Thymosin beta 4 is overexpressed in human pancreatic cancer cells and stimulates proinflammatory cytokine secretion and JNK activation

Zhang, Yuqing; Feurino, Louis W.; Zhai, Qihui; Wang, Hao; Fisher, William E.; Chen, Changyi; Yao, Qizhi; Li, Min

doi:10.4161/cbt.7.3.5415

Cited by 49 publications

(34 citation statements)

References 27 publications

(32 reference statements)

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“…The nonmalignant pancreatic cell line HPDE-E6E7 was a gift from Dr. Min Li (53) and the nonmalignant hTERT-HPNE human pancreatic duct cell line was obtained from ATCC. Cells were maintained in the culture media recommended by the provider for about 3 passages before the experiments were carried out.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Radvanyi

Yin

et al. 2017

Clinical Cancer Research

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Purpose We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). Experimental Design shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells. Results HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several PC cells or tumors. Conclusion These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis and immunotherapy of PC.

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Section: Methodsmentioning

confidence: 99%

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Radvanyi

Yin

et al. 2017

Clinical Cancer Research

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“…Upregulation of Tβ4 expression has also been found in melanoma cell lines isolated from metastatic tumors and in clinical metastatic melanoma tissues (Nummela et al 2006). The induction of migration and invasion by Tβ4 has also been reported in various cancer cells including the uterine cervix (Oh et al 2008), prostate (Iguchi et al 2008), pancreas (Zhang et al 2008), kidney (Hall 1991), and bladder cancer (Wang et al 2012). However, the functional role of Tβ4 in the process of EMT in OSCCs has not yet been studied.…”

Section: Introductionmentioning

confidence: 95%

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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“…This abundant peptide influences numerous cellular functions, including migration, attachment and spreading of endothelial and cancer cells [4]–[7]. Further, Tβ4 stimulates angiogenesis, cell proliferation, differentiation, wound healing and growth rate [8]–[11], prevents apoptosis and heart failure [12], as well as plays important roles in development and immune response after bacterial or viral challenge [13]–[14]. In addition, Tβ4 has been shown to be involved in cellular anti-oxidation activities because this peptide can be oxidized to sulfoxide [15] and to scavenge reactive oxygen species (ROS) that functions as signaling molecules in tumor progression [7].…”

Section: Introductionmentioning

confidence: 99%

β-Thymosins and Hemocyte Homeostasis in a Crustacean

et al. 2013

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Thymosin proteins are well known for their actin-binding activity. Thymosin beta 4 (Tβ4) has been associated with biological activities in tissue repair and cell migration via interaction with ATP-synthase in vertebrates, while the information of similar thymosin functions in invertebrates is limited. We have shown previously that ATP-synthase is present on the surface of crayfish hematopoietic tissue (HPT) cells, and that astakine 1 (Ast1, an invertebrate cytokine) was found to interact with this β-subunit of ATP synthase. Here, we identified five different β-thymosins from Pacifastacus leniusculus, designated Pl-β-thymosin1-5. The two dominant isoforms in brain, HPT and hemocytes, Pl-β-thymosin1 and 2, were chosen for functional studies. Both isoforms could bind to the β-subunit of ATP-synthase, and Pl-β-thymosin1, but not Pl-β-thymosin2, significantly increased extracellular ATP formation. Moreover, Pl-β-thymosin1 stimulated HPT cell migration in vitro and Ast1 blocked this effect. Pl-β-thymosin2 increased the circulating hemocyte number at an early stage after injection. Additionally, in vivo injection of Pl-β-thymosin1 resulted in significant reduction of reactive oxygen species (ROS) production in crayfish HPT whereas Pl-β-thymosin2 had a similar but transient effect. Both Pl-β-thymosins induced the expression of Ast1 and superoxide dismutase (SOD) transcripts, while silencing of endogenous Pl-β-thymosin 1 and 2 by RNAi resulted in significant reduction of the Ast1 and SOD transcripts. The diverse effects exhibited by Pl-β-thymosin1 and Pl-β-thymosin2 indicates that these proteins are involved in a complex interaction that regulates the hematopoietic stem cell proliferation and differentiation.

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Thymosin beta 4 is overexpressed in human pancreatic cancer cells and stimulates proinflammatory cytokine secretion and JNK activation

Cited by 49 publications

References 27 publications

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

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

β-Thymosins and Hemocyte Homeostasis in a Crustacean

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