TABLE 3.
In vitro studies of MIF in pancreatic cancer.
| Cell types | Interventions | Key findings | Refs |
|---|---|---|---|
| MIA PaCa-2, PANC-1 | MIF knockdown/knockout | 1) hypoxia induced MIF expression and secretion in PC cell lines in a HIF-1α–dependent manner; 2) MIF was required for maximal hypoxia-induced HIF-1α stabilization in PC cell lines; 3) MIF bound to CSN5 in PC cell lines and MIF depletion resulted in a loss of CSN5 binding and stabilization of HIF-1α | Winner et al. (2007) |
| MIA PaCa-2, AsPC-1, BxPC-3, Capan-1, CFPAC-1, HPAF-II, PANC-1, Colo357, PANC-89, PancTuI, PT-45, PT-64 | MIF knockdown | 1) qRT-PCR of MIF in PC cell lines showed PT-45, CFPAC-1, PancTuI, and Capan-1 cells displayed the highest MIF expression (Ct < 6.5), Panc-89 and Panc-1 showed low expression levels (Ct > 8). AsPC-1, Colo357, BxPC-3, PT-64, HPAF-II, and MIA PaCa-2 showed an average expression of MIF (7 < Ct < 8); 2) MIF knockdown cells showed decreased proliferation and viability and increased apoptosis; 3) MIF knockdown downregulated total Akt expression but increased phosphitylation at the Thr308 residue of Akt | Denz et al. (2010) |
| PANC-1, Capan-2 | Overexpression and knockdown of MIF, gemcitabine | 1) MIF overexpression decreased E-cadherin and increased vimentin in PC cells, consistent with the features of EMT; 2) MIF overexpressing PC cells showed significantly higher invasive ability and increased proliferation than vector control cells, sensitivity to gemcitabine was reduced | Funamizu et al. (2013) |
| PANC-1, Capan-2, HPDE6, HIT-T15 | Knockin and knockdown of MIF, rMIF, PP1, AZD0530 | 1) rMIF inhibited insulin secretion of isolated mouse islets and HIT-T15 cells on a dose-dependent pattern; 2) rMIF depressed VDCC Ca2+ currents in HIT-T15 cells via regulating Src family tyrosine kinase activity; 3) the regulatory effect of PANC1, Capan-2, and MIF-expressing HPDE6 cells on insulin secretion from islet cells was significantly ameliorated by using PP1 or AZD0530 | Tan et al. (2014) |
| PANC-1, BxPC-3, ASPC-1, HEK293 | Knockdown of DDT and MIF, 4-IPP | 1) knockdown of MIF and DDT synergistically inhibited ERK1/2 and Akt phosphorylation, increased p53 expression and attenuated proliferation and invasion of PANC-1 cells; 2) 4-IPP reduced PANC-1 proliferation and colony formation | Guo et al. (2016) |
| PANC-1, CFPAC-1, Capan-2, MIA PaCa-2 | LY294002 (PI3K/Akt inhibitor), AZD6244 (MEK inhibitor) | 1) MIF-induced increase in miR-301b targets and reduces NR3C2 levels in PANC-1 and Capan-2 cell lines; 2) NR3C2 inhibited proliferation, colony formation, migration, invasion, and enhances sensitivity of PC cell lines to gemcitabine; 3) MIF enhanced PC cell lines invasiveness by targeting NR3C2 through the upregulation of miR-301b; 4) AZD6244 didn’t alter miR-301b or NR3C2 in MIF-overexpressing PC cell lines; 5) treatment of MIF-overexpression PC cells with LY294002 resulted in miR-301b decrease and NR3C2 increase | Yang et al. (2016) |
| PANC-1, BxPC-3 | MIF knockdown | 1) knockdown of MIF suppressed proliferation and invasion of PDAC cells; 2) knockdown of MIF inhibited the activation of Akt and ERK, and suppressed the expression of cyclin D1 and MMP-2 | Wang et al. (2018) |
| Hamster PBMCs, HapT1 | Recombinant MaMIF, ISO-1, MaMIF knockdown | 1) the primary sequence, biochemical properties, and crystal structure of MaMIF showed great similarity with human MIF; 2) recombinant MaMIF induced significantly higher expression of TNF-α, IL-6, and VEGF in hamster PBMCs than non-treated group, ISO-1 suppressed the expression of these factors in PBMCs; 3) recombinant MaMIF showed no effect on the overall growth of HapT1 cells; 4) intracellular MIF knockdown by siRNA or inactivation by ISO-1 reduced overall growth of HapT1 cells | Suresh et al. (2019) |
MIF, macrophage migration inhibitory factor; PC, pancreatic cancer; HIF-1α, hypoxia inducible factor-1α; CSN5, COP9 signalosome subunit five; PDAC, pancreatic ductal adenocarcinoma; AUC, area under the receiver operating characteristic curve; EMT, epithelial-to-mesenchymal transition; IHC, immunohistochemistry; PTX3, pentraxin3; rMIF, recombinant MIF; PP1, protein phosphatase one; AZD0530, saracatinib; VDCC, voltage-gated calcium channel; PanIN, pancreatic intraepithelial neoplasias; DDT, D-dopachrome tautomerase; 4-IPP, 4-iodo-6-phenylpyrimidine; ERK, extracellular signal-regulated kinases; oxMIF, oxidative MIF; PI3K, phosphoinositide 3-kinase; MEK, mitogen-activated protein kinase; NR3C2, nuclear receptor subfamily three group C member two; MMP-2, matrix metalloproteinase-2; PBMCs, peripheral blood mononuclear cells; MaMIF, Mesocricetus auratus MIF; ISO-1, (S, R)-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; VEGF, vascular endothelial growth factor.