CXCL12–CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy

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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Gemcitabine Resistance Induced by Interaction between Alternatively Spliced Segment of Tenascin-C and Annexin A2 in Pancreatic Cancer Cells

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.33.1261 ◽

2010 ◽

Vol 33 (8) ◽

pp. 1261-1267 ◽

Cited By ~ 28

Author(s):

Xiao-Guang Gong ◽

Yun-Fu Lv ◽

Xin-Qiu Li ◽

Fu-Guo Xu ◽

Qing-Yong Ma

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Annexin A2 ◽

Tenascin C ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

Alternatively Spliced

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Silencing GS Homeobox 2 Alleviates Gemcitabine Resistance in Pancreatic Cancer Cells by Activating SHH/GLI1 Signaling Pathway

Digestive Diseases and Sciences ◽

10.1007/s10620-021-07262-1 ◽

2021 ◽

Author(s):

Lu Zhuang ◽

Yao Yao ◽

Lisi Peng ◽

Fang Cui ◽

Cui Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

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

Cell Death and Disease ◽

10.1038/cddis.2017.311 ◽

2017 ◽

Vol 8 (7) ◽

pp. e2924-e2924 ◽

Cited By ~ 23

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.

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Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells

Journal of Surgical Research ◽

10.1016/j.jss.2012.05.065 ◽

2012 ◽

Vol 178 (2) ◽

pp. 758-767 ◽

Cited By ~ 42

Author(s):

Shingo Kagawa ◽

Shigetsugu Takano ◽

Hideyuki Yoshitomi ◽

Fumio Kimura ◽

Mamoru Satoh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Mtor Signaling ◽

Annexin Ii ◽

Mtor Signaling Pathway ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

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Retraction: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgz056 ◽

2019 ◽

Vol 40 (2) ◽

pp. e16-e16

Author(s):

I-Lu Lai ◽

Chih-Chien Chou ◽

Po-Ting Lai ◽

Chun-Sheng Fang ◽

Lawrence A Shirley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

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Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0777-7 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 13

Author(s):

Guangbing Xiong ◽

Chang Liu ◽

Gang Yang ◽

Mengyu Feng ◽

Jianwei Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Noncoding Rna ◽

Poor Prognosis ◽

Reference Sequence ◽

Gemcitabine Resistance ◽

Cerna Network ◽

Pancreatic Cancer Cells

Abstract Background Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. Methods Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. Results Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. Conclusion Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

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