Expression of DIAPH1 is up‐regulated in colorectal cancer and its down‐regulation strongly reduces the metastatic capacity of colon carcinoma cells

Abstract

In most cases, metastatic colorectal cancer is not curable, thus new approaches are necessary to identify novel targets for colorectal cancer therapy. Actin-binding-proteins (ABPs) directly regulate motility of metastasising tumor cells, and for cortactin an association with colon cancer metastasis has been already shown. However, as its depletion only incompletely inhibits metastasis, additional, more suitable cellular targets have to be identified. Here we analyzed expression of the ABPs, DIAPH1, VASP, N-WASP, and fascin in comparison with cortactin and found that, besides cortactin, DIAPH1 was expressed with the highest frequency (63%) in colorectal cancer. As well as cortactin, DIAPH1 was not detectable in normal colon tissue and expression of both proteins was positively correlated with metastasis of colorectal cancer. To analyse the mechanistic role of DIAPH1 for metastasis of colon carcinoma cells in comparison with cortactin, expression of the proteins was stably downregulated in the human colon carcinoma cell lines HT-29, HROC-24 and HCT-116. Analysis of metastasis of colon carcinoma cells in SCID mice revealed that depletion of DIAPH1 reduced metastasis 60-fold and depletion of cortactin 16-fold as compared with control cells. Most likely the stronger effect of DIAPH1 depletion on colon cancer metastasis is due to the fact that in vitro knock down of DIAPH1 impaired all steps of metastasis; adhesion, invasion and migration while down-regulation of cortactin only reduced adhesion and invasion. This very strong reducing effect of DIAPH1 depletion on colon carcinoma cell metastasis makes the protein a promising therapeutic target for individualized colorectal cancer therapy.Formation of metastasis is a complex process, starting with strong morphological and functional changes of tumor cells.

Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis

“…This includes morphogenesis, cytokinesis, cell polarization, adhesion, and migration [35][36][37][38]. DIAPH1 downregulation was reported to suppress invasion and/or migration in breast cancer, colon cancer, and glioblastoma [39][40][41]. We found that FMNL1 regulates DIAPH1 expression not only to control actin assembly during meiosis as previously described [19] but also to promote GBM cell migration.…”

Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells

“…Therefore, a model where Abi1 and Cortactin act cooperatively in invadopodia at the leading edge of colorectal carcinoma is quite conceivable; phosphorylated Abi1 would then support local actin reorganization via activation of nucleation-promoting factors, giving rise to a branched actin network required for ECM attachment and invadopodia formation (schematically depicted in Figure 5) [4,16]. This model is supported by the fact that upregulation of Abi1-interacting formins and class I NPFs has been reported to be associated with enhanced metastasis in CRC, and increased MMP9 secretion upon Abi1 overexpression has been shown in breast cancer [16,25,38]. However, in the present study, we could not show a significant decrease in MMP-9 secretion after STI571 treatment, why we conclude that the impact of Abi1 phosphorylation seems to lie in invadopodia formation rather than MMP-9 secretion by CRC cells.…”

Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion

“…Different from other studies showing DIAPH1-mediated cytoskeletal effects upon lysophosphatidic acid (LPA) stimulation [ 18 , 19 ], our previous studies were all based on non-stimulated cells [ 20 ]. LPA mainly accumulates at sites of wound healing, where it is required for platelet activation and for stimulation of endothelial stress fiber formation [ 21 ].…”

“…This insight of its metastasis-promoting activity in colon cancer cells was additionally confirmed by a subcutaneous SCID mouse model, showing that lung metastasis of HCT-116 cells was almost completely blocked after depletion of DIAPH1. However, since we have detected an accumulation of DIAPH1-depleted cells in bone marrow aspirates of SCID mice, we could not exclude that DIAPH1 depletion promotes metastatic outgrowth in organs other than lung [ 20 ].…”