Overexpression of the thymosin β-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma

Abstract

Cell-matrix and cell-cell adhesive interactions play important roles in the normal organization and stabilization of the cell layer in epithelial tissue. Alterations in the expression and function of these adhesion systems that cause a switch to a migratory phenotype in tumor invasion and metastasis are critical for the malignant conversion of epithelial cells. Thymosin b-4 (Tb-4) is the major actinsequestering protein that has been shown to be upregulated in a wide variety of human carcinomas and has been implicated to be involved in altering the motility of certain tumors. We have recently demonstrated that the growth rate, colony formation in soft agar, and motility, all good indicators for malignant progression, of SW480 colon carcinoma cells are dramatically increased by enforced Tb-4 expression. To test the hypothesis that overexpression of this G-actin sequestering peptide also promotes tumor invasion, we examined not only the invasion capability of Tb-4-overexpressing SW480 cells, but also the expression levels of Tb-4 as well as several proteins that participate in different stages of tumor progression in matched samples of human primary colorectal adenocarcinoma and liver metastases from several patients. A marked increase on the invasiveness in Tb-4-overexpressing SW480 cells with increased levels and activity of matrix metalloproteinase-7 (MMP-7) was observed. Furthermore, the levels of Fas as well as the susceptibility to Fas ligand-mediated apoptosis in Tb-4-overexpressing cells were significantly decreased. Interestingly, the levels of Tb-4 mRNA, b-catenin, c-Myc, and MMP-7 in metastatic liver lesions were relatively higher, whereas the levels of E-cadherin and Fas were significantly lower than those in the matched primary colorectal tumors. These results suggest that upregulation of Tb-4, by promoting the disruption of cell-cell adhesion and a consequential activation of the b-catenin signaling, could be a key event in the acquisition of growth advantages as well as invasive phenotypes in human colorectal carcinomas.

Profilin-1 is a negative regulator of mammary carcinoma aggressiveness

“…Clearly, literature has documented evidence of elevated expression of thymosin b4 (a G-actin-sequestering protein that inhibits actin polymerisation) and loss of tropomyosin (an F-actin-stabilizing protein) correlating with increased aggressiveness of carcinoma cells (Franzen et al, 1996;Kobayashi et al, 2002;Wang et al, 2004). In fast migrating tumour cells, a moderate decrease in cellular F-actin level can potentially enhance cell motility by either increasing the availability of G-actin for actintreadmilling, and/or decreasing the overall rigidity of cell cortex (enhances membrane deformability).…”

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

“…The increased expression of T␤4 correlates with the invasive capability of the cells, the degree of morphologic transformation, and disintegration of actin filaments (21). Recent studies have also correlated increased T␤4 expression with potentiated cell growth (13,22) but this observation seems not to be universal (2,10).…”

“…Although it is a typical intracellular polypeptide, it plays numerous roles, both intracellularly and extracellularly. Numerous observations indicate that T␤4 is involved in adhesion and spreading of fibroblasts (1,2), differentiation of endothelial cells (3,4), directional migration of endothelial cells and keratinocytes (5)(6)(7)(8), angiogenesis (3-6, 9, 10), wound healing (6,7,11), hair follicle growth (8), and apoptosis (12,13), and has been described to possess anti-inflammatory properties (11,14). In addition, elevated T␤4 expression has been observed in various malignant cell lines and tumors (15)(16)(17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20).…”

Thymosin 4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma

“…16,17 An adenoviralbased overexpression of Tβ4 was applied in a colon cancer and melanoma model showing increased growth, motility and invasive capacities in vitro and a larger tumor load in vivo. 18,19 Since proliferation, migration and invasion are part of the hallmarks of the biology of MM, we were interested in investigating an involvement of Tβ4 in this disease. We first investigated the Tβ4 expression pattern in 298 primary MM-cell samples and 14 normal plasma cell samples from healthy donors.…”