Overexpression of the thymosin β-10 gene in human ovarian cancer cells disrupts F-actin stress fiber and leads to apoptosis

Lee, Jun Young; Zhang, Wei; Choi, Ji Yoon; Cho, Yong Suk; Lee, Sun Hee; Kim, Jung-whan; Hu, Limei; Xu, Jie; Liu, Jinsong; Lee, Je Ho

doi:10.1038/sj.onc.1204683

Cited by 46 publications

(15 citation statements)

References 27 publications

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“…Furthermore, the expression of SPP1 in OS lesions has been correlated with improved overall survival (Dalla-Torre et al , 2006). Although there is some evidence connecting TMSB10 expression to carcinogenesis (Lee et al , 2001; Sardi et al , 2002; Alldinger et al , 2005), this is the first report linking TMSB10 expression to good chemotherapeutic response in OS. In addition, good responders had significantly higher levels of ACP5/TRAP gene expression than poor responders.…”

Section: Discussionmentioning

confidence: 80%

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone

et al. 2010

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Background:Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Patients who respond poorly to chemotherapy have a higher risk of metastatic disease and 5-year survival rates of only 10–20%. Therefore, identifying molecular targets that are specific for OS, or more specifically, metastatic OS, will be critical to the development of new treatment strategies to improve patient outcomes.Methods:We performed a transcriptomic analysis of chemo-naive OS biopsies and non-malignant bone biopsies to identify differentially expressed genes specific to OS, which could provide insight into OS biology and chemoresistance.Results:Statistical analysis of the OS transcriptomes found differential expression of several metallothionein family members, as well as deregulation of genes involved in antigen presentation. Tumours also exhibited significantly increased expression of ID1 and profound down-regulation of S100A8, highlighting their potential as therapeutic targets for OS. Finally, we found a significant correlation between OS and impaired osteoclastogenesis and antigen-presenting activity. The reduced osteoclastogenesis and antigen-presenting activity were more profound in the chemoresistant OS samples.Conclusion:Our results indicate that OS displays gene signatures consistent with decreased antigen-presenting activity, enhanced chemoresistance, and impaired osteoclastogenesis. Moreover, these alterations are more pronounced in chemoresistant OS tumour samples.

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Section: Discussionmentioning

confidence: 80%

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone

et al. 2010

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“…In our previous study, we reported that Tβ 10 mRNA levels were elevated in normal ovaries, as compared to other tissues, such as spleen, thymus, prostate, testis, small intestine, colon, and peripheral blood leukocytes, but the mRNA levels of Tβ 10 were decreased in ovarian cancers [23]. We, therefore, confirmed the mRNA and protein expression levels of thymosin β 10 (Tβ 10 ) in serous type ovarian cancer and mucinous type ovarian cancer, as well as in cervical cancer and immortalized ovarian cancer cell lines, such as 2774, OVCAR3, and SKOV3.…”

Section: Resultsmentioning

confidence: 89%

Thymosin β10 Expression Driven by the Human TERT Promoter Induces Ovarian Cancer-Specific Apoptosis through ROS Production

Kim

Lee

2012

PLoS ONE

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Thymosin β10 (Tβ10) regulates actin dynamics as a cytoplasm G-actin sequestering protein. Previously, we have shown that Tβ10 diminishes tumor growth, angiogenesis, and proliferation by disrupting actin and by inhibiting Ras. However, little is known about its mechanism of action and biological function. In the present study, we establish a new gene therapy model using a genetically modified adenovirus, referred to as Ad.TERT.Tβ10, that can overexpress the Tβ10 gene in cancer cells. This was accomplished by replacing the native Tβ10 gene promoter with the human TERT promoter in Ad.TERT.Tβ10. We investigated the cancer suppression activity of Tβ10 and found that Ad.TERT.Tβ10 strikingly induced cancer-specific expression of Tβ10 as well as apoptosis in a co-culture model of human primary ovarian cancer cells and normal fibroblasts. Additionally, Ad.TERT.Tβ10 decreased mitochondrial membrane potential and increased reactive oxygen species (ROS) production. These effects were amplified by co-treatment with anticancer drugs, such as paclitaxel and cisplatin. These findings indicate that the rise in ROS production due to actin disruption by Tβ10 overexpression increases apoptosis of human ovarian cancer cells. Indeed, the cancer-specific overexpression of Tβ10 by Ad.TERT.Tβ10 could be a valuable anti-cancer therapeutic for the treatment of ovarian cancer without toxicity to normal cells.

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“…Therefore, the increased growth rate and cell cycle progression of the Tb-4 overexpressers ( Figure 5 and Table 1) could be attributed to the higher levels of both nuclear b-catenin and c-Myc found in these cells (Figures 6 and 7) because the latter is not only a downstream target of the former (He et al, 1998;Sellin et al, 2001) but also a facilitator of cell cycle progression (He et al, 1998). On the contrary, Tb-4 overexpression did not affect the growth rate of mouse fibrosarcoma (QR-32) cells (Kobayashi et al, 2002) and overproduction of Tb-10 even impaired the growth of human ovarian cancer (PA-1 and Skov3) cells (Lee et al, 2001). These discrepancies are most likely attributed to the different intracellular microenvironments.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the thymosin β-4 gene is associated with malignant progression of SW480 colon cancer cells

Wang¹,

Chen²,

Hsiao³

et al. 2003

Oncogene

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Thymosin b-4 (Tb-4), a small peptide originally isolated from calf thymus, modulates the formation of F-actin microfilaments by sequestering the monomeric G-actin. Recent studies have shown that overexpression of the Tb-4 gene occurs not only in many human carcinomas but also in the highly metastatic melanomas and fibrosarcomas. However, little is known about the specific growth advantages acquired by different tumors from this genetic abnormality. To address the above questions, Tb-4-overexpressing human colon carcinoma (SW480) cells were established by stable transfection and their phenotypic changes were monitored. We found that both the morphology and the cortical actin cytoskeleton of SW480 cells were altered by Tb-4 overexpression. Moreover, both cellular level and that distributed over the intercellular junctions of the E-cadherin were decreased in the Tb-4 overexpressers, which were accompanied by a twofold increase in their saturation densities. Meanwhile, these cells also exhibited an increased ability to form colonies in soft agar. Interestingly, a dramatic increase of growth rate was detected in the Tb-4 overexpressers, which might be attributed to an accelerated proliferation induced by cMyc that was activated by nuclear b-catenin. Finally, a motility increase of these cells was demonstrated by two independent migration assays, which was accompanied by an enhanced focal contact. Taken together, our data suggest that the drastic growth property and motility changes of the SW480 cells overexpressing Tb-4 gene are due mainly to a deregulated cell-cell adhesion arisen from the downregulation of E-cadherin, plus uncontrolled cell proliferation owing to the upregulation of b-catenin, both resulted from a breakdown of actin microfilaments caused by the overexpression of this G-actin sequestering peptide.

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Overexpression of the thymosin β-10 gene in human ovarian cancer cells disrupts F-actin stress fiber and leads to apoptosis

Cited by 46 publications

References 27 publications

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone

Thymosin β10 Expression Driven by the Human TERT Promoter Induces Ovarian Cancer-Specific Apoptosis through ROS Production

Overexpression of the thymosin β-4 gene is associated with malignant progression of SW480 colon cancer cells

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