Journal
EXPERIMENTAL CELL RESEARCH
Volume 369, Issue 1, Pages 120-128Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2018.05.013
Keywords
Gemcitabine resistance; Hypoxia; MiR-301a; Pancreatic cancer; TAp63
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Funding
- National Natural Science Foundation of China [81372640]
- Shanghai Sailing Program [17YF1415700]
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Hypoxia is a hallmark of pancreatic cancer (PC) and is associated with gemcitabine resistance. However, the mechanisms underlying hypoxia-induced gemcitabine resistance in PC remain greatly unknown. Our previous work showed that miR-301a, a hypoxia-sensitive miRNA, is involved in PC metastasis under hypoxia via regulation of its target gene P63. Here, we showed that miR-301a was upregulated in a NF-kappa B independent manner and promoted gemcitabine resistance under hypoxic conditions in vitro. In addition, TAp63, a member of the P63 family, reversed hypoxia-induced gemcitabine resistance by promoting degradation of HIF-1 alpha. Furthermore, we proved that TAp63 was a functional downstream target of miR-301a and mediated the biological properties of miR-301a in PC. Taken together, these findings indicate that miR-301a exerts as a critical regulator involved in hypoxia-induced gemcitabine resistance in PC and may have potentials to be a therapeutic target for PC patients.
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