited enhanced catenin expression (~10-fold, p < 0.001). Western blot analysis showed that 4-AAQB significantly downregulated β-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in U87MG and DBTRG-05MG cells, dose-dependently. 4-AAQB–induced downregulation of catenin positively correlated with reduced Sox2 and Oct4 nuclear expression in the cells. Furthermore, 4-AAQB markedly reduced the viability of U87MG and DBTRG-05MG cells with 48 h IC50 of 9.2 M and 12.5 M, respectively, effectively inhibited the nuclear catenin, limited the migration and invasion of GBM cells, with concurrent downregulation of catenin, vimentin, and slug; similarly, colony and tumorsphere formation was significantly attenuated with reduced expression of c-Myc and KLF4 proteins. Conclusions: Summarily, we show for the first time that 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM in vitro, with in vivo validation; thus projecting 4-AAQB as a potent therapeutic agent for anti-GBM target therapy.

Download Full-text

Long Non-coding RNA DLEU2L Targets miR-210-3p to Suppress Gemcitabine Resistance in Pancreatic Cancer Cells via BRCA2 Regulation

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.645365 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fei Xu ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Critical Role ◽

Migration And Invasion ◽

Pancreatic Cell ◽

Clinical Issue ◽

Pancreatic Cancer Cells

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

Download Full-text

TRPM2 promotes pancreatic cancer by PKC/MAPK pathway

10.1101/2020.11.09.373035 ◽

2020 ◽

Author(s):

Rui Lin ◽

Xunxia Bao ◽

Hui Wang ◽

Sibo Zhu ◽

Zhongyan Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nude Mice ◽

Transcriptome Analysis ◽

Cell Model ◽

Mapk Pathway ◽

Tissue Sample ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Migration And Invasion ◽

Tumor Bearing

AbstractBackgroundThe mechanism of pancreatic cancer(PA) is not fully understanded. In our last report, TRPM2 plays a promising role in pancreatic cancer. However, the mechanism of TRPM2 is still unknown in this dismal disease. This study was designed to investigate the role and mechanism of TRPM2 in pancreatic cancer.MethodsTRPM2 overexpressed and siRNA plasmid were created and transfected with pancreatic cancer cell line(BxPC-3) to construct the cell model. We employed CCK-8, Transwell, scratch wound, and nude mice tumor bearing model to investigate the role of TRPM2 in pancreatic cancer. Besides, we collected the clinical data, tumor tissue sample(TT) and para-tumor sample(TP) from the pancreatic cancer patients treated in our hospital. We analyzed the mechanism of TRPM2 in pancreatic cancer by transcriptome analysis, Westernblot, and PCR.ResultsOverexpressed TRPM2 could promote pancreatic cancer in proliferation, migration, and invasion ability in no matter the cell model or nude mice tumor bearing model. TRPM2 level is highly negative correlated to the overall survival and progression-free survival time in PA patients, however, it is significantly increased in PA tissue as the tumor stage increases. The transcriptome analysis, GSEA analysis, Westernblot, and PCR results indicates TRPM2 is highly correlated with PKC/MAPK pathways.ConclusionTRPM2 could directly activate PKCα by calcium or indirectly activate PKCε and PKCδ by increased DAG in PC, which promote PC by downstream MAPK/MEK pathway activation.

Download Full-text

3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Biology ◽

10.3390/biology11010029 ◽

2021 ◽

Vol 11 (1) ◽

pp. 29

Author(s):

Chakrabhavi Dhananjaya Mohan ◽

Min Hee Yang ◽

Shobith Rangappa ◽

Arunachalam Chinnathambi ◽

Sulaiman Ali Alharbi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tyrosine Kinases ◽

Present Report ◽

Migration And Invasion ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Substantial Toxicity ◽

Transcription 3 ◽

Constitutive Phosphorylation

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

Download Full-text

Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-04201-w ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Xiao-ren Zhu ◽

Shi-qing Peng ◽

Le Wang ◽

Xiao-yu Chen ◽

Chun-xia Feng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Phosphoenolpyruvate Carboxykinase ◽

Human Pancreatic Cancer ◽

Migration And Invasion ◽

Potential Therapeutic Target ◽

Protein Levels ◽

Pancreatic Cancer Cells

AbstractPancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

Download Full-text