Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma

Werner, Thomas; Tamkan-Ölcek, Yasemin; Dizdar, Levent; Riemer, Jasmin; Wolf, Achim; Cupisti, Kenko; Verde, Pablo Emilio; Knoefel, Wolfram Trudo; Krieg, Andreas

doi:10.1038/bjc.2016.5

Cited by 37 publications

(29 citation statements)

References 51 publications

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“…A pre‐existing tissue microarray (TMA) containing human GEP‐NEN specimens was used to assess the expression of phosphorylated MEK (pMEK) . Immunohistochemistry of TMAs and xenograft‐derived specimens, as well as the analysis of pMEK expression levels using the immunoreactive score (IRS) reported by Remmele, were conducted as previously described . This score is assessed semiquantitatively by grading the intensity of staining (0 = no staining; 1 = weak staining; 2 = strong staining; 3 = very strong staining) as well as the percentage of positive cells (0 = no positive cells; 1 = <10% positive cells; 2 = 11–50% positive cells; 3 = 51–80% positive cells; 4 = 81–100% positive cells).…”

Section: Methodsmentioning

confidence: 99%

BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma

Dizdar

Werner

Drusenheimer

et al. 2018

Intl Journal of Cancer

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To determine the role of BRAF mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAF mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAF mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAF mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAF mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAF mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAF mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAF positive NEC xenografts. High frequencies of BRAF mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.

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Section: Methodsmentioning

confidence: 99%

BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma

Dizdar

Werner

Drusenheimer

et al. 2018

Intl Journal of Cancer

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“…Survivin overexpression has been observed in types of endocrine cancer including differentiated and medullary thyroid cancer, while was not upregulated in benign pituitary adenoma (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, survivin has not been proven to discriminate between thyroid follicular cancer and adenoma (17,18).…”

Section: Introductionmentioning

confidence: 99%

Survivin DEx3 as a biomarker of thyroid cancers: A study at the mRNA and protein level

et al. 2017

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Abstract. Survivin and its splice variants DEx3 and 2B are involved in pathogenesis of numerous types of cancer. Proliferating cell nuclear antigen (PCNA) level correlates with cellular proliferation. The present study aimed to analyze the potential utility of survivin and its splice variants DEx3 and 2B as biomarkers for thyroid cancer. PCNA, survivin and its splice variants DEx3 and 2B expressions were analyzed in 22 tissue samples (15 thyroid cancers and 7 benign lesions) by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry (IHC). There was significantly higher staining for survivin (P=0.019), survivin DEx3 (P=0.001), survivin 2B (P=0.0149) and PCNA (P=0.0237) in thyroid malignant tumors when compared with benign lesions. The receiver operating characteristics curve analysis has shown that the cut-off points of survivin IHC expression >2 [sensitivity 46.7%; specificity 100%; area under curve (AUC) 0.810; P= 0.0005] and survivin DEx3 IHC expression >0 (sensitivity 86.7%; specificity 100%; AUC 0.933; P<0.0001) were the best predictors of thyroid malignancy. Additionally, PCNA staining >1 (sensitivity 93.3%; specificity 71.4%; AUC 0.790; P=0.0243) and survivin 2B >2 (sensitivity 46.7%; specificity 100%; AUC 0.824; P= 0.0002) were the best predictors of thyroid cancer. In conclusion, the present study exhibited that survivin DEx3 expression has high specificity and sensitivity for discrimination between benign thyroid lesions and cancers. Survivin DEx3 may be considered a biological marker of thyroid malignancy and therefore applied in clinical practice. IntroductionThe incidence of thyroid cancer in developed countries has increased (1). Histopathological examination remains the gold standard for the diagnosis and classification of thyroid lesions excised during surgery (2). In addition, molecular markers of thyroid cancers may be used as diagnostic and even prognostic tools (3,4). Certain markers may also be targets for non-conventional therapy.Survivin, a protein belonging to the family of apoptosis inhibitors, is involved in cell-cycle regulation and proliferation (5,6). Survivin overexpression has been observed in types of endocrine cancer including differentiated and medullary thyroid cancer, while was not upregulated in benign pituitary adenoma (7-16). However, survivin has not been proven to discriminate between thyroid follicular cancer and adenoma (17,18). The two survivin splice variants 2B and DEx3 demonstrate different biological properties. Survivin 2B is involved in apoptosis activation. By contrast, anti-apoptotic survivin DEx3 is suggested to be associated with tumor aggressiveness, advanced stage and poor prognosis in numerous types of cancer (5). We have previously reported survivin and its DEx3 mRNA variant overexpression in thyroid cancer (19,20).Another nuclear protein, proliferating cell nuclear antigen (PCNA), is also involved in replication, so its level correlates with cellular proliferation (21).The aims of the present study were to confirm the findin...

