Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

Nemolato, Sonia; Restivo, Angelo; Cabras, Tiziana; Coni, Pierpaolo; Zorcolo, Luigi; Orrù, Germano; Fanari, Mattia; Cau, Flaviana; Gerosa, Clara; Fanni, Daniela; Messana, Irene; Castagnola, Massimo; Casula, G.; Faa, Gavino

doi:10.4161/cbt.13.4.18691

Cited by 39 publications

(29 citation statements)

References 41 publications

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“…** P < 0.01 versus control SCC-15 cells; ## P < 0.01 compared with control SCC-25 cells strongly increased the invasiveness of OSCCs and induced the activation of MMP-2. This is consistent with a report by Nemolato et al (2012), showing upregulation of Tβ4 expression in invading tumor cells with features of EMT. Tβ4-upregulated colorectal cancer cells are more invasive, and Tβ4-downregulated cells show decreased MMP-2 expression (Piao et al 2014).…”

Section: Discussionsupporting

confidence: 94%

Thymosin β4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma

et al. 2015

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The epithelial-to-mesenchymal transition (EMT) plays a vital role in carcinogenesis, invasion, and metastasis of many epithelial tumors including oral squamous cell carcinoma (OSCC), a common malignancy of the head and neck. However, the functional role of the actin-sequestering protein thymosin β4 (Tβ4) in the EMT in OSCCs remains unclear. Thus, we investigated whether overexpression of Tβ4 could induce in vitro tumorigenesis such as cell proliferation and anchorage independency and an EMT-like phenotype in OSCCs. Also, we examined whether it affects invasiveness and cell motility-associated signaling molecules. Tβ4-overexpressing OSCCs, SCC-15_Tβ4 and SCC-25_Tβ4, enhanced cell proliferation and colony formation. In addition, we observed that Tβ4 overexpression induced an EMT-like phenotype, accompanied by a decrease in expression of the epithelial cell marker E-cadherin and an increase in expression of mesenchymal cell markers vimentin and N-cadherin. Also, the expression level of Twist1, an EMT-inducing transcription factor, was significantly enhanced in SCC-15_Tβ4 and SCC-25_Tβ4 cells. Tβ4 overexpression augmented in vitro invasion and MMP-2 activity and enhanced the phosphorylation of paxillin and cortactin and expression of LIMK1. Taken together, these results suggest that Tβ4 overexpression could be one of the causes of tumorigenesis and progression in OSCCs. Further investigation on the Tβ4 molecule would encourage the development of specific targets for cancer treatment.

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Section: Discussionsupporting

confidence: 94%

Thymosin β4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma

et al. 2015

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“…The previously reported diffuse cytoplasmic immunostaining was substituted by a focal reactivity, mainly represented by a perinuclear spot-like staining pattern highly suggestive of a translocation of Tβ4 from vacuoles towards the trans-Golgi network. A similar cytoplasmic localization of Tβ4 has been previously observed by our group in the human normal colon mucosa, in the proximity of colon cancer [29]. In that study, Tβ4-immunoreactive perinuclear spots were frequently detected in the enterocytes covering the intestinal mucosa in close proximity of colon cancer.…”

Section: Discussionsupporting

confidence: 90%

Cellular Trafficking of Thymosin Beta-4 in HEPG2 Cells Following Serum Starvation

