The Prognostic Impact of TGF-β1, Fascin, NF-κB and PKC-ζ Expression in Soft Tissue Sarcomas

Valkov, Andrey Yurjevich; Sørbye, Sveinung Wergeland; Kilvaer, Thomas K.; Dønnem, Tom; Smeland, Eivind; Bremnes, Roy M.; Busund, Lill-Tove

doi:10.1371/journal.pone.0017507

Cited by 31 publications

(26 citation statements)

References 45 publications

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“…However, several recent reports have implicated PKCζ as a predictor of poor outcome for cancer patients. High PKCζ predicts poor disease-specific survival of patients with soft tissue sarcoma [39]. Likewise, PKCζ is elevated in prostate cancer, and high PKCζ expression predicts poor survival of prostate cancer patients [36].…”

Section: Discussionmentioning

confidence: 99%

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Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

Butler

Buzhardt

et al. 2013

PLoS ONE

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Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells.

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Section: Discussionmentioning

confidence: 99%

“…While PKCζ expression has been recently characterized to be elevated and predict poor survival in several cancers [36], [39], little is known about the regulation of PKCζ expression. However, PKCζ has been shown to be activated by several signaling pathways known to promote oncogenic signaling in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

Butler

Buzhardt

et al. 2013

PLoS ONE

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“…This may be related to differences in expression of sexual hormone receptors (ER and PGR) in male and female STS patients [7,8]. In previous studies, we have shown the prognostic value of female steroid hormone receptors in STSs, both alone and in coexpression with TGF-β, fascin and Akt isoforms [7-9]. Such prognostic impact is not surprising, since both ER and PGR regulate growth and cell differentiation upon ligand-dependent and ligand-independent activation and are in essence growth factors.…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of Skp2, ER and PGR in male and female patients with soft tissue sarcomas

et al. 2013

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BackgroundS-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins. The purpose of this study is to clarify the prognostic significance of expression of Skp2 related to gender, estrogen receptor (ER) and progesterone receptor (PGR) in soft tissue sarcomas (STS). Skp2 has been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. Optimized treatment of STS requires better identification of high-risk patients who will benefit from adjuvant therapy. The prognostic significance of Skp2 related to ER and PGR in STS has not been sufficiently investigated.MethodsTissue microarrays from 193 STS patients were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the expression of Skp2, ER and PGR.ResultsIn univariate analyses, high tumor expression of Skp2 correlated (p = 0.050) with reduced disease-specific survival (DSS). In subgroup analyses expression of PGR in males (p = 0.010) and in patients older than 60 years (p = 0.043) were negative prognostic factors for DSS. Expression of ER in females was a positive prognostic factor for DSS (p = 0.041). In co-expression analyses in the whole cohort, low expression of Skp2 in combination with low expression of ER was positive for DSS (p = 0.049). In females high expression of Skp2 in combination with low expression of ER was a negative prognosticator (p = 0.021). In the multivariate analyses, age (p = 0.012), malignancy grade (p < 0.001), wide resection margins (P = 0.010), ER negative / PGR positive co-expression profile (p = 0.002) and ER positive / PGR negative co-expression profile (p = 0.015) were independent negative prognostic factors for DSS. In females expression of Skp2 (p = 0.006) was associated with shorter DSS.ConclusionsWe found diverse prognostic impacts of expression of Skp2, ER, PGR and DSS in male and female patients with STS. In men, but not women, ER positive / PGR negative co-expression profile was an independent negative prognostic factor for DSS. In women, but not men, high expression of Skp2 was associated with reduced DSS.

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“…PBS (phosphate buffer saline) was used in replacement of primary antibody as a blank control. The section was considered as expressing the protein if cellular staining ≥5%, following the methods described previously [26, 27]. …”

Section: Methodsmentioning

confidence: 99%

Methylation and Expression of Retinoblastoma and Transforming Growth Factor-β1 Genes in Epstein-Barr Virus-Associated and -Negative Gastric Carcinomas

Liu

Tang

Zhang

et al. 2012

Gastroenterology Research and Practice

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Background. Retinoblastoma (RB) and transforming growth factor-β1 (TGF-β1) are important tumor-related factors. Methods. A series of 30 EBV-associated gastric carcinoma (EBVaGC) and 38 matched EBV-negative gastric carcinoma (EBVnGC) tissues were examined for the promoter methylation of RB by methylation-specific PCR (MSP) method. The expression of RB and TGF-β1 in gastric carcinoma tissues was detected by immunohistochemistry. Results. The methylation rate of RB gene in EBVaGC and EBVnGC was 80.0% (24/30) and 50.0% (19/38), respectively. The difference of RB methylation rate between EBVaGC and EBVnGC was significant (χ 2 = 6.490, P = 0.011). There was no significant difference for RB expression between EBVaGC (43.3%, 13/30) and EBVnGC (63.2%, 24/38), and also for TGF-β1 between EBVaGC (56.7%, 17/30) and EBVnGC (63.2%, 24/38). RB methylation was not reversely correlated with RB expression in gastric carcinoma tissues (χ 2 = 2.943, P = 0.086, r = 0.208). RB methylation, loss expression of RB, and TGF-β1 expression were significantly associated with tumor invasion and lymph node metastasis (P < 0.05), but was not associated with sex, age, histological subtype (differentiation status) and tumor location. Conclusions. Methylation of RB is a common event in gastric carcinomas and EBV induces methylation of RB in EBVaGC, which may contribute to the development of gastric carcinomas. EBV has no significant effect on induction of TGF-β1 expression. Detection of RB methylation, RB expression, and TGF-β1 expression may be helpful to judge the status of tumor invasion and lymph node metastasis in gastric carcinomas.

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The Prognostic Impact of TGF-β1, Fascin, NF-κB and PKC-ζ Expression in Soft Tissue Sarcomas

Cited by 31 publications

References 45 publications

Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

Prognostic impact of Skp2, ER and PGR in male and female patients with soft tissue sarcomas

Methylation and Expression of Retinoblastoma and Transforming Growth Factor-β1 Genes in Epstein-Barr Virus-Associated and -Negative Gastric Carcinomas

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