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ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells

Liu, Mingyang ; Zhang, Yuqing ; Yang, Jingxuan ; Cui, Xiaobo ; Zhou, Zhijun ; Zhan, Hanxiang ; Ding, Kai ; Tian, Xiang ; Yang, Zhibo ; Fung, Kar-Ming A. ; Edil, Barish H. ; Postier, Russell G. ; Bronze, Michael S. ; Fernandez-Zapico, Martin E. ; Stemmler, Marc P. ; Brabletz, Thomas ; Li, Yi-Ping ; Houchen, Courtney W. ; Li, Min

Gastroenterology (New York, N.Y. 1943), 2020-02, Vol.158 (3), p.679-692.e1 [Periódico revisado por pares]

United States: Elsevier Inc

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ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells
Autor: Liu, Mingyang ; Zhang, Yuqing ; Yang, Jingxuan ; Cui, Xiaobo ; Zhou, Zhijun ; Zhan, Hanxiang ; Ding, Kai ; Tian, Xiang ; Yang, Zhibo ; Fung, Kar-Ming A. ; Edil, Barish H. ; Postier, Russell G. ; Bronze, Michael S. ; Fernandez-Zapico, Martin E. ; Stemmler, Marc P. ; Brabletz, Thomas ; Li, Yi-Ping ; Houchen, Courtney W. ; Li, Min
Assuntos: Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenocarcinoma - secondary ; Adenocarcinoma - therapy ; Animals ; Antimetabolites, Antineoplastic - metabolism ; Antimetabolites, Antineoplastic - therapeutic use ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; Cell Line, Tumor ; Cell Proliferation - genetics ; Cisplatin - pharmacology ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - metabolism ; Deoxycytidine - pharmacology ; Deoxycytidine - therapeutic use ; Drug Resistance, Neoplasm - genetics ; EMT ; Equilibrative Nucleoside Transporter 1 - metabolism ; Fluorouracil - pharmacology ; Gene Knockdown Techniques ; Humans ; Integrin alpha3 - genetics ; Integrin alpha3 - metabolism ; Integrin beta1 - metabolism ; JNK Mitogen-Activated Protein Kinases - metabolism ; Male ; Mice ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation ; Oncogene ; Pancreas ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Pancreatic Neoplasms - therapy ; Phosphorylation ; Signal Transduction ; Signal Transduction - genetics ; Spheroids, Cellular - drug effects ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Survival Rate ; Zinc Finger E-box-Binding Homeobox 1 - genetics
É parte de: Gastroenterology (New York, N.Y. 1943), 2020-02, Vol.158 (3), p.679-692.e1
Notas: Study concept and design: Mingyang Liu, Yuqing Zhang, Jingxuan Yang and Min Li. Acquisition of data: Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Zhijun Zhou, Xiang Tian, and Min Li. Analysis and interpretation of data: Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Zhijun Zhou, Hanxiang Zhan, Xiang Tian, Zhibo Yang, Kar-Ming Fung, and Min Li. Drafting the manuscript and critical revision: Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Zhijun Zhou, Hanxiang Zhan, Kai Ding, Xiang Tian, Zhibo Yang, Kar-Ming Fung, Barish H. Edil, Russell G. Postier, Michael S. Bronze, Martin E. Fernandez-Zapico, Marc P. Stemmler, Thomas Brabletz, Yi-Ping Li, Courtney W. Houchen, and Min Li. All the authors have approved the final version of the paper.
Equal contributions.
Author contributions
Descrição: Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1–knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3β1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3β1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents. [Display omitted]
Editor: United States: Elsevier Inc
Idioma: Inglês

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ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells

United States: Elsevier Inc

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