et al. 2013

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Thymosin beta-4 (Tβ4) is an ubiquitous multi-functional regenerative peptide, related to many critical biological processes, with a dynamic and flexible conformation which may influence its functions and its subcellular distribution. For these reasons, the intracellular localization and trafficking of Tβ4 is still not completely defined and is still under investigation in in vivo as well as in vitro studies.In the current study we used HepG2 cells, a human hepatoma cell line; cells growing in normal conditions with fetal bovine serum expressed high levels of Tβ4, restricted to the cytoplasm until 72 h. At 84 h, a diffuse Tβ4 cytoplasmic immunostaining shifted to a focal perinuclear and nuclear reactivity. In the absence of serum, nuclear reactivity was localized in small granules, evenly dispersed throughout the entire nuclear envelop, and was observed as earlier as at 48 h. Cytoplasmic immunostaining for Tβ4 in HepG2 cells under starvation appeared significantly lower at 48 h and decreased progressively at 72 and at 84 h. At these time points, the decrease in cytoplasmic staining was associated with a progressive increase in nuclear reactivity, suggesting a possible translocation of the peptide from the cytoplasm to the nuclear membrane. The normal immunocytochemical pattern was restored when culture cells submitted to starvation for 84 h received a new complete medium for 48 h.Mass spectrometry analysis, performed on the nuclear and cytosolic fractions of HepG2 growing with and without serum, showed that Tβ4 was detectable only in the cytosolic and not in the intranuclear fraction. These data suggest that Tβ4 is able to translocate from different cytoplasmic domains to the nuclear membrane and back, based on different stress conditions within the cell.The punctuate pattern of nuclear Tβ4 immunostaining associated with Tβ4 absence in the nucleoplasm suggest that this peptide might be localized in the nuclear pores, where it could regulate the pore permeability.

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“…A study investigating Tβ4 expression in a limited number of human colon cancers reported highly variable immunostaining for Tβ4 in tumor cells and in endothelial and stromal cells (10). A recent study from our group showed strong Tβ4 cytoplasmic immunostaining in the tumor cells of the vast majority of colorectal adenocarcinomas (15). In this study, Tβ4 expression was found even in adenomas with low-grade dysplasia, representing the earliest stage of colorectal tumorigenesis.…”

Section: Discussionmentioning

confidence: 87%

“…Recently, Tβ4 immunoreactivity was detected by our group in the vast majority of colon carcinomas, where it showed a patchy distribution and well-differentiated areas that were significantly more reactive than less-differentiated tumor zones. Moreover, the localization of Tβ4 changed during cancer progression, moving from the cell membrane to the Golgi apparatus (15). …”

Section: Introductionmentioning

confidence: 99%

Thymosin ß4 expression in colorectal polyps and adenomas

Nemolato¹,

Cabras²,

Restivo³

et al. 2013

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OBJECTIVE:Thymosin beta 4 (Tβ4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation. Recently, a role for Tβ4 has been proposed in experimental and human carcinogenesis, including gastrointestinal cancer. This study was aimed at evaluating the relationship between Tβ4 immunoreactivity and the initial steps of carcinogenesis.METHODS:In total, 60 intestinal biopsies, including 10 hyperplastic polyps, 10 sessile serrated adenomas/polyps, 15 colorectal adenomas with low-grade dysplasia, 15 adenomas with high-grade dysplasia, 15 adenocarcinomas and 10 samples of normal colon mucosa, were analyzed for Tβ4 expression by immunohistochemistry.RESULTS:Weak cytoplasmic reactivity for Tβ4 was detected in the normal colon mucosa. No reactivity for Tβ4 was found in hyperplastic and sessile serrated polyps/adenomas. Tβ4 expression was observed in 10/15 colorectal adenocarcinomas. In adenomas with low-grade dysplasia, Tβ4 immunoreactivity was mainly detected in dysplastic glands but was absent in hyperplastic glands. Tβ4 immunoreactivity was characterized by spot-like perinuclear staining. In high-grade dysplastic polyps, immunostaining for Tβ4 appeared diffuse throughout the entire cytoplasm of dysplastic cells. Spot-like perinuclear reactivity was detected in adenocarcinoma tumor cells.CONCLUSIONS:Our study shows for the first time that Tβ4 is expressed during different steps of colon carcinogenesis. The shift of Tβ4 immunolocalization from low-grade to high-grade dysplastic glands suggests a role for Tβ4 in colorectal carcinogenesis. However, the real meaning of Tβ4 reactivity in dysplastic intestinal epithelium remains unknown.

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Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

Cited by 39 publications

References 41 publications

Thymosin β4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma

Thymosin β4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma

Cellular Trafficking of Thymosin Beta-4 in HEPG2 Cells Following Serum Starvation

Thymosin ß4 expression in colorectal polyps and adenomas

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