Critical role of hnRNP A1 in activating KRAS transcription in pancreatic cancer cells: A molecular mechanism involving G4 DNA

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.

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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.

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

Pancreas ◽

10.1097/00006676-200203000-00007 ◽

2002 ◽

Vol 24 (2) ◽

pp. 161-168 ◽

Cited By ~ 11

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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The Ratio of Pancreatic Stellate Cells to Pancreatic Cancer Cells Plays a Critical Role in Modulating Carcinoma Cell Behaviour

Gastroenterology ◽

10.1016/s0016-5085(11)62960-0 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-713

Author(s):

Raghu Kadaba ◽

Fieke Froeling ◽

Erdinc Soylu ◽

Satyajit Bhattacharya ◽

Ian Hart ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Carcinoma Cell ◽

Critical Role ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Cell Behaviour ◽

Pancreatic Cancer Cells

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Role of KGF in regulating biological behavior of pancreatic cancer cells

World Chinese Journal of Digestology ◽

10.11569/wcjd.v21.i20.1961 ◽

2013 ◽

Vol 21 (20) ◽

pp. 1961

Author(s):

Yi-Feng Jin

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Biological Behavior ◽

Pancreatic Cancer Cells

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Abstract 4166: Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells

10.1158/1538-7445.am2017-4166 ◽

2017 ◽

Author(s):

Chen Chen ◽

Shujie Zhao ◽

Xiangru Zhao ◽

James W. Freeman

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Adaptive Plasticity ◽

Pancreatic Cancer Cells

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Differential Dependency of Human Pancreatic Cancer Cells on Targeting PTEN via PLK 1 Expression

Cancers ◽

10.3390/cancers12020277 ◽

2020 ◽

Vol 12 (2) ◽

pp. 277

Author(s):

Jungwhoi Lee ◽

Jungsul Lee ◽

Woogwang Sim ◽

Jae-Hoon Kim

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Intracellular Signaling ◽

Biomarker Discovery ◽

Human Pancreatic Cancer ◽

Normal Tissues ◽

Pancreatic Cancer Cells ◽

Prognostic Implications ◽

Plk1 Expression

Even though the tumour suppressive role of PTEN is well-known, its prognostic implications are ambiguous. The objective of this study was to further explore the function of PTEN expression in human pancreatic cancer. The expression of PTEN has been dominant in various human cancers including pancreatic cancer when compared with their matched normal tissues. The pancreatic cancer cells have been divided into PTEN blockade-susceptible and PTEN blockade-impassible groups dependent on targeting PTEN by altering intracellular signaling. The expression of PTEN has led to varying clinical outcomes of pancreatic cancer based on GEO Series (GSE) data analysis and Liptak’s z analysis. Differential dependency to PTEN blockade has been ascertained based on the expression of polo-like kinase1 PLK1 in pancreatic cancer cells. The prognostic value of PTEN also depends on PLK1 expression in pancreatic cancer. Collectively, the present study provides a rationale for targeting PTEN as a promising therapeutic strategy dependent on PLK1 expressions using a companion biomarker discovery platform.

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