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“…Proliferating cell nuclear antigen (PCNA) is closely related to cellular DNA synthesis and can be used to label cells that are mitotically active; interestingly, it is highly expressed in nasopharyngeal carcinoma cells. X-related apoptosis inhibitory protein (XIAP) is the strongest inhibitor of apoptosis in the IAP family [24][25][26], and survivin is also an apoptosis-inhibiting protein widely expressed in tumor cells [19]; together, these factors promote DNA replication and can influence the proliferation and apoptosis of tumor cells. e proapoptosis gene Bax and the antiapoptosis gene Bcl-2 belong to the Bcl-2 family and play opposing roles in apoptosis regulation.…”

Section: Discussionmentioning

confidence: 99%

Isoimperatorin Induces Apoptosis of Nasopharyngeal Carcinoma Cells via the MAPK/ERK1/2 Signaling Pathway

Liu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objective. To investigate the effect of isoimperatorin on nasopharyngeal carcinoma CNE2 cell apoptosis and the role of the MAPK/ERK1/2 signaling pathway in inducing apoptosis. Methods. Real-time cellular analysis technology (RTCA) and MTT were used to detect cell proliferation; Annexin V-FITC/PI dual-fluorescence flow cytometry analysis, Hoechst 33342 staining, and mitochondrial membrane potential detection kit were used to detect cell apoptosis; western blot was used to detect protein expression. Results. Different concentrations of isoimperatorin (10 μM, 20 μM, 30 μM, and 40 μM) significantly inhibited the nasopharyngeal carcinoma CNE2 cell proliferation, and 48 h later, the inhibitory effect of the 40 μM treatment was significantly higher than that of 10 μM and 20 μM. Treatment for 48 h significantly induced nasopharyngeal carcinoma cell apoptosis and resulted in nuclear pyknosis and fragmentation. At the same timepoint, the expression levels of proliferation-related protein PCNA as well as antiapoptosis proteins XIAP, survivin, and Bcl-2 were decreased by drug treatment, the expression level of proapoptosis protein Bax was increased, and the expression of the key MAPK/ERK1/2 signaling pathway proteins p-c-Raf, p-MEK, and p-ERK1/2 of were decreased. After activation of the MAPK/ERK1/2 signaling pathway by isoprenaline hydrochloride (ISO), the efficacy of isoimperatorin to downregulate p-c-Raf, p-MEK, and p-ERK1/2 expressions in the MAPK/ERK1/2 signaling pathway and proliferation-related protein PCNA as well as antiapoptosis proteins XIAP, surviving, and Bcl-2 was reduced compared with that of isoimperatorin alone, the effect of upregulating the proapoptotic protein Bax was reduced, and the apoptosis rate was also decreased. Conclusion. Isoimperatorin can induce nasopharyngeal carcinoma CNE2 cell apoptosis through the MAPK/ERK1/2 signaling pathway.

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Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma

Cited by 37 publications

References 51 publications

BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma

BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma

Survivin DEx3 as a biomarker of thyroid cancers: A study at the mRNA and protein level

Isoimperatorin Induces Apoptosis of Nasopharyngeal Carcinoma Cells via the MAPK/ERK1/2 Signaling Pathway

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Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma

Cited by 37 publications

References 51 publications

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma

Survivin DEx3 as a biomarker of thyroid cancers: A study at the mRNA and protein level

Isoimperatorin Induces Apoptosis of Nasopharyngeal Carcinoma Cells via the MAPK/ERK1/2 Signaling Pathway

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BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma

BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma