The Determination of VEGF and MVD, among Patients with Primary Breast Cancer

Thielemann, Anna; Kopczyński, Zygmunt; Filas, Violetta; Bręborowicz, J; Grodecka-Gazdecka, Sylwia; Baszczuk, Aleksandra

doi:10.1007/s12253-008-9040-1

Cited by 12 publications

(12 citation statements)

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“…When staining intensities were quantified, breast cancer tissues exhibited significantly lower levels of ZNF24 and significantly higher levels of VEGF compared with NATs (supplemental Figure 5). Combined with the findings by Thielemann et al 27 in which increased VEGF levels and microvessel density were found in human breast cancer tissues, our results suggest that ZNF24 may play a negative role in the initiation and/or progression of human breast cancer by inhibiting tumor angiogenesis through regulation of VEGF expression.…”

Section: Levels Of Znf24 and Vegf Are Inversely Correlated In Human Bsupporting

confidence: 86%

Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo

Jia

Hasso

Chan

et al. 2013

Blood

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Key Points• ZNF24 represses VEGF transcription through direct binding to an 11-bp fragment of the VEGF proximal promoter.• ZNF24 functions as a negative regulator of developmental and tumor angiogenesis by inhibiting VEGF transcription.VEGF is a key regulator of normal and pathologic angiogenesis. Although many trans-activating factors of VEGF have been described, the transcriptional repression of VEGF remains much less understood. We have previously reported the identification of a SCAN domain-containing C2H2 zinc finger protein, ZNF24, that represses the transcription of VEGF. In the present study, we identify the mechanism by which ZNF24 represses VEGF transcription. Using reporter gene and electrophoretic mobility shift assays, we identify an 11-bp fragment of the proximal VEGF promoter as the ZNF24-binding site that is essential for ZNF24-mediated repression. We demonstrate in 2 in vivo models the potent inhibitory effect of ZNF24 on the vasculature. Expression of human ZNF24 induced in vivo vascular defects consistent with those induced by VEGF knockdown using a transgenic zebrafish model. These defects could be rescued by VEGF overexpression. Overexpression of ZNF24 in human breast cancer cells also inhibited tumor angiogenesis in an in vivo tumor model. Analyses of human breast cancer tissues showed that ZNF24 and VEGF levels were inversely correlated in malignant compared with normal tissues. These data demonstrate that ZNF24 represses VEGF transcription through direct binding to an 11-bp fragment of the VEGF proximal promoter and that it functions as a negative IntroductionVEGF is a key angiogenic factor during embryogenesis, as demonstrated by the embryonic lethality and abnormal blood vessel development of mice lacking a single VEGF allele. 1 It also plays critical roles in normal physiologic processes such as maintaining vascular stability 2 and promoting skeletal muscle differentiation. 3 Across a wide range of human cancers, VEGF serves as a principle proangiogenic factor. For example, VEGF levels are elevated in breast cancer patients 4 and are inversely correlated with patient survival. 5 Transcriptional regulation of VEGF has been defined in part by its many transcriptional activators, including Sp1, HIF-1, and STAT3. 6,7 In contrast, only the p53 family proteins and the von Hippel-Lindau (VHL) tumor suppressor have been discovered and well characterized as transcriptional repressors of VEGF.Zinc finger protein 24 (ZNF24, also known as ZNF191 or Kox17) was originally identified in an attempt to discover novel C2H2 zinc finger proteins in the hematopoietic system. 8 It possesses 4 Kruppel-like C2H2 zinc finger domains within the c-terminus that function as DNA-binding domains. 9 These domains bind to the TCAT repeats of the HUMTH01 microsatellite located in the first intron of the tyrosine hydroxylase gene in in vitro studies. 9,10 No in vivo function relevant to this observation has been documented to date. The N-terminus of ZNF24 contains a SCAN box domain that primarily serves as a dimerizat...

