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Review
. 2023 Feb 15;15(4):1230.
doi: 10.3390/cancers15041230.

microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer

Naotake Funamizu  1 , Masahiko Honjo  1 , Kei Tamura  1 , Katsunori Sakamoto  1 , Kohei Ogawa  1 , Yasutsugu Takada  1
Affiliations
Review

microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer

Naotake Funamizu et al. Cancers (Basel). .

Abstract

Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.

Keywords: biomarker; chemoresistance; gemcitabine; microRNA; pancreatic cancer.

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Conflict of interest statement

The authors declare no conflict of interest for this article.

Figures

Figure 1
Figure 1
Association between microRNAs related to EMT (Epithelial–mesenchymal transition) and gemcitabine resistance. EMT is well known to increase drug resistance, cell proliferation, and invasiveness through acquiring properties like cancer stem cells.
Figure 2
Figure 2
Association of microRNAs with TME (tumor microenvironment) and gemcitabine resistance. TME works to the advantage of cancer cell survival by, for example, inducing gemcitabine resistance and enhancing cell proliferation.
Figure 3
Figure 3
Association of miRNAs with metabolism and gemcitabine resistance. Mainly, transporter and deoxycytidine kinase (dCK) are associated with the activation of gemcitabine. Conversely, cytidine deaminase (CDA) and ribonucleotide reductase (RR) are associated with the inactivation of gemcitabine. These transporters and enzymes are controlled by miRNAs, which results in gemcitabine resistance in pancreatic cancer.
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