In this study, we have investigated the role and mechanism of Bcl-2 on tumor cell invasion and metastasis by using Bcl-2 overexpressing non-small cell lung cancer cells.
Mechanistic studies revealed that CCL28 mediated intracellular activation of the mitogen-activated protein kinase (MAPK) signaling pathway to promote breast cancer cell proliferation and metastasis by upregulating anti-apoptotic protein Bcl-2 and suppressing cell adhesion protein β-catenin.
These mRNAs encode proteins that play significant roles in all aspects of malignancy including angiogenesis factors (VEGF, FGF-2), onco-proteins (c-myc, cyclin D1, ODC), pro-survival proteins (survivin, BCL-2) and proteins involved in tumor invasion and metastasis (MMP-9, heparanase).
Taken together, spongistatin 1 not only proved to be a potent experimental drug but also served as a chemical tool to examine the role of the antiapoptotic protein Bcl-2 in pancreas carcinoma, thereby supporting the hypothesis of a link between apoptosis signaling and metastasis.
Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33 %) than in patients with bcl-2-positive tumours (12 %; p = 0.04) at the time of diagnosis.
Taken together, the combination of curcuma zedoary and kelp could inhibit the proliferation and metastasis of liver cancer cells in vivo and in vitro by inhibiting endogenous H2S production and down-regulating the pSTAT3/BCL-2 and VEGF pathway, which provides strong evidence for the application of curcuma zedoary and kelp in treatments of liver cancer.
The epithelial-mesenchymal transition (EMT), which supports cancer cell invasion and metastasis, is promoted by pro-survival members (e.g., Bcl-2 and Bcl-X<sub>L</sub>) of the Bcl-2 protein family, which are well-known key apoptosis regulators.
Such TNF-induced NF-kappaB-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin.
Moreover, Eca109 cells treated with H<sub>2</sub>O<sub>2</sub> alone had enhanced cell proliferation and metastasis but decreased cell apoptosis, as compared with those without any treatment; meanwhile, the declined Cyt C, Bax, and cleaved caspase-3, as well as the elevated Bcl-2 were also observed in Eca109 cells in the H<sub>2</sub>O<sub>2</sub> group, which were reversed by Propofol or Dkk1.
The mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues were significantly lower than those in the relatively healthy, adjacent breast tissues (p < 0.05); the lower the degree of tumor differentiation, the lower the mRNA and protein expressions of Beclin1 and Bcl-2 (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for lymph node metastasis were significantly lower than those negative for lymph node metastasis (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for distant metastasis were significantly lower than those negative for distant metastasis (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for ki67 were significantly lower than those negative for ki67 (p < 0.05).
In vitro inducing the expression of HO-1 promoted the proliferation and metastasis of A2780 and Skov-3 cells, with the increased expressions of mesenchymal marker (Vimentin), epithelial-mesenchymal transition-associated transcript factor (Zeb-1), anti-apoptotic protein (Bcl-2), and the decreased expressions of epithelial marker (Keratin) and pro-apoptotic protein (Bax).
Mechanistically, R-flurbiprofen was found to have pleiotropic effects, changing levels of cell cycle factors like Cyclin D1 and CKD4, apoptotic protwins like caspase3 and Bcl-2, and protwins that affect metastasis, like metalloproteases.
The expression of bcl-2 or accumulation of p53 protein in prostate cancer metastases did not significantly influence patient survival or the extent of metastatic disease.
When bcl-2 over-expression was studied in relation to nodal status, hormone receptor status and chemo- and hormone therapy, no significant difference was observed between different subgroups of patients. bcl-2 expression was also associated with a significantly lower risk of distant metastasis (p = 0.04).
We consider some correlations are needed to be done also with other consecrated histological (as Clark level, Breslow indexes, presence of ulceration, mitotic index, intratumor inflammatory infiltrate, etc.) and immunohistochemical markers [cadherins, vascular endothelial growth factor (VEGF), bcl-2, etc.] of prognosis and metastasis.
Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFκB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD<sup>+</sup>4, CD<sup>+</sup>8, NK1.1 T cells in spleen).
After exposure to the compound, the modulated genes were involved in inflammatory responses as with the mitogen-activated protein kinase 14 (MPK 14), or in tumor and metastasis progression as with the matrix metalloproteinase 17 (MMP 17), in cell proliferation as with c-jun and c-fos, and moreover in the apoptotic process as with interferon alpha-inducible protein (IFI), BAX and BCL-2.
Administration of VGB4 led to the regression of 4T1 murine MCT growth through decreased expression of p-VEGFR1 and p-VEGFR2 and abrogation of ERK1/2 and AKT activation followed by considerable decrease of tumor cell proliferation (Ki67 expression) and angiogenesis (CD31 and CD34 expression), induction of apoptosis (increased p53 expression, TUNEL staining and decreased Bcl2 expression), and suppression of metastasis (increased E-cadherin and decreased N-cadherin, NF-κB and MMP-9 expression).
The level of miR-371-5p was associated with clinical stage and distant metastasis in patients with NPC, and was inversely associated with the protein level of BCL-2 in NPC tissues.
Two miRNAs, hsa-miR-17-5p and hsa-miR-16-5p, were identified as having the highest associations with targeted mRNAs [such as B-cell lymphoma 2 (BCL2), small body size/mothers against decapentaplegic 3 (SMAD3) and suppressor of cytokine signaling 1 (SOCS1)] and pathways associated with epithelial-mesenchymal transitions and other processes linked with cancer metastasis (including cell cycle, adherence junctions and extracellular matrix-receptor interaction). mRNAs for two genes [HECT, UBA and WWE domain containing 1 (HUWE1) and BCL2] were found to have the highest associations with miRNAs, which were down-regulated in brain metastasis specimens of breast cancer.