ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Abstract

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

• Authors: Yen-Hao Su, Tung-Wei Hsu, Hsin-An Chen, Chih-Ming Su, Ming-Te Huang, Ta-Hsien Chuang, J Leo Su, Chia-Ling Hsieh, Ching-Feng Chiu
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 236 Issue 6 Pg. 4420-4434 (06 2021) ISSN: 1097-4652 [Electronic] United States
• PMID: 33184874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Antimetabolites, Antineoplastic
• Sp1 Transcription Factor
• SP1 protein, human
• Deoxycytidine
• Extracellular Signal-Regulated MAP Kinases
• DICER1 protein, human
• Ribonuclease III
• DEAD-box RNA Helicases
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• DEAD-box RNA Helicases (genetics, metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Inbred NOD
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, enzymology, genetics, pathology)
• Ribonuclease III (genetics, metabolism)
• Signal Transduction
• Sp1 Transcription Factor (genetics, metabolism)
• Transcriptional Activation
• Xenograft Model Antitumor Assays
• Gemcitabine
• Mice