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Section: Levels Of Znf24 and Vegf Are Inversely Correlated In Human Bsupporting

confidence: 86%

Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo

Jia

Hasso

Chan

et al. 2013

Blood

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“…VEGF-A is a member of the VEGF family, and has been confirmed to be a key regulator of angiogenesis. Since the number of newly formed blood vessels within a tumor is usually measured by MVD, both MVD and VEGF-A are good indicators of angiogenesis (Thielemann et al, 2008;Sanaat et al, 2014;Della-Morte et al, 2015). However, the correlation between SIPA1 expression and angiogenesis in gastric tumor tissues was unclear so far.…”

Section: Discussionmentioning

confidence: 99%

Dynamic relationship between SIPA1 gene and protein expression and the development of gastric cancer

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Association of signal-induced proliferation-associated 1 (SIPA) gene and protein expression with gastric cancer development was examined. SIPA1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and western blot, respectively, in 40 gastric tumor and tumor-adjacent normal tissues. SIPA1, VEGF-A, and FVIII levels in 60 gastric tumor and 40 tumoradjacent normal tissues were examined by immunohistochemical staining. Correlations between SIPA1, VEGF-A, and microvessel density (MVD) were analyzed. SIPA1 mRNA levels were significantly lower in tumor tissues than in tumor-adjacent normal tissues (P < 0.05). Similarly, protein levels were significantly lower in tumor tissues (0.3043 ± 0.1062) than in tumor-adjacent normal tissues (0.5423 ± 0.0682, P < 0.05). Positive staining rates of SIPA1 (48.3%) and VEGF-A (36.7%) were lower and higher, respectively, in tumor tissues than in tumor-adjacent normal tissues (65.0 and 2.5%, P < 0.05). Positive protein staining rates in tumor tissues correlated with the degree of differentiation, lymph node metastases, and clinical grading (P < 0.05) and not with sex, age, or tumor size (P > 0.05). Significantly higher MVD (57.4 ± 9.3) was observed in tumor tissues displaying positive SIPA1 staining than in tumor-adjacent normal tissues (41.2 ± 5.7, P < 0.05). SIPA1 and VEGF-A expression in tumor tissues were negatively correlated (r = -0.736, P < 0.05). SIPA1 and its protein may play important roles in gastric cancer invasion, metastasis, and biological behavior. Low SIPA1 levels in gastric cancer may accelerate tumor development and progression by promoting VEGF-A expression to increase vascular density.

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“…Lots of scholars [9][10][11][12][13][14] had discussed the relationship between VEGF and MVD in tumors, and most of them believed that the MVD count increased significantly with the increase of the expression of VEGF. In our study, we also find MVD count was higher in VEGF positive group than that in VEGF negative group.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of vascular endothelial growth factor in benign and malignant tissues of breast

Xu¹,

Liu

Wang

et al. 2008

Chin. J. Cancer Res.

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Objective: To detect the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) count in breast benign affection, breast atypical hyperplasia and breast carcinoma in situ, and to clarify the relationship between VEGF expression, MVD and the clinicopathological features of these diseases. Methods: The expression of VEGF and MVD count in 115 cases breast benign diseases (including 40 breast fibroid tumor，40 breast cystic hyperplasia and 35 intraductal papilloma, 19 breast atypical hyperplasias and 32 breast carcinomas in situ were examined by immunohistochemistry staining (SP-method). Results: The positive rate of VEGF in breast benign diseases, breast atypical hyperplasia and breast carcinoma in situ were 21.74%(25/115)、31.58.% (6/19)and 53.13%(17/32) respectively. It was the lowest in breast benign affection group, and was the highest breast carcinoma in situ group. The expression of VEGF increased gradually in the three groups (P<0.05). The MVD count of the three groups were 14.41±2.59, 18.89±4.47 and 21.13±4.12 respectively, It was the lowest in breast benign affection group, and was the highest breast carcinoma in situ group. The MVD count of the three groups increased gradually (P<0.05). In VEGF positive group, MVD count was 19.41±4.78; In VEGF negative group, MVD count was 14.91±3.15. The MVD count was higher in VEGF positive group than that in VEGF negative group (P<0.05). Conclusion:The results of this study suggested that VEGF could promote microvessel growth in breast tumors. The occurrence and progression of breast cancer might be related with the expression of VEGF.Key Words: Breast benign disease; Breast atypical hyperplasia; Breast carcinoma in situ; Vascular endothelial growth factor(VEGF); Microvessel density (MVD)

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The Determination of VEGF and MVD, among Patients with Primary Breast Cancer

Cited by 12 publications

References 50 publications

Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo

Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo

Dynamic relationship between SIPA1 gene and protein expression and the development of gastric cancer

Expression and clinical significance of vascular endothelial growth factor in benign and malignant tissues of breast

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