Proliferation pathway |
Suppressed the transcription and protein expressions of the CDK2 and CDK4 cyclin-dependent kinases, cyclin E, cyclin D1, and the E2F1 transcription factor, up-regulated miR-34a expression correlating with down-regulation of the miR-34a target gene (CDK4), decreased Wnt5-α/β expression, increased the expressions of NKD2 and Axin2, down-regulated β-catenin, suppressed the phosphorylation of ERK1/2, inhibited the mRNA and protein expression of ERK1/2, suppressed the transcription and expression of ERK1/2 downstream effectors c-Fos and c-Myc, up-regulated expression of p53, inhibited calmodulin (CaM) and phosphodiesterase (PDE1), accumulated Camp, activated cAMP-dependent protein kinase A (PKA) |
Apoptotic pathway |
Decreased p53 expression [50]; up-regulated Bax expression, down-regulated Bcl-2, Bcl-xL and Procaspase-3, increased caspase-9 activation [55]; induced the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria, decreased the mitochondrial membrane potential, activated the caspase-3, caspase-8, and caspase-9 [106]; and increased the ratio of Bax/Bcl-2; increased ROS level, triggered the intrinsic pathway of apoptosis [114], activated p38 MAPK [115]; increased miR-16 expression and decreased COX-2 expression [38] and PGE2 production [19]; decreased Mcl-1 expression, increased Bak and Noxa expression [62]; inhibited ERK phosphorylation [95]; induced necroptosis [57]; decreased HSP70 expression [116] |
Cell cycle |
Reduced the transcription activity of CDK2, CDK4, cyclin E [55]; increased the expression of CD71 [117]; up-regulated the expression of p21Cip1 and p27Kip1 [118]; decreased G2/M-associated proteins cyclin B1, CDC2 and MDM2 expressions, suppressed the expression of Forkhead box protein M1 (FOXM1) [51]; increased miR-34a expression, down-regulated miR-34a target gene [83] |
Invasion and metastasis |
Down-regulated MMP-9 and MMP-2 [110]; suppressed Rac1 siRNA deactivates NF-κB activity [107]; down-regulated the expression of ADAM17, p-EGFR and p-AKT [103]; inhibited the transcription of u-PA, MMP-2 and MMP-7, suppressed AP-1 and NF-κB-transactivation [87]; activated Wnt/β-catenin signaling pathway [91]; reduced vWF expression and macrophage infiltration, decreased expression of pFAK [21] |
Angiogenesis |
Reduced expression of the vascularization-related proteins HIF-1α and VEGF [119]; reduced the level of KDR, decline the transcriptional activity of ανβ3, reduced the levels of MMP2, MMP9 and BMP1 |
Oxidative damage reaction |
Reduced the level of CD71 [120]; increased intracellular levels of reactive oxygen species (ROS) [64, 115] |
Chemosensitivity and radiosensitivity |
Down-regulated RAD51 and impair DNA DSBs repair, induced DSBs and inhibited the clongenic formation of tumor cells [121]; activated the MAPK pathway by TGF β often in a DPC-4independent manner, down-regulated P15/CDKN1B, up-regulated CDCA4 and CDC2L6 with DPC4 activation [122]; increased Cyclin B1 expression, affected multiple pathways including RNA transport, the spliceosome, RNA degradation, p53 signaling and MAPK [123]; elevated amount of cH2AX foci/nucleus, attenuation of survivin expression [23]; increased the NO level [42] |
Microenviroment |
Reduced the number of Treg [124], increased the proportion of IFN-γ/I-4, reduced PGE2, inhibited the produce of NO and cytokines (IL-1-b, IL-6, TNF-α, VEGF) [125] |