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

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

COL11A1 is the Key Target Gene of MIST1 on Tumor Progression of Pancreatic Cancer

10.21203/rs.3.rs-793040/v1 ◽

2021 ◽

Author(s):

Yang Li ◽

Zhiqiang Liu ◽

Ying Sun ◽

Dianyun Ren ◽

Yongfeng Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Progression ◽

Cancer Cells ◽

Target Gene ◽

Animal Experiments ◽

Migration And Invasion ◽

Cancer Cell Growth ◽

Pancreatic Cancer Cells

Abstract Background: MIST1, a component of BHLH transcription factors, has been documented to be an important factor in tumor progression of pancreatic cancer, but the molecular mechanism is still unknown.Methods: COL11A1 was screened as a candidate key target gene of MIST1 in pancreatic cancer by ChIP -seq assay and verified by RT-PCR and Western Blotting on MIST1-overexpression pancreatic cancer cells. ChIP and dual-luciferase assays were performed to study the binding domain of MIST1 and COL11A1. Transwell invasion, wound healing, MTT, colony formation assays and animal experiments were performed to investigate the roles of COL11A1 expression on pancreatic cancer cells. Clinical data and TCGA datasets were used to evaluate the role of COL11A1 expression on prognosis for patients with pancreatic cancer.Results: MIST1 could bind to the promoter of COL11A1 as a negative transcription factor in pancreatic cancer. Overexpression of COL11A1 promotes pancreatic cancer cell growth, migration and invasion in vitro and in vivo. Expression of COL11A1 was upregulated in pancreatic cancer and positively correlated with a worse prognosis for patients with pancreatic cancer. Conclusions: These results demonstrated COL11A1 as a carcinogen in pancreatic cancer, and it acts as the key target gene of MIST1 on tumor progression of pancreatic cancer. COL11A1 can act as a potential therapeutic target of pancreatic cancer which is superior to MIST1.

Download Full-text

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568210204916170096 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-11

Author(s):

P. Ulivi ◽

C. Arienti ◽

W. Zoli ◽

M. Scarsella ◽

S. Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Antitumor Efficacy ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

Download Full-text

Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽

10.3390/cancers13092017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2017

Author(s):

Lital Sharvit ◽

Rinat Bar-Shalom ◽

Naiel Azzam ◽

Yaniv Yechiel ◽

Solomon Wasser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Liquid ◽

Human Pancreatic Cancer ◽

P53 Signaling ◽

Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

Download Full-text

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

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

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.

Download Full-text

Non-thermal plasma-treated solution demonstrates antitumor activity against pancreatic cancer cells in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-017-08560-3 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 53

Author(s):

Kim Rouven Liedtke ◽

Sander Bekeschus ◽

André Kaeding ◽

Christine Hackbarth ◽

Jens-Peter Kuehn ◽

...

Keyword(s):

Pancreatic Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Thermal Plasma ◽

Pancreatic Cancer Cells ◽

Non Thermal Plasma

Download Full-text

Nordihydroguaiaretic acid inhibits growth and induces apoptosis in human pancreatic cancer cells in vitro and in vivo

Gastroenterology ◽

10.1016/s0016-5085(00)84291-2 ◽

2000 ◽

Vol 118 (4) ◽

pp. A540

Author(s):

Thomas Seufferlein ◽

Michael J. Seckl ◽

Michael Beil ◽

Hardi Luhrs ◽

Roland M. Schmid ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Nordihydroguaiaretic Acid ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

Download Full-text

m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.696371 ◽

2021 ◽

Vol 11 ◽

Author(s):

Congjun Zhang ◽

Shuangyan Ou ◽

Yuan Zhou ◽

Pei Liu ◽

Peiying Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Western Blotting ◽

Protein Level ◽

Cytidine Deaminase ◽

Critical Role ◽

Human Pancreatic Cancer ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

ObjectivePancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N6-methyladenosine (m6A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive.MethodsThe mRNA and protein level of m6A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine‐resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance.ResultsWe found that gemcitabine treatment significantly increased the expression of m6A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model.ConclusionOur study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

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