Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells

Abstract

The guanine nucleotide exchange factor Tiam1 regulates numerous biologic properties including migration and invasion. We demonstrated previously that colon tumor cells biologically selected for increased migration were increased in Tiam1 expression. Cells selected for increased Tiam1 expression or that ectopically overexpress Tiam1 were increased in metastatic potential. Here, we demonstrate that Tiam1 regulates additional functions associated with metastasis, including reduced cellular adhesion and resistance to anoikis. Tiam1 effects on cellular migration are mediated through its downstream substrate, Rac. Increased Tiam1 expression also leads to anoikis-resistance, whereas decreasing Tiam1 expression by siRNA sensitizes cells to this form of apoptosis; however, Tiam1's regulation of anoikis is Rac-independent. Staurosporine sensitivity is also Rac-independent, suggesting Tiam1's effects on apoptosis require other effectors. As many of the observed phenotypes are characteristic of a transition of transformed epithelial cells to a mesenchymal-like phenotype, we also examined biochemical properties associated with an EMT. We demonstrate an increase in vimentin expression in cell lines that overexpress Tiam1 and have a more metastatic phenotype. Concomitant with this increase, we observe a decrease in E-cadherin expression in these cells. Lastly, we stained a panel of human colorectal specimens and adjacent normal tissue, and demonstrate that Tiam1 is overexpressed in a subset of human colorectal tumors. In summary, in colon tumor cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may represent a marker of colon tumor progression and metastasis in a subset of tumors.

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

“…T cell lymphoma invasion and metastasis 1 (Tiam1) serves as a specific GEF for Rho GTPase Rac1 (16). Although it has been well established that Tiam1 plays important roles in tumor progression and metastasis (17)(18)(19)(20), the specific mechanisms regulating its activity and protein stability are far from clear (21,22). It has been reported that Src-induced adherens junction disassembly and cell migration involve phosphorylation and degradation of Tiam1, likely through calpain proteases (20).…”

“…Moreover, Tiam1 negatively regulated anoikisinduced apoptosis in a Rac1-independent manner, suggesting that other effectors are probably involved in this form of cell death (18). It has also been reported that Tiam1 is required for * This work was supported by National Natural Science Foundation of China Grants 31221064 and 81272235 (to W. W) .…”

Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma

“…Tiam1 is a potent modifier of oncogenic Ras-induced skin tumor initiation, promotion and progression (13). Moreover, numerous studies have demonstrated that the upregulation of Tiam1 is associated with an aggressive phenotype and a poor clinical outcome in several types of malignant tumors, including breast (14), colon (15), prostate (16), liver (17) and nasopharyngeal (11) esophageal squamous cell carcinoma (18). However, to date, the correlation between Tiam1 expression and ovarian carcinoma has not been adequately investigated.…”

Expression of microRNA-10a, microRNA-342-3p and their predicted target gene TIAM1 in extranodal NK/T-cell lymphoma, nasal type

“…Overexpression of TIAM1 has been reported in various solid tumors (5)(6)(7)(8)(9)(10)(11)(12). In addition, previous studies have demonstrated that TIAM1 modulates a number of cellular processes considered to be associated with tumor progression, including cell apoptosis, invasion and migration (13)(14)(15)(16)(17)(18) To gain insight into the potential role of miR-10a, miR-22, miR-340, miR-342-3p, miR-590-5p and TIAM1 in the pathogenesis of ENKTCL, the present study examined the expression levels of these miRNAs and their target gene TIAM1 in ENKTCL tissues, in order to assess whether the expression levels of these molecules correlated with the clinical features of patients with ENKTCL